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IntroductionThe mammalian kinesin superfamily proteins (KIFs) are microtubule and ATP-dependent molecular motors, which were first identified in 1985 as axonal transporters in squid and bovine brains.1 Forty-five different kinesin family kamagra for sale member (KIF) genes were identified in the mouse genome so far, 44 of which are present in the human genome. Phylogenetic analysis based on sequence homology between the human and the mouse genome led to the classification of KIF genes into 16 families, from kinesin-1 to kinesin-14B (figure 1).2 The first kinesins discovered belong to the kinesin-1 family (KIF5A, KIF5B and KIF5C), and they form a heterotetramer of two heavy chains and two light chains (KLC1-4).2 KIF genes encode KIFs, a specific class of motor proteins generating intracellular motility by driving directional transport of various cargoes such as organelles, protein complexes and mRNAs along the microtubule system.2 Studies using knockout mouse models by Hirokawa and colleagues significantly contributed to elucidate the roles of kinesins in mammalian physiology. Their role in transport is fundamental to cellular logistics and performance, and kamagra for sale the molecular motors are not only effectors of signal transduction cascades but also transport and/or bind to important signal transduction molecules to actively modulate their function.3Phylogenetic tree of mammalian kinesin superfamily genes identified in the human (and mouse) genome and classified in 16 subfamilies (from kinesin 1 to 14B) (adapted from Hirokawa et al 3)." data-icon-position data-hide-link-title="0">Figure 1 Phylogenetic tree of mammalian kinesin superfamily genes identified in the human (and mouse) genome and classified in 16 subfamilies (from kinesin 1 to 14B) (adapted from Hirokawa et al3).The first kinesins were observed in the context of axonal transport in neurons, and a novel disease entity of ‘motor–proteinopathy’ was proposed for the pathogenesis of axonal neuropathies in 2001.4 Due to their role in cellular membrane trafficking, however, kinesins are essential for the functioning of many polar cell types, such as neurons, epithelial cells, sperm cells or stem cells during organogenesis.

Kinesins also play a fundamental role in cell-cycle dynamics, both during mitotic and meiotic processes. They regulate chromosomal condensation and alignment, spindle formation, cytokinesis and cell-cycle progression.5 It is estimated kamagra for sale that about a dozen kinesins are involved in the cell cycle. Among these, there is a specific subclass of chromokinesins (kinesin 4 and kinesin 10 family) which are able to bind chromosomes.6 Recently, KIFs were discovered to act as microtubule stabilisers (KIF26A and KIF21A) and depolymerisers (KIF2A and KIF2C), activities which are important for both cellular morphogenesis and mammalian development, playing a role in neuronal and axonal morphology and ciliogenesis.7Alterations in motor kinesins are leading to human disease by various pathological mechanisms, including cancer and multifactorial and monogenic disorders.

Variants in 18 out of the 44 human KIF genes were identified to cause monogenic disorders, following different modes of Mendelian inheritance and associated with a kamagra for sale wide spectrum of clinical signs. These range from lethal and multiple to isolated congenital anomalies—including birth defects potentially detectable in the foetal period by current prenatal imaging studies—to postnatally apparent neurodevelopmental disorders, intellectual disability and neurological conditions.We will review the current state of knowledge of the biological processes kinesins are involved in and discuss their emerging role in human disease, particularly in birth defects and congenital anomaly syndromes. Birth defects remain a leading cause of perinatal lethality in industrialised countries.8 Structural anomalies are recognised with increasing reliability during early pregnancy by the use of high-resolution ultrasound technologies, thus raising questions about diagnosis, aetiology, prognosis and recurrence risk, particularly in the presence of more than one anomaly, which most likely indicates a genetic aetiology.

We identify recurrent phenotype patterns caused by alterations in KIF genes, and we outline the complexity of phenotype–genotype correlations mirroring the processes of intracellular microtubule-mediated kamagra for sale transport and movement, in which kinesins play a fundamental role. There are likely many more relationships between the clinical signs and the genetic variants to be identified in the future, and the functional network of kinesins and their role in human disease need to be further elucidated. We propose to introduce the term kamagra for sale ‘kinesinopathies’ for this group of conditions, which are phenotypically and genetically overlapping and characterised by the functional impairment of a specific group of molecular motors.

We hope that their systematic approach leads to a better recognition in clinical practice, as well as in genome-wide sequencing for diagnosis and research, and opens strategies for the future development of molecular therapies.KIF structureAll KIFs have a phylogenetically well-conserved motor domain head, consisting of an ATP-binding motif and a microtubule-binding domain. Depending on the position of the motor domain, kinesins can be subdivided into N-kinesins (amino-terminal motor domain), M-kinesins (middle-region motor domain) and C-kinesins (carboxy-terminal motor domain).2 Most kinesins kamagra for sale belong to the N-kinesin subgroup, but members of the kinesin 13A family (figure 1) belong to the M-kinesin subtype, while KIF1C, KIF2C and KIF3C belong to the C- kinesin subfamily.3 Both N-kinesins and C-kinesins are responsible for plus end and minus end-directed motility, M-kinesins for depolymerisation of microtubules in tubulin molecules. However, there are a few exceptions to this categorisation.9 The motor domain head attaches to the neck, the coiled coil stalk and the tail.

The kinesins’ neck is family-specific and responsible for the direction of motility or regulation of activity. The coiled coil stalk and tail are kamagra for sale involved in kinesin dimerisation and/or interactions with cargoes. Kinesins typically use scaffold proteins and adaptor proteins to bind their cargoes but can sometimes bind the cargo directly.

Scaffolds and adaptors might also kamagra for sale have regulatory roles in kinesin-driven intracellular transport, that is, recognising specific cargoes and regulating their loading and unloading.3Role of KIFs in physiology and diseaseThe application of genome-wide sequencing for gene identification in research or for clinical diagnostic purposes significantly contributes to the identification of KIF candidate genes. Genotype–phenotype correlations in KIF gene-related disorders, together with functional and animal studies, continue to elucidate the complex involvement of KIFs in human developmental pathways and disease. Table 1 kamagra for sale summarises the monogenic conditions caused by variants affecting the function of KIF genes.View this table:Table 1 Specific monogenic disorders caused by variants affecting the function of KIF genesView this table:Table 2 Summary of phenotypes and genotypes of KIF149 26 30 31The kinesins’ functions in physiological processes, however, are complex and still incompletely understood, but their role in cell-cycle progression and regulation, including both meiosis and mitosis, in intracellular trafficking, axonal transport, microtubule activity and ciliogenesis, is increasingly studied.

Figure 2 summarises the clustering of KIF genes according to their functional roles and the phenotypical consequences as identified to date in 32 out of the 44 human kinesin genes.Assignment and clustering of KIF genes to various functions and relation to birth defect or monogenic phenotype groups. Detailed phenotypes are shown kamagra for sale in tables 1 and 3. Cancer and multifactorial conditions are not included.

CNS, central nervous system." data-icon-position data-hide-link-title="0">Figure 2 Assignment and clustering of KIF genes to various functions and relation to birth defect or monogenic phenotype groups. Detailed phenotypes are kamagra for sale shown in tables 1 and 3. Cancer and multifactorial conditions are not included.

CNS, central kamagra for sale nervous system.Kinesins play a pivotal role during early development and organogenesis. Microcephaly is one of the most frequently associated clinical signs, mirroring a defect in the regulation of the final number of neurons during development.10KIF4A is a motor protein that translocates PRC1, a cytokinesis protein, to the ends of the spindle microtubules during mitosis, regulates the PARP1 activity in brain development and the survival of neurons, and is a member of the L1CAM recycling pathway. Variants in L1CAM cause X-linked isolated kamagra for sale and syndromic hydrocephalus.

KIF4A was recently proposed as a candidate gene for hydrocephalus.11KIFs are involved in neuronal branching, and microtubule depolarisation, operated by KIF2A M-kinesin, was suggested to suppress collateral branch extension during brain development, leading to anomalies of cortical development, including agyria and pachygyria, subcortical band heterotopia and corpus callosum anomalies.12Functional disruption of KIF genes in knockout mice often results in embryonic lethality, for example, for Kif18A, Kif10, Kif3A, Kif3B and Kif5B,13–17 highlighting the importance of kinesins in embryonic and foetal development. A study on KIF16B demonstrated that microtubule-based trafficking is responsible for early development and stem cell survival.18 KIF26B is essential in kidney development, contributing to the adhesion of mesenchymal cells to the ureteric bud.3 KIF26A was suggested to play a role in enteric nervous system development, because knockout mice develop a megacolon and enteric nerve hypoplasia,19 and to negatively regulate nociceptive sensation.20A significant number of KIFs play a prominent role in ciliogenesis and cilia function. They regulate cilia length, ciliary kamagra for sale assembly/disassembly and can have motile cilia-specific functions.21 Some KIFs, specifically found in primary cilia (PC), regulate the length of the axoneme and its disassembly when re-entering the cell cycle.KIF7, also a key component of the Hedgehog signalling pathway, is responsible for cilia length regulation through suppression of microtubule polymerisation.7 KIF7 variants cause hydrolethalus, acrocallosal, and Joubert and Al-Gazali-Bakalinova syndromes.22 Kif2A knockout mice have severe brain defects, and KIF2A variants in humans lead to microcephaly because of cell-cycle delay in cellular progenitors resulting from cilia disassembly defects.

KIF24, belonging to the same kinesin 13 family, plays a role in both microtubule depolymerising activity and regulation of the early steps of ciliogenesis. Other PC-related KIFs recently identified are KIF5B, KIF1C and KIF13B, and a potential role in cilia was hypothesised for KIF11 and KIF14.KIF3 protein complex (KIF3A-KIF3B-KAP3 heterotetramer) is a molecular motor necessary for intraflagellar transport (IFT) but kamagra for sale is also involved in ciliogenesis of motile cilia. Kif3a-knockout or Kif3b-knockout mice are prenatally lethal, exhibiting anomalies similar to ciliopathy phenotypes, including the disturbance of left–right body determination.3KIF19A is localised at the tip of motile cilia and performs motor and microtubule-depolymerising activities during IFT.

Kif19a-knockout mice present with hydrocephalus and female infertility, common signs in ciliary kamagra for sale defects, due to abnormally elongated cilia with altered motility, not able to generate proper fluid flow.9Further KIFs, which may have specific roles in motile cilia, are KIF27, KIF9, KIF6 and KIF18B. Regarding the involvement of numerous KIFs in cilia-related processes, it is not surprising that many disorders caused by variants affecting KIF gene function are presenting with anomalies reminiscent of ciliopathies.Kinesin motors have a fundamental role in neuronal function, as they are responsible for the transport of synaptic vesicle precursors and transmitter receptors along axons and dendrites from the neuron body.3 Molecular motor activity as for KIF1A, KIF5 and KIF17 is important for higher brain functions, such as learning and memory through regulation of synaptic transmission.5 Dysfunction can be associated with intellectual disability and global developmental delay (table 1).Impaired function can also result in peripheral neuropathies (KIF5A, KLC2, KIF1A and KIF1B) and ocular motility disorders (KLC2 and KIF21A)23 24 when axon elongation in the peripheral nervous system and optic nerve is affected. KIF5A variants are associated with epileptic phenotypes both in humans and mice25 because the transport of neurotransmitter receptors is disturbed and inhibitory regulation is altered.Due to their role in cell-cycle regulation, kinesins are important in male spermatogenesis and female oogenesis.

They are kamagra for sale involved in all steps of spermatogenesis 26 and, based on previous animal studies, they may represent a potential target to treat male infertility. In female meiosis, 13 KIF genes were studied in animal models. There is some evidence that kinesin expression is vulnerable to maternal kamagra for sale ageing and environmental factors, such as oocyte cryopreservation and alcohol consumption.

It may be promising to expand research in this field in order to clarify the mechanisms and factors contributing to oocyte quality decline.27Many kinesins were extensively studied in the fields of cancer development, progression and therapy. Deregulation of the mitotic kinesins kamagra for sale by both overexpression and decreased expression causes cancer progression or can be a prognostic marker in various tumours.28 The cell-permeable small-molecule mitotic inhibitor monastrol was discovered in 199929 and was shown to arrest cells in mitosis by specifically inhibiting KIF11, a kinesin important for spindle bipolarity. The bipolar mitotic spindle is replaced by a monoastral microtubule array surrounded by a ring of chromosomes, which gave the inhibitor its name.

The mitotic spindle is kamagra for sale now a well-known target of chemotherapy, and inhibitors of the mitotic kinesins KIF11, KIF10 and KIF1C are being studied for this purpose.28 30 The redundancy of some kinesins allows them to escape pharmacological inhibition. For example, in the absence of KIF10, KIF15 is able to replace all of its essential functions in spindle assembly. Cilia-related KIF7, KIF13B and KIF27 are involved in SHh signalling and may be a future target in cancer research.28Some kinesins confer susceptibility to a range of multifactorial, metabolic and neurodegenerative conditions.

KIF13B contributes to the enhancement of endocytosis of low-density lipoprotein (LDL) receptor-related protein 1 that is involved in kamagra for sale the recognition and internalisation of LDL and factor VIII. Kif13b-knockout mice have hypercholesterolaemia and higher factor VIII serum levels.5 KIF12 is implicated in the pathogenesis of type 2 diabetes, protecting pancreatic β cells from the oxidative stress caused by nutritional excess.5 Variants in KIF1B or KIF21B confer susceptibility to multiple sclerosis (OMIM %612596, #126200).31 32 KIF5A was associated with Amyotrophic lateral sclerosis (OMIM #617921).33 KIF3 complex and KIF17 were recently uncovered to be involved in schizophrenia.34 35 Further studies, however, are needed to clarify the precise role of KIFs in neurodegenerative processes and psychiatric conditions.KIF14 -related birth defects. Lessons learntAdvances in next-generation sequencing technologies have revolutionised our understanding of Mendelian disorders, including birth defect phenotypes, by sequencing the coding kamagra for sale genome (exome) or entire genome at an unprecedented resolution in a comparably short time span.

The technology has been extensively used for gene identification approaches in research for many years, enabling unparalleled genotype–phenotype correlations and the definition of novel pathways of related genes and disorders at an accelerated pace, traditionally focusing on postnatal disorders. Filges and Friedman36 postulated kamagra for sale that a number of novel disease genes causing birth defects could be identifiable through the investigation of lethal foetal phenotypes since they would represent the extreme end of allelic milder and viable postnatal phenotypes with less specific or recognisable anomaly patterns. Based on embryonically or perinatally lethal mouse models (www.informatics.jax.org and www.dmdd.org.uk), it is estimated that knockout variants in about 30% of human protein coding genes may present with a phenotype of early lethality.

The identification of KIF14 loss of function variants in fetuses with a lethal multiple congenital anomaly syndrome and the subsequent description of the allelic postnatal viable phenotype and further functional characterisation of KIF14 in developmental processes are recent examples of how to study those embryonic lethal phenotypes in order to understand the role of genes for which little to nothing is known.Filges et al identified autosomal recessive compound heterozygous loss of function variants in KIF14 using family-based exome sequencing in a recurrent severe lethal phenotype (OMIM #616258). It was the first human phenotype reported due to variants in the human KIF14 kamagra for sale gene (figure 3).37 The two affected siblings presented with intrauterine growth retardation (IUGR), oligohydramnios, severe microcephaly, renal cystic dysplasia or agenesis, genital tract malformations (uterine hypoplasia and vaginal atresia), as well as cerebral and cerebellar hypoplasias with partial or total agenesis of the vermis, arhinencephaly, agenesis of occipital lobes/corpus callosum at second trimester ultrasound scan. Cross-species comparison to the laggard spontaneous mice mutant, characterised by homozygous variants of the Kif14 gene,38 confirmed a phenotypical overlap.

An increased number of binucleated cells in the tissue histology of the two fetuses were in concordance with the key role of KIF14 during mitosis participating in chromosomes’ congression and alignment, as well as kamagra for sale in cytokinesis39 and the observation of binucleated cells as a consequence of failed cytokinesis in mammalian KIF14 knockdown cells. During cytokinesis, PRC1 localises KIF14 at the central spindle and midbody, which in turn recruits citron rho-interacting kinase (CIT) to the midbody. CIT, in turn, acts as a negative kamagra for sale regulator of KIF14 activity.

Knockdown of KIF14 in mammalian cells results in impaired localisation of CIT during mitosis.40Structure of KIF14 and summary of all published KIF14 variants affecting function.10 37 41 42 The N-terminal region (aa 1–356) is important for its interactions with PRC1 and the protein’s localisation at the central spindle and midbody. The kinesin motor domain (aa 358–701) is responsible for the microtubule-dependent ATPase activity. The FHA domain (aa kamagra for sale 825–891).

Stalk and tail region (aa 891–1648) are necessary for the interaction with the protein CRIK (aa 901–1189, red diagonal lines). There are four additional coiled-coil domains (light blue-coloured areas).61 FHA, forkhead associated kamagra for sale. Aa, amino acid." data-icon-position data-hide-link-title="0">Figure 3 Structure of KIF14 and summary of all published KIF14 variants affecting function.10 37 41 42 The N-terminal region (aa 1–356) is important for its interactions with PRC1 and the protein’s localisation at the central spindle and midbody.

The kinesin motor domain kamagra for sale (aa 358–701) is responsible for the microtubule-dependent ATPase activity. The FHA domain (aa 825–891). Stalk and kamagra for sale tail region (aa 891–1648) are necessary for the interaction with the protein CRIK (aa 901–1189, red diagonal lines).

There are four additional coiled-coil domains (light blue-coloured areas).61 FHA, forkhead associated. Aa, amino acid.Filges et al pointed out that KIF14 should be considered a candidate gene for viable postnatal phenotypes, including isolated microcephaly.34 Additional individuals with autosomal recessive variants in KIF14 and isolated primary microcephaly were then described9 41 42 (table 2).Impaired cytokinesis, increased apoptosis and reduced cell motility were confirmed in cells from the described patients, pointing to a new cellular pathway in the pathogenesis of microcephaly.43 Apart from one case with small kidneys with increased echogenicity, none of these 18 patients had associated kidney anomalies. However, a targeted exome sequencing study in 204 unrelated patients with congenital anomalies of the kidney and urinary tract (CAKUT) reported two more cases of renal anomalies, bilateral hypoplasia or agenesis, caused by KIF14 variants.44 Further nine cases had an associated renal phenotype, which ranged from bilateral renal agenesis to cystic or non-cystic renal hypodysplasia.42 Table 2 and figure 3 summarise KIF14 variants and the kamagra for sale associated phenotypes.

Loss of function variants more likely lead to multiple congenital anomalies, while hypomorphic variants result in a milder phenotype without renal involvement, although phenotype–genotype correlations remain preliminary for the time being.The phenotypical spectrum ranging from isolated primary microcephaly to congenital anomalies reminiscent of ciliopathy phenotypes suggested a complex role for KIF14 in developmental processes and raised a number of questions about the relationship between its established role in cell division and its possible function in ciliary pathways. Functional studies of absent KIF14 protein in the development of human foetal tissues and mutant zebrafish provided evidence for similarities and differences between mitotic events occurring during proliferation in the development of both brain and kidney.42 The observation that KIF14-stained midbodies accumulate within the lumen of the branch tips of ureteric buds in human foetal kidneys kamagra for sale provided a key clue to better understand the mechanism through which the loss of KIF14 affects both brain and kidney development in humans. It was previously demonstrated that the secretion and accumulation of midbody remnants in the cerebrospinal fluid in mice during the early stages of brain development correspond to the amplification of neural progenitors.45 Kif14 mutant zebrafish phenotypes supported the hypothesis of a potential role for KIF14 in cilia.

In vitro and in vivo analyses suggested that loss of kif14 causes ciliary anomalies through an accumulation of mitotic cells in ciliated tissues but failed to kamagra for sale establish a direct functional link.21 42 Further mechanisms remain to be elucidated. Overexpression of KIF14 in various types of tumours was suggested to be a possible prognostic marker and a potential target for therapeutic purposes.46Kinesinopathies in birth defect phenotypes. Recurrent themesIn the last few years, an increasing number of variants in KIF genes were described to cause isolated as well as multiple congenital anomalies.

There is a huge variability of phenotypes caused by kamagra for sale variants even within the same gene. However, we can identify recurrent clinical signs that should alert the clinician to suspect a KIF gene-related disorder and the molecular geneticist to include KIF genes in multigene-panel and genome-wide sequencing approaches. This will become particularly relevant in prenatal and perinatal medicine, which focuses on the detection of structural anomalies in the fetus and the newborn by using ultrasound kamagra for sale and MRI or autopsy when the outcome is lethal.

We have summarised the predominant and recurrent structural anomalies in kinesinopathies reported so far that would likely become apparent during the foetal period in table 3 and the syndromic disorders in table 1.View this table:Table 3 KIF gene-related structural congenital anomalies recurrently described in prenatal phenotypesSupplemental materialConsistent with the kinesins’ role in the development of the central nervous system (CNS), brain anomalies of various degrees are a frequent clinical sign, particularly microcephaly, but include lissencephaly, polymicrogyria, thinned or agenesis of the corpus callosum, arhinencephaly, cerebral hypoplasia or atrophy, cerebellar hypoplasia or atrophy, brainstem hypoplasia and a molar tooth sign on brain imaging.12 22 37 44 47–51Primary microcephaly can be detected prenatally or at birth12 22 47 48 50 51 and can present as an isolated or syndromic condition as, for example, caused by variants in KIF149 or in KIF11 (microcephaly with or without chorioretinopathy, lymphoedema or mental retardation. OMIM #152950).48KIF7 variants were related to macrocephaly in kamagra for sale the presence of congenital hydrocephalus (hydrolethalus syndrome LS2, OMIM # 614120). Isolated hydrocephalus was reported for KIF4A in a single case.11Foetal akinesia and arthrogryposis (KIF5C12, KIF1434 and KIF26B50) are likely secondary to the neurological compromise of the fetus but can also appear as an early sign of abnormal CNS development, which should prompt specialist CNS sonographic and MRI evaluation of the fetus.Further anomalies of the limbs include camptodactyly (KIF26B50), clubfoot (KIF1A51), rocker-bottom feet (KIF26B50) and congenital lymphoedema of the limbs (dorsa of feet, lower extremities and, rarely, hands) in cases with KIF11 gene mutations.48 In particular, KIF7 gene variants have been related to various anomalies of the hands (tapered fingers, fifth finger clinodactyly, brachydactyly, preaxial or postaxial polydactyly, bifid terminal phalanges of the thumbs, spindle-shaped fingers, clinodactyly and soft tissue webbing) and feet (toe syndactyly, preaxial or postaxial polydactyly, and duplicated halluces).22CAKUT and genital anomalies are reported in various kinesinopathies including renal agenesis or hypoplasia (KIF1437 and KIF1252), ureteral hypoplasia (KIF1437), congenital megabladder (KIF1252) and vesicoureteral reflux (KIF1252), uterine hypoplasia and vaginal atresia (KIF1437) and hypospadias and chordae (KIF16B49).IUGR is recurrently detected (KIF5C12, KIF1437, KIF1053, KIF1554 and KIF2A12) and is particularly relevant when occurring simultaneously with one of the other recurrent clinical signs, indicating a potential syndromic KIF-related disorder.

Oligohydramnios or polyhydramnios is most likely secondary to a primary organ anomaly.There are a few kinesinopathy syndromes that have been specifically reported to be lethal, such as the ciliary phenotype (OMIM #616258), caused by variants in KIF1434, and hydrolethalus syndrome (OMIM #614120), caused by variants in KIF7.22 However, lethality is usually closely related to the specific major anomalies, and it can be hypothesised that such a lethal phenotype will exist for all KIF gene-related disorders.Developmental delay, intellectual disability, seizures, and sensory and motor disturbances of the peripheral nervous system, as well as eye anomalies, such as microphthalmy, optic nerve pallor, fibrosis of extraocular muscles and chorioretinopathy, will escape detection in the foetal period but are reported in postnatal patients.Kinesin pathways in birth defectsFunctional studies of kinesins in birth defects are still sparse, and little is known about their networks and pathways. In order to improve our understanding, we used the Ingenuity Pathway Analysis (IPA Qiagen, Redwood City, California, kamagra for sale USA) to visualise and analyse the connections between the 13 kinesin motor proteins associated with structural congenital anomalies (KIF5C, KIF1A, KIF1BP, KIF14, KIF16B, KIF7, KIF4A, KIF11, KIF10, KIF26B, KIF12, KIF15 and KIF2A) and in up to 10 of each of their most significant downstream proteins. The connections are defined as protein–protein interactions, activation, regulation of binding, expression, localisation, phosphorylation, protein–RNA interactions, molecular cleavage, ubiquitination, protein–DNA interactions, inhibition, translocation and transcription.

Figure 3 displays kamagra for sale the results. We used the software Gephy55 to look for all possible interactions between all proteins of the network and also used the IPA data to retrieve the canonical pathways involved. Figure 4 and online supplementary material, table 4, kamagra for sale summarise the results.

KIF7, KIF14 and KIF12 are located within the same network, and because of multiple connections between themselves and their downstream proteins, it is not surprising that they are all involved in kidney anomalies. IPA data are based on current publications and are therefore subject to bias because proteins that kamagra for sale are most interconnected are also most probably those that have been more extensively studied. However, we consider the KIF genes coding for proteins seeming less important within the network to be strong candidates for future studies of human developmental disorders.IPA of the 13 kinesins known to be involved in birth defects with respect to their position in the cell.

Proteins displayed on the right side of the figure, below the tag ‘other’, are those for which no subcellular location is known. Birth defect-related kinesins and their connection with each other are highlighted kamagra for sale in green. Light blue-coloured downstream proteins are those which are known to cause birth defects when altered.

Yellow-coloured proteins are those involved in neurological disorders overlapping with the clinical kamagra for sale features of kinesinopathies. The legend of the biological function associated with every molecule is displayed on the right. Path Designer by IPA was used kamagra for sale for the figure design.

IPA, Ingenuity Pathway Analysis." data-icon-position data-hide-link-title="0">Figure 4 IPA of the 13 kinesins known to be involved in birth defects with respect to their position in the cell. Proteins displayed on the right side of the figure, below the tag ‘other’, are those for which no subcellular location is known. Birth defect-related kinesins and their connection with each other are highlighted kamagra for sale in green.

Light blue-coloured downstream proteins are those which are known to cause birth defects when altered. Yellow-coloured proteins are kamagra for sale those involved in neurological disorders overlapping with the clinical features of kinesinopathies. The legend of the biological function associated with every molecule is displayed on the right.

Path Designer by IPA was used for kamagra for sale the figure design. IPA, Ingenuity Pathway Analysis.Closing remarks and future perspectivesNovel KIF genes are increasingly identified, and there is a growing body of literature demonstrating the impact of kinesin dysfunction in human disease. We propose to introduce the term kinesinopathies for conditions caused by variants in KIF genes, since recurrent and common functional and phenotypical themes can be observed kamagra for sale.

In analogy to ciliopathies56 and rasopathies,57 the delineation of the clinical, genetic and functional hallmarks of kinesinopathies will be important to better recognise these conditions, to understand the pathomechanisms and to ultimately improve the clinical management of the patients. Previously, the unified view of the phenotype characteristics of ciliary dysfunction allowed a tremendous increase in awareness, both in clinic and research, and the further identification of yet unrecognised ciliary disorders and the genes and proteins involved in their pathogenesis.56Remarkable progress was achieved in assigning function to kinesins through their study in isolated and multiple congenital anomaly phenotypes. They are kamagra for sale one large superfamily of molecular motors out of three (kinesins, dyneins and myosins), which is of key importance in several fundamental cellular processes using microtubules as rails for directional anterograde intracellular transport, including its regulation and modulating signal transduction.5 Kinesin motors are most important for the movement of chromosomes along the spindles during chromosome segregation, regulation of spindle formation, cell division and cytokinesis.

These essential and broad cellular functions are critical for many physiological processes such as neuronal function and survival, some ciliary functions and ciliogenesis, determination of the left/right asymmetry of our body and regulation of organogenesis, thus explaining the impact and emerging recognition of kinesins in embryonic and foetal development. Defects can result in neuropathies, higher brain functions and structural kamagra for sale brain anomalies. Multiple congenital anomalies, including the kidney and urinary tract and limb anomalies, are repeatedly reported.

Microcephaly, which is usually not associated with genes implicated in specific ciliary mechanisms, and CNS anomalies are the most recurrent clinical kamagra for sale signs in both the prenatal and postnatal phenotypes described so far. The discovery of the implication of KIF14 in microcephaly further suggested a possible novel role of other microcephaly proteins in cytokinesis. A number of syndromic kinesinopathies present, however, with phenotype patterns reminiscent of ciliopathies.

So far, however, a direct functional impact was kamagra for sale confirmed in only a few and could not be demonstrated, for example, for KIF14, despite an overlapping clinical pattern. In turn, ciliopathies are a clinically and genetically heterogeneous group of conditions themselves. Studying tissue and cell type-specific function and expression may help to further define the specific defects related to the individual aberrant kinesin.The pleiotropic nature of human kinesinopathies, however, is just emerging, but their study promises to provide important insights into human kamagra for sale developmental pathways.

Seemingly unrelated clinical entities are highlighting a common theme. In a relatively short time span, monogenic KIF-related kamagra for sale disorders were identified to present with often severe and lethal antenatal anomalies, with multiple or isolated congenital anomalies, neurodevelopmental and neurological disorders, or an increased susceptibility to multifactorial conditions. We focused on the emerging role of kinesins in structural congenital anomalies because, as illustrated for the KIF14 gene, great potential to decipher allelic viable phenotypes and developmental pathways lies in the study of these human knockout phenotypes at the severe end of the phenotypical spectrum.

Knockout variants in about 30% of human protein coding genes in our genome may present with a phenotype of early lethality, and KIF genes seem to play an important role in such fundamental processes of human development. Identifying and characterising the variants, genes and phenotypes will extend our knowledge on early human development and pathomechanisms, and kamagra for sale will ultimately also improve the clinical utility of genome-wide sequencing approaches for prenatal and postnatal application by our increased ability to interpret loss of function and hypomorphic variants alike. Furthermore, kinesins were extensively studied in cancer research and therapeutic strategies targeting their specific functions, such as the example of monastrol and other inhibitors of the mitotic kinesins may be adopted in the future.

There are likely many more kinesinopathies to be unravelled in the kamagra for sale field of birth defects because of their pivotal role in cellular logistics, but their recognition in clinics and research will depend on our ability to identify and characterise the common clinical, molecular and functional themes of these disorders and to use them to improve our understanding of their disease mechanisms.IntroductionIntellectual disability (ID) affects about 3% of individuals worldwide and raises significant issues in terms of diagnostic, management and genetic counselling. The presence of pigmentation anomalies in a patient with ID represents helpful clinical clues in order to narrow the range of aetiological hypothesis. Hypomelanosis of Ito (HMI, MIM #300337) is an unspecific term encompassing a heterogeneous group of disorders characterised by cutaneous hypopigmented whorls and streaks along Blaschko’s lines and variable extracutaneous features affecting the musculoskeletal and nervous systems.1 The cutaneous pattern therefore represents a kamagra for sale non-specific hallmark of mosaicism in these neurocutaneous conditions.

Genetic mosaicism is due to postzygotic mutations, either chromosomal rearrangements or point mutations, whereas random X inactivation in females leads to functional mosaicism.2 Unravelling the molecular basis of pigmentary mosaicism (PM) is still a challenge due to clinical and genetic heterogeneity, technical difficulties in detecting mosaic mutations by classical sequencing approaches and the complexities of obtaining affected tissue. As part kamagra for sale of a collaborative group, we recently reported de novo mutations in exons 3 and 4 of transcription factor E3 (TFE3) as the cause for HMI in four unrelated individuals, including one male, as well as syndromic ID without pigmentary disorders in a female.3TFE3 belongs to the MITF family of mammalian basic helix–loop–helix zipper transcription factors, together with TFEB and TFEC. All four can form homodimers or heterodimers with each other.4 Embryonic expression of TFE3 orthologues Tfe3a and Tfe3b was demonstrated in the zebrafish in a wide range of tissues.5 TFE3 subcellular localisation plays a crucial role in the regulation of cellular homeostasis and embryonic stem cell (ESC) differentiation.

The phosphorylated TFE3 is retained in the cytoplasm, whereas dephosphorylated protein translocates to the nucleus to promote the transcription of target genes involved in lysosomal biogenesis and autophagy.6 TFE3 relocalisation to the nucleus is driven on various stressors, such as starvation,7 8 DNA damage,9 mitochondrial damage,10 Golgi stress11 and pathogens12 in an mTORC1-dependent manner, and oxidative stress13 or cadmium exposition14 in an mTORC1-independent manner. Moreover, lysosomal signalling-induced nucleocytoplasmic redistribution of TFE3 is essential to the regulation of ESC renewal.3 15 By restricting nuclear localisation and activity of Tfe3, lysosome activity, the tumour suppressor protein folliculin and the Ragulator kamagra for sale protein complex enable the exit from pluripotency and therefore drive differentiation. Conversely, enforced nuclear Tfe3 enables ESCs to withstand differentiation.15 In humans, TFE3 mutations have long been known in cancer.

Gene fusions by translocations or other chromosomal rearragements involving TFE3 and five partner genes have indeed been reported to occur in a subset of renal cell carcinomas (RCCs), referred to as ‘TFE-fusion RCC’, and, more rarely, to lung sarcoma and perivascular epithelioid cell tumours.16 Beyond these data on TFE3 function, by the report of a series of 17 individuals harbouring de novo mutations in exons 3 and 4 of TFE3, we emphasise their phenotype and bring additional clinical insight toward the recognition of this novel developmental disorder.ResultsWe describe a series kamagra for sale of 17 patients carrying a de novo mutation in TFE3, 5 of them being previously published with limited clinical information.3 Twelve were females and five were males. Their age ranged from 12 months to 22 years. Five were referred for HMI, five for kamagra for sale syndromic ID and five for suspicion of storage disorder.Clinical dataThe clinical features are summarised in table 1.

Additional information can be found in online supplementary data 1.Supplemental materialView this table:Table 1 Clinical and molecular features of the 17 patients with an TFE3 mutationNeonatal course was remarkable for nine patients. History of jaundice, hepatomegaly or feeding difficulties was reported for three patients each, hypoglycaemia for two and cholestasis for one. All these features were transient.Developmental delay, usually severe and noticeable from the first months of life, was a constant feature kamagra for sale in all the individuals.

Only 6 patients were able to walk at the time of the study, whereas 11 were still unable to walk. All patients were non-verbal, except for two older patients who could kamagra for sale speak a few words. Neurological examination was abnormal in 12 individuals and consisted in truncal hypotonia, associated with lower limb spasticity (6 individuals) or ataxia (2 adults).

Behavioural issues such as autistic features and sleeping disturbance were noted for 11 patients kamagra for sale. Eleven patients developed epilepsy, onset in the first decade and characterised as intractable in three of them. Brain MRI was normal in 10 individuals and abnormal in 6 patients (hydrocephaly, short corpus callosum, Dandy-Walker malformation, arachnoid cyst, periventricular white matter lesions, delayed myelination and cerebral atrophy).

The sensory anomaly was congenital hearing loss (5 patients), and ophtalmological anomalies (10 patients) consisted of strabismus, hyperopia, retinal degeneration, depigmented macule on the iris, oculomotor apraxia or impaired vision of cortical origin.Facial dysmorphism kamagra for sale shared among the patients consisted in coarseness, flat nasal bridge, short nose with anteverted nares, widely spaced eyes, almond-shaped eyes, thick lips, facial hypertrichosis, fleshy earlobe, and full and pink cheeks (figure 1). Twelve patients had pigmentation anomalies, located on Blaschko’s lines for 10 of them (figure 2). One was diagnosed kamagra for sale at 4 years old with histiocytofibroma.

Moderate to severe postnatal growth retardation affected 10 patients, who had a length between −2.0 and −4.5 SD. Obesity affected 13 kamagra for sale individuals. Skeletal anomalies were frequent (11 individuals) and consisted of flat or clubfeet, hyperlordosis, scoliosis, hip dislocation, limitation of elbow extension and genu valgum.

Recurrent s of the upper airways were noted in five kamagra for sale patients. One had a documented neutropenia. Early-onset chronic interstitial lung disease was reported in two patients.

Nail clubbing was noted kamagra for sale in two individuals. Visceral malformations consisted of congenital heart defect (left ventricle dilatation, aortic insufficiency and patent ductus arteriosus) in three patients, umbilical hernia in three individuals, lateral semicircular canal dysplasia, posterior plagiocephaly, sleep apnoea syndrome, anteriorly displaced anus and hypospadias in one individual each.Facial phenotypes of seven patients. (A–C) Patient 5, kamagra for sale aged 6 months (A,B) and 3 years (C).

(D) Patient 8, aged 5 years. (E,F) Patient 2, aged 5 kamagra for sale and 20 years. (G–I) Patient 3, aged 1 year (G) and 3 years (H,I).

(J,K) Patient 13, aged 22 years. (L–O) Patient kamagra for sale 6, aged 8 months (L), 20 months (M) and 3 years (N,O). (P,Q) Patient 10 aged 22 years." data-icon-position data-hide-link-title="0">Figure 1 Facial phenotypes of seven patients.

(A–C) Patient kamagra for sale 5, aged 6 months (A,B) and 3 years (C). (D) Patient 8, aged 5 years. (E,F) Patient 2, kamagra for sale aged 5 and 20 years.

(G–I) Patient 3, aged 1 year (G) and 3 years (H,I). (J,K) Patient 13, aged 22 years. (L–O) Patient 6, aged 8 months (L), 20 months (M) kamagra for sale and 3 years (N,O).

(P,Q) Patient 10 aged 22 years.Cutaneous features. (A) Patient 3 kamagra for sale. Umbilical hernia, widely spaced nipples and hypopigmentation on the left side of the abdomen.

(B) Patient kamagra for sale 17. Hypotonia, umbilical hernia and widely spaced nipples. (C) Patient kamagra for sale 8.

Blaschko’s lines on the back. (D) Patient 6. Hypopigmentation on the left side of the abdomen kamagra for sale.

(E) Patient 7. Blaschko’s lines on the abdomen and kamagra for sale right side of the trunk. (F) Patient 13.

Hand. Note clubbing of thumbnail and loose skin. (G) Patient 17.

Blaschko’s lines on the left side of the abdomen. (H) Patient 17. Hand.

Note tapering fingers and wrinkled skin. (I) Patient 1. Linear hypopigmentation on the back.

(J) Patient 6. Blaschko’s lines on the back. (K) Patient 3.

Blachko’s lines on the right lower limb. (L) Patient 6. Blaschko’s lines on the right lower limb.

(M,N) Patient 7. Linear hyperpigmentation on the lower limbs. (O) Patient 11.

Blaschko’s lines on the back." data-icon-position data-hide-link-title="0">Figure 2 Cutaneous features. (A) Patient 3. Umbilical hernia, widely spaced nipples and hypopigmentation on the left side of the abdomen.

(B) Patient 17. Hypotonia, umbilical hernia and widely spaced nipples. (C) Patient 8.

Blaschko’s lines on the back. (D) Patient 6. Hypopigmentation on the left side of the abdomen.

(E) Patient 7. Blaschko’s lines on the abdomen and right side of the trunk. (F) Patient 13.

Hand. Note clubbing of thumbnail and loose skin. (G) Patient 17.

Blaschko’s lines on the left side of the abdomen. (H) Patient 17. Hand.

Note tapering fingers and wrinkled skin. (I) Patient 1. Linear hypopigmentation on the back.

(J) Patient 6. Blaschko’s lines on the back. (K) Patient 3.

Blachko’s lines on the right lower limb. (L) Patient 6. Blaschko’s lines on the right lower limb.

(M,N) Patient 7. Linear hyperpigmentation on the lower limbs. (O) Patient 11.

Blaschko’s lines on the back.Molecular resultsThe characteristics of the 13 different de novo TFE3 variants identified in the 17 unrelated individuals are summarised in table 2. All but one were missense variants, affecting nine different aminoacids. One was a splice donor mutation.

This mutation was reported a few weeks ago in a patient with a similar phenotype.21 Two variants were localised in exon 3 and 11 in exon 4 (figure 3). All were absent from public databases and were predicted to be pathogenic by prediction softwares. TFE3 protein and localisation of the missense variants identified.

In bold are variants identified in two patients. In bold and underlined is the variant identified in three patients. In green is the intronic variant." data-icon-position data-hide-link-title="0">Figure 3 TFE3 protein and localisation of the missense variants identified.

In bold are variants identified in two patients. In bold and underlined is the variant identified in three patients. In green is the intronic variant.View this table:Table 2 Molecular data of the 13 de novo TFE3 mutations.

Characteristics, inheritance, frequency in the public database GnomAD, prediction scores regarding pathogenicity (Polyphen, Grantham and CADD (Combined Annotation Dependant Depletion) scores). The transcript is NM_006521.5The putative mosaicism was assessed through X inactivation studies in females and analysis of the exome sequencing data in males, by checking the total number of reads covering the variant, as well as the number of reads supporting the presence of the variant (table 1). Allele frequencies in females were always consistent with a constitutional heterozygous mutation.

X inactivation was skewed in blood of the female patients 1, 3 and 7 and in fibroblasts of Patient 2. X inactivation was random in fibroblasts of Patient 1 and 3. Regarding the male patients, the mutation was identified in 65% of the reads for Patient 17% and 88% of the reads for Patient 15 (106/120).

No mosaicism was detected in the blood of Patient 13, 14 and 16 despite the presence of pigmentary manifestations in Patient 16.DiscussionTFE3 functions in signalling of the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1). The PIK3-AKT-mTOR pathway plays a role in the regulation of cellular growth, proliferation, survival and metabolism. Overactivation of the mTOR signalling is responsible for neurocutaneous disorders and cancers.22 Somatic mutations in TSC1, TSC2, AKT3, PIK3CA and MTOR are responsible for focal cortical dysplasia type II (MIM607341),23–25 hemimegalencephaly26 and megalencephaly.27 The phenotype ascribed to germline TSC1/TSC2, PTEN, MTOR and PK3R2/AKT3/CCND2 mutations – respectively in tuberous sclerosis (TS, MIM 191100), Cowden syndrome (CS, MIM 158350), Smith-Kingsmore syndrome (MIM 616638) and Megalencephaly, Polymicrogyria, Polydactyly and Hydrocephalus syndrome 1, 2 and 3 (MPPH1/2/3, MIM 603387/615939/615938) - is characterised by the association of ID, epilepsy, brain malformations and skin tumours.

Similarly, all the individuals harbouring a de novo TFE3 mutation reported in the series presented with a severe neurodevelopmental disorder. Delayed psychomotor development was constant. The youngest patient to acquire independent walking was 30 months old, and more than half of the patients aged over 18 months (57%), did not acquire walk at the last examination.

Conversely to patients with MTOR, AKT3 or PTEN mutation, none of the patients described in this series had macrocephaly. Brain imaging was abnormal in 35% of the patients. Hydrocephaly and corpus callosum dysgenesis, identified in respectively three and one individual, were previously reported in patients with mosaic gain of function MTOR mutations.28 29 One patient had surgery to remove an early-onset histiocytofibroma.

However, no other skin tumour was reported, either in this patient or in any other from the series.Pigmentation anomalies, along Blaschko’s lines or, for one patient, as a large hyperpigmented area, were present in a majority of the individuals (71%) in the series, including 40% of the males and 83% of the females. PM along Blaschko’s lines is highly suggestive of genetic mosaicism.30 Genomic mosaicism is defined by the presence of at least two cell populations with different genotypes in an individual originating from one zygote and mainly occurs through post-zygotic event, whereas females can present with functional (epigenetics) mosaicism due to X inactivation.2 PM is a classical feature of X-linked male-lethal genodermatosis, such as incontinentia pigmenti (IP, MIM #308300), focal dermal hypoplasia (FDH, MIM #305600), chondrodysplasia punctuata type 2 (Conradi-Hunermann-Happle syndrome, CDPX2, MIM #302960) and linear skin defects with multiple congenital anomalies (LSDMCA1, MIM #309801). In these conditions, the overwhelming predominance of affected females is a consequence of the male lethality, and the PM a manifestation of the functional mosaicism occurring in females.

Similarly, the majority of individuals with de novo TFE3 variants in our cohort were females (sex ratio female:male was 12:5 (2.4)). The study of X-inactivation on non-cultured fibroblasts was consistent with functional mosaicism in two affected females with PM who harboured random X-inactivation, whereas a third female without PM had skewed X-inactivation. In IP, FDH and CDPX2, most hemizygous males die in utero.

However, there have been reports of surviving males 31–33 with an estimated prevalence around 10% in FDH and IP.32 34 The majority of them are explained by post-zygotic mutations or chromosomal anomalies (Klinefelter syndrome). Non-mosaic males have also been reported in FDH and IP – respectively about 17% and 45% of the affected males harbour a non-mosaic variant.32 35 In our series, males represented 29% of the patients with a de novo TFE3 variant. A mosaic variant was identified in blood for half of them.

None had Klinefelter syndrome. Interestingly, mosaicism was detected in only one out of the two males with PM, and one male with a mosaic variant had no pigmentation anomalies noted on examination. It is still possible that subtle pigmentation anomalies were missed on examination.

Moreover, somatic mosaicism can be difficult to detect. Recent studies have shown that a large proportion of de novo mutations presumed to be germline had in fact occurred as post-zygotic event.36 In the males of this cohort, WES was performed on leucocytes-derived DNA and no other tissue was studied. Therefore, it is possible that a low mosaicism was not detected.

Finally, it is probable than TFE3 mutations account for a significant proportion of patients with HMI. Indeed, in this population, the high frequency of ID, epilepsy, coarse facial features has long been emphasised in the literature.37By its ability to bind the coordinated lysosomal enhancement and regulation (CLEAR) sites in the promotor region of target genes, TFE3 is involved in the control lysosomal biogenesis, autophagy and endocytosis.8 Several patients of the series indeed had clinical and biochemical features that pointed toward an inborn error of metabolism. Lysosomal storage disorder was suspected due to the variable association of coarse facial features (88%), skeletal anomalies (65%) –flat or clubfeet, hyperlordosis, hip dislocation, limitation of elbow extension, genu valgum, scoliosis–, postnatal growth retardation (59%), history of speech or developmental regression (29%) congenital hearing loss (29%), recurrent upper airways s (29%) neonatal liver anomalies such as hepatomegaly and cholestasis (18%), upper airways s (24%), umbilical hernia (18%), sleep apnoea syndrome (6%) and aortic insufficiency (6%).

Other metabolic anomalies observed in the series were obesity, defined in children by body mass index (BMI) (weight/height2) above the WHO curve, present in the oldest patients (76%), neonatal transient hypoglycaemia (12%), and hyperlactataemia (6%). Dysregulation of lipid metabolism, via suppression of thermogenesis and decreased lipolysis, thus leading to increased adipose tissue, was previously observed in adipose-specific TFE3 transgenic mice.38 Similarly to lysosomes, mitochondrias have a key role in cellular metabolism, including autophagy. Recent data demonstrate that mitochondrial and lysosomal metabolisms are interrelated.39 Muscle biopsy, performed in two individuals from this cohort, showed fat and glycogen accumulation, muscular fibre size irregularity, without evidence of mitochondrial dysfunction.

Interestingly in the more recent data, evidences showing that TFE3 plays a role in the regulation of the circadian oscillations of the expression of genes involved in autophagy and lipid metabolism, and that Tfe3 knock-out mice had abnormal circadian behaviour.40 Indeed, in our series, five patients (29%) were noted to have sleep disturbance. This could be due to circadian rhythms alteration. Finally, TFE3 has been shown to be involved in the regulation of innate immune response in macrophages via the FLCN-AMPK signalling axis,41 and of B-lymphocytes activation.42 Along these lines, four patients of the series (24%) had a history of recurrent s, associated with documented neutropenia in one of them.

As shown in table 3, a summary of the frequency of the features observed in the cohort, facial dysmorphism was constant and strikingly similar among the patients. More than two-third had anteverted nares, broad flat nasal bridge, almond-shaped and widely spaced eyes, puffy cheeks and coarse facial features (thick lips and fleshy earlobes). More than half had facial hypertrichosis.

All individuals presented with at least four of the above features. One patient had an extreme facial phenotype of hypertelorism, bifid nose and bilateral cleft lip and palate. Whether these frontonasal dysplasia features may be associated with the TFE3 mutation remains unclear.

No other mutation in known genes was found in Patient 1’s exome sequencing data.View this table:Table 3 Frequency of the clinical features observed in the seriesTFE3 is a highly conserved protein, intolerant to loss of function as supported by data from the GnomAD browser43 (probability of being loss-of-function intolerant (pLI) evaluated at 0.98, observed:expected ratio=0.06) and to missense variants (Z=2.15). Moreover, TFE3 does not, or only in a few tissues, escape X inactivation, suggesting that TFE3 gene dosage is crucial to cell function.44 45 In vitro, Villegas et al recently showed that the absence of either TFE3 exon 3 or 4 resulted in a nuclear gain-of-function Tfe3 allele in ESCs, indicating that both exons 3 and 4 are required for Tfe3 inactivation.3 Nuclear localisation and resistance to differentiation were proved in Tfe3 knock-out (K.O.) ESCs expressing murine Tfe3 alleles (Gln118Pro and Pro185Leu, corresponding to mutations Gln119Pro and Pro186Leu identified in individuals referred to as patients 1 and 2 in this series). Based on the analysis of TFE3 secondary structure,46 indicating that residues 110–215 are predicted to form a domain of two stable alpha helices that might be disrupted by mutations in exons 3 and 4, and the observation of a similar phenotype in patients harbouring mutations in exons 3 and 4, it was suggested that Tfe3 exons 3 and 4 form a Rag binding fold whose structural integrity is indispensable for lysosome-mediated cytoplasmic Tfe3 inactivation.3 In this series, the recurrent mutations Arg117Gln, Leu191Pro and Thr187Met were present in respectively two, two and three patients.

The aminoacid in position 187 was mutated in five patients. In addition, 13 of the described mutations were localised between positions p.184 and p.201. This proximity could account for the absence of obvious genotype–phenotype correlation.

The canonical splice site variant in intron 4 identified in patient 9 might lead to in-frame exon skipping of exon 4. The clinical picture of the patient with this splice site variant perfectly fits with the syndrome described here. As a consequence, we raise the hypothesis of a gain-of-function effect of this variant.In conclusion, de novo mutations in exons 3 and 4 of the X-linked gene TFE3 are responsible for a neurocutaneous disorder with specific and recognisable facial dysmorphism, lysosomal storage disorder-like features and PM.

This series unravels TFE3 as a major gene responsible for HMI and for a rare cause of syndromic ID. Furthermore, we provide clinical and molecular data on a previously unidentified lysosomal storage disorder, in which new insights, especially biochemical features, will probably be investigated further, together with the description of more patients. Further delineation of this phenotype will indeed allow a better understanding of the link between lysosomal signalling and development.

Finally, the evidence for mosaicism in this recently described disorder highlights the importance of considering mosaic variants on next-generation sequencing reports in diagnostic, including for patients without suggestive phenotype..

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20% with discount code. DM205. Sunday ScariesSunday Scaries is a CBD company with a sense of humor. With the brand name referring to those anxious feelings you get when you aren’t looking forward to Monday, these gummies aim to take it all away and make you smile in the moment.Sunday Scaries’ regular CBD gummies are a cool take on the classic original gummy bears.

Fruit-flavored and made with 10 mg of CBD each, they are free of THC and a perfect snack any time, day or night. Choose between the standard recipe and the Vegan AF recipe.One of the great things about the Sunday Scaries brand is their unique gummies meant to celebrate their community and their chosen causes.Their Rainbow Jerky contains 10 mg of CBD as well, but comes in bite-sized rainbow-colored pieces that are coated in sweet and sour sugar. The best thing about these is that $1 from every purchase goes to The Trevor Project, an organization with a mission of preventing suicide among LGBTQ+ youth.You can also choose for your purchase to go toward helping to fund breast cancer research. For every order you place of the latest addition, Bra Berries (strawberry-flavored CBD gummies with vitamin C infused), Sunday Scaries will donate $2 to The Pink Agenda.6.

R+R MedicinalsR+R Medicinals is the brand that finally makes the CBD gummy right - with their 25mg Full-Spectrum Gummies, you can really feel the difference. Vegan, sugar coated, no artificial flavors or colors, and simple ingredients make this gummy option a clear winner compared to other gummies on the market. Each gummy is packed with 25mg of Full-Spectrum CBD and other minor cannabinoids from their CO2 extracted, USDA Certified Organic, proprietary Cherry strain of hemp. R+R partnered with a local candy manufacturer to create these one-of-a-kind gummies.

Unlike most other ‘sprayed’ gummies, they truly infuse their CBD into the formula and ensure the hemp flavor doesn’t overpower the deliciousness of each piece. Each jar has 30 gummies at 25mg each - 750mg total for the jar, with a mix of peach, strawberry, and green apple flavors. This is an outstanding bang for your buck for a Full-Spectrum product at only $46.99. Full-battery certificates of analysis are available for each batch on their website along with a 30-Day Risk Free Trial.

New customers can use the code "RRWORKS20" for 20% off their first order!. 7. Evn CBD GummiesEvn CBD understands that, while CBD oil is the most direct route to hemp-based wellness, CBD gummies are a lot tastier and more fun.Evn uses 100 percent THC-free CBD extracted from organically grown hemp plants, to ensure that professionals and athletes can get their daily dose in worry-free.Pop them into your gym bag or your briefcase and enjoy them as a discreet snack any time you’re feeling the strain throughout the day.When you want to get a great night’s sleep, take 1-3 of these 10 mg CBD gummies and feel yourself start to relax.Choose between a classic sweet gummy bear flavor, gummies with a sour punch, or order a package of both. After all, variety is the spice of life!.

8. Charlotte’s Web Sleep CBD GummiesWhile full-spectrum CBD gummies have a more pungent flavor than their CBD isolate counterparts, there are some benefits to getting a gummy made with a more robust formula.Charlotte’s Web CBD gummies are made with the full-spectrum CBD that made the brand famous. They include a potent combination of additional cannabinoids like CBC, CBG, and CBN, and are made with some of the best hemp grown in the United States.One thing that may make the sleep CBD gummies a little more palatable is the fact that the CBD used to make them is CO2 extracted. The flavor is milder than it is in the oil made with an ethanol extraction, and you may find you appreciate the way they taste.These CBD gummies are infused with 3 mg of melatonin in addition to their 10 mg of CBD.

They are flavored with natural flavorings and contain no artificial colors.We like that you can choose different sizes. Go with a 30-count jar if you are just giving them a try. Or if you know what you are looking for, order the 90-count jar to take you through a couple of months.9. ElixinolElixinol has been involved in the hemp industry since before it was an industry in the US.

For 25 years, the company has been doing research, educating the public, and perfecting the products it offers.The brand is a partner of the Realm of Caring, which is an organization dedicated to advocacy, research, and education, for individuals with conditions that can be improved with the use of CBD and cannabis products.These CBD gummies may have a strong, bitter aftertaste because they are made with full-spectrum CBD, but they are vegan, cruelty-free, and naturally flavored.Choose between mixed berry, passionfruit, or pineapple flavors, or order an assortment of flavors if you’re having trouble picking just one.When you are just getting started and you aren’t sure which kinds of gummies are right for you, you can try a 4-pack of any of the flavors you want. Otherwise, go for a jar of 30 to get quality sleep all through the month.10. Bluebird BotanicalsAnother great company with a conscience, Bluebird Botanicals puts its heart and soul into every batch of CBD it makes.The CBD gummies are no exception. Made with 15 mg of full-spectrum hemp extract each, these gummies are sweetened with pure organic cane sugar.

They contain no artificial flavors or colors.Bluebird Botanicals is on a mission to make CBD radically accessible to everyone, through education, support and advocacy.The company is a certified B Corporation, meaning that it lives up to its reputation of care and concern for its customers, its employees, its community, and the environment.11. Joy OrganicsJoy Organics has quickly made a name for itself in the CBD industry because of its careful attention to quality, its consistent products, and its focus in putting the customer first.Joy Organics is one of the few CBD companies out there that you can just call anytime you have a question. Service agents genuinely care about the consumer, and it is evident in the fact that they work until your questions are answered and you are satisfied. The CBD gummies from Joy Organics are flavored naturally, and they come in green apple and strawberry lemonade.They are made with 10 mg of THC-free broad-spectrum CBD each, and customers give their flavor rave reviews.

All Joy Organics products come with a 30-day money back guarantee, and you are encouraged to try the whole product before requesting a refund.Bonus. Infinite CBD GummiesInfinite CBD makes a variety of CBD-infused gummies, and you are certain to find something you absolutely love from this creative company.We think it’s a blast that all of its products are outer-space themed, and the asteroid gummies are out of this world.Choose between classic-flavored or sour CBD asteroids made with CBD isolate for a milder flavor, broad-spectrum CBD gummies for a THC-free entourage effect, or the seasonal flavor, warm apple pie.This article contains affiliate links to products. Discover may receive a commission for purchases made through these links.Our liver plays a major role in supporting our overall health, including helping with the metabolic process, digestion, and proper blood circulation, as well as cleansing the body of harmful toxins. However, most people damage their livers without even knowing it, with things like drinking too much alcohol, eating processed or fried foods, or even being just a little overweight.

That’s why many people have been turning to natural liver health supplements. A good quality liver supplement is an effective solution to help repair liver damage and optimize liver functioning. Ranking the Best Liver Health Supplements On The Market We reviewed the top brands and found the best 5 liver supplements on the market today. See our full list below.

1MD LiverMD Live Conscious LiverWell Gaia Herbs Liver Cleanse 1. 1MD LiverMD LiverMD delivers 6 powerful, clinically studied ingredients in one groundbreaking, exclusive 1MD formula to help purify and optimize liver function for better energy, metabolism, and overall health. This doctor-formulated liver support stands out because it includes EvnolMax, which is a clinical strength tocotrienol, and Siliphos, the bioavailable active ingredient in milk thistle. LiverMD is also made with zinc, selenium, and other ingredients that work to help detox and repair your liver.

Additionally, 1MD offers a 90-day, risk-free, money-back guarantee, proving the company stands behind its products. BUY HERE 2. Live Conscious LiverWell LiverWell’s formula combines optimal liver health ingredients, including clinically studied milk thistle, NAC, and alpha lipoic acid to name a few. Their product is shown to aid liver function, metabolism, and whole-body detoxification.

LiverWell is best for those who need to reduce the effects of environmental toxins and struggle with metabolic issues. LiverWell’s use of powerful antioxidants has also been shown to reduce and repair damage done to liver and kidney health from free radicals in the body. Beyond that, LiveWell offers a comprehensive 365-day return policy, so everyone can try their products completely risk-free. BUY HERE 3.

Gaia Herbs Liver Cleanse Liver Cleanse’s unique proprietary blend covers a vast range of liver supporting nutrients that are all-natural and entirely herbal. While it does contain milk thistle, it lacks several key ingredients, such as zinc, selenium, or any form of Vitamin E. This limits its ability to support your liver health. The transparent labeling showcases all the ingredients included in its proprietary formula.

Gaia Herbs takes a simple approach to producing a good quality liver support supplement for a low price range.Ask any nutritionist and they'll tell you that our health is a reflection of the lifestyle we lead and what we put on our plates. The food we eat not only satisfies our hunger. It also fuels our bodies with energy to carry on. In today’s fast-paced life, there's limited time to make elaborate home-cooked meals.

It's no wonder that 80 percent of Americans' total calorie consumption is thought to come from store-bought foods and beverages. Many of these food items are considered ua-processed, causing a growing rate of concern for human health among scientists.Breaking Down Ua-Processed FoodsYou may be wondering what exactly ua-processed foods are. The concept of processing refers to changing food from its natural state, according to Harvard Health Publishing. Methods of accomplishing this include canning, smoking, pasteurizing and drying.

Ua-processed foods take processing one step further by adding multiple ingredients such as sugar, preservatives and artificial flavors and colors. Commercially prepared cookies, chips and sodas are just a few of many examples of foods that fall into the highly processed category. In order to further understand ua-processed foods, we must first explore the different levels of food processing. The term ua-processed was first coined by Carlos Monteiro, a professor of nutrition and public health at the University of Sao Paulo, Brazil.

Monteiro also created a food classification system called NOVA that has become a popular tool in categorizing different food items. The NOVA Food Classification system contains four different groups:Unprocessed/Minimally Processed Foods. Think 100 percent natural and healthy. This group includes foods such as fruits, vegetables, eggs, meats and milk.

Unprocessed foods are considered completely natural and are typically obtained directly from plants and animals. Minimally processed foods are also natural foods that have had very minor changes such as removal of inedible parts, fermentation, cooling, freezing, and any other processes that won't add extra ingredients or substances to the original product.Processed Culinary Ingredients. This group has everything to do with flavor and typically contains ingredients such as fats and aromatic herbs that are extracted from natural foods. These ingredients are then used in homes and restaurants to season and cook items such as soups, salads and sweets.

Many of these extracted ingredients can also be stored for later use. Processed Foods. Most processed foods contain at least two or three added ingredients such as salt, sugar and oil. Think of this group as a combination of the first two groups.

In other words, processed culinary ingredients or flavors that are added to natural foods. Examples include fruits in sugar syrup, bacon, beef jerky and salted nuts. Ua-Processed Foods. Last and least healthy on the NOVA scale are ua-processed foods.

This group is considered highly processed due to a large amount of added ingredients. Nova typically classifies this group as industrial formulations made entirely or mostly from substances such as oils, fats, sugar, starch and proteins as well as flavor enhancers and artificial colors that make these foods appear more attractive. Frozen items such as pre-prepared burgers or pizzas, candies, sodas, chips and ice cream are a few examples. On a daily basis, the ua-processed category is not the best source of your nutritional intake.

But there's still hope for our frozen pizza and chocolate lovers. Caroline Passerrello, spokesperson for the Academy of Nutrition and Dietetics, suggests that there may be a place on our plates for processed foods. Everything in ModerationIt's often said that most things are OK in moderation. But does this saying ring true for ua-processed foods?.

According to Passerrello, ua-processed foods like cookies, chips and sodas are more energy than nutrient-dense. This means that while the energy and calories are present, the nutrients we require like vitamins and minerals are often lacking. This can become a cause for concern because our bodies require both energy and nutrients to function properly.A 2017 study that followed the dietary intakes of 9,317 participants found that Americans were eating ua-processed foods at alarming rates. Foods, in this case, were classified according to the NOVA scale.

The results of the study showed that on average more than half of the calories of the participants came from ua-processed foods. These foods failed to deliver proper nutrients. Participants that consumed more ua-processed food lacked proper protein, calcium, fiber, potassium, and vitamins A, C, D and E in their diets. In contrast, participants that consumed higher amounts of unprocessed or minimally processed foods had a better overall diet with adequate amounts of the different nutrients.So, a balanced diet of the different food groups may just be the way to go.

But what happens when we overindulge in ua-processed foods on a regular basis?. Because ua-processed foods are typically filled with sugar and fat, they've been linked to numerous health risks including obesity, heart disease and stroke, type-2 diabetes, cancer and depression.Passerrello explains that overconsumption of highly processed foods over time can also lead to vitamin and mineral deficiencies. In addition, processed foods tend to have higher amounts of sodium, which is often used to extend their shelf life. Consuming too much sodium can lead to feelings of dehydration and cause muscle twitches.The health risks associated with overconsumption of ua-processed foods can easily pile up, but luckily, there are some healthy alternatives that we can choose to incorporate into our diet.

Eat This Not ThatCutting down on ua-processed foods definitely seems like a good start to a healthy and balanced diet, but it's only the first step. "It's not just the ua-processed food itself that is the concern, but what else we are, or are not, eating — as well as what our bodies need and ultimately, what foods we have access to on a regular basis," says Passerrello.Health and nutrition can vary from person to person, so there is definitely no hard and fast rule as to what goes and what stays. However, Passerrello advises that if you are in a position in life with your time, taste and budget to make a choice between an ua-processed food item and a minimally processed food item, you should typically opt for the minimally processed food.Yes, frozen dinners may be an easy option after a long day of work. However, an easy alternative that can save time could be meal prepping in advance.

A homemade alternative such as a simple rice dish or burritos can be easy to make in batches and store away for the week. Another simple way to slowly decrease your intake of processed foods is to check food labels for excess amounts of salt or sugar. Instead of sodas, Passerrello suggests opting for orange juice or milk that are fortified with calcium and vitamin D.Ultimately, choosing healthy foods is a matter of providing your body with the proper nutrients it needs while also incorporating your personal tastes and preferences. A handful of chips and a frozen pizza may not be the healthiest treat, but they won't do serious damage as long as ua-processed foods aren't your main and only form of nutrients..

With summer in full swing, many people are kicking off their shoes — kamagra for sale and it’s not just happening at the beach or in the park. Walking or running barefoot has gained popularity over the past decade, as have minimalist shoes designed to imitate the feel of going barefoot.Claims abound that ditching shoes can improve strength and balance, resolve hip, back or knee ailments, and prevent painful foot deformities like bunions or fallen arches. But is barefoot actually better or is it kamagra for sale just a fad?.

Like all other animals, humans evolved to walk without shoes. Then, as our ancestors strode across the savannas in search of food and shelter, they eventually figured out how to protect kamagra for sale their feet from extreme temperatures and sharp objects. Wrap them in animal hides.

These early versions of shoes kamagra for sale likely enabled our species to travel farther, faster, and more safely.The oldest shoes discovered date back to 8,000 years ago. However, fossil evidence indicates that our species probably began wearing sandals or moccasins over 40,000 years ago. Cushioned shoes, however, only came on the scene about 300 kamagra for sale years ago.

Some studies show that these padded soles have shifted the foot’s form and function.Human feet are complicated and sophisticated machines, containing almost one-quarter of all bones in the body. Each foot has 200,000 nerve endings, 26 bones, 30 joints, and more than 100 muscles, tendons and ligaments, all of which work together seamlessly as we move around. So it stands to reason that covering those many intricate parts with a shoe will change how kamagra for sale we move.In his 2009 bestseller Born To Run Christopher McDougall championed the now-popular idea that modern, cushioned shoes are the cause of many muscular-skeletal injuries — at least for runners.

McDougall studied the Tarahumara tribe in Mexico, whose members often run over 100 miles up and down stony trails in nothing but thin, homemade sandals. He ditched his padded sneakers, curing his own running-related injuries and spawning a movement to go back to barefoot basics.A 2010 study showed that barefoot runners do put less stress on kamagra for sale their feet. They take shorter strides, and strike with the middle of their foot first while curling their toes more.

This spreads out the force more evenly across the kamagra for sale foot.Wearing a cushioned shoe with a heightened heel, on the other hand, enables runners to take longer strides and strike the ground heel-first. Landing on the heel generates up to three times more force than landing on the forefoot, sending shock waves up the skeletal system.Shoes seem to change the way we walk, too. Barefoot walkers take shorter strides and step more lightly — mostly to test whether there’s something painful beneath the foot before it takes the body’s full kamagra for sale weight.Some research shows that modern shoes have changed humans’ foot shape over time.

For example, people in India who are habitually barefoot have wider feet than Westerners, whose more slender, shorter feet gave less ability to spread out the pressure of impact.Shoes can also interfere with neural messages set from our feet to our brain about the ground beneath us. Researchers from Harvard recently studied 100 adults, mostly from Kenya, to see whether calluses act similarly to shoes in terms of dulling the signaling between foot kamagra for sale and brain.Calluses are the evolutionary solution for thorns or stones. The skin on our feet is thicker than almost anywhere else on the body.

Study subjects who walked barefoot most of the time had more calluses than their shod peers, which protected their feet but still allowed better tactile stimulation than shoes. Researchers also found that uncushioned, minimal shoes functioned more similarly to walking on callused bare feet than to wearing cushioned shoes.But the jury is still out kamagra for sale on whether going shoeless translates to better overall outcomes for the body.A literature review from 2017 evaluated the long-term effects of habitually walking or running barefoot, and found no difference in relative injury rates compared to shoe-wearing folks. However, walking or running barefoot did appear to result in less foot deformities.As for children, a study released this year found no statistical differences in the gait or force exerted by 75 children, aged 3 to 9 years old, who walked both barefoot and in shoes across the same ground.

A different study published in 2017 found that “evidence is small" for barefoot locomotion’s long-term effects kamagra for sale on foot characteristics. In fact, after comparing the foot morphology of 810 children and adolescents who were habitually shod versus habitually barefoot, they concluded that “permanent footwear use may play an important role in childhood foot development and might actually be beneficial for the development of the foot arch.”Minimalist shoes that give a barefoot feel but protective covering might just be the wave of the future — or, rather, a return to our prehistoric roots. A 2020 study evaluated the gait of 64 adults kamagra for sale and found they had better gait performance walking with minimalist shoes than walking barefoot.It seems our ancestors were on to something when they began wrapping their feet in leather millennia ago.

While letting your feet roam naked occasionally certainly isn’t a bad idea, most of us probably shouldn’t toss our shoes in the trash any time soon.This article contains affiliate links to products. We may receive a commission for purchases made through these links.When it comes to finding the best CBD gummies for sleep, you kamagra for sale have a lot of choices. The problem is that they aren’t necessarily all made with your wellness in mind.Even though CBD-lovers everywhere are more educated about CBD than they were when the market first took off, there are still plenty of misconceptions and misinformation driving an inconsistent industry.On one end, you have CBD companies dedicated to creating the safest, purest, best CBD products on the market.

On the other, companies just out to make a quick buck with no concern for the customer or the environment.We have put together a list to make it easier to find the kind of CBD gummies that promote a great night’s sleep with only the finest ingredients and kamagra for sale highest standards. The brands listed here make some of the best CBD gummies for sleep that you can find on the market today.1. Verma Farms CBD GummiesHere’s the thing with CBD gummies.

They don’t always taste very kamagra for sale good. Gummy candies are already difficult enough to get right as far as texture and flavor are concerned, but then add the pungent taste of most CBD products and you have a whole new challenge.Verma Farms, however, has perfected the CBD gummy hands-down.They come in a variety of juicy, Hawaiian-inspired flavors, a couple of different textures, and there are even sugar-free gummies for people with dietary restrictions.Choose between sweet and sour sugar-coated fruit rings with flavors like Blueberry Wave and Peachy Pau Hana. Or go with a classic kamagra for sale gummy bear texture and mixed fruit flavors.

The choice is yours, and you can pick between a potent concentration of 25 mg per gummy, or something milder at 12.5 mg per gummy.Verma Farms CBD is extracted from naturally and sustainably grown hemp. The CO2 method of kamagra for sale extraction is clean and easy on the environment, and it leads to some of the best, purest finished products you can find.Made with the purest CBD you will ever find, Verma Farms gummies are 100 percent free of THC.2. Penguin CBD GummiesPenguin CBD’s mascot (a penguin, in case you couldn’t guess) is a textbook example of how CBD is supposed to help you feel.

Ready to deal with life’s ups and downs, all the while keeping calm and waddling on.Penguins are super chill, and that’s how you kamagra for sale should feel when you incorporate Penguin CBD’s sweet and sour little gummies into your daily or bedtime routine.Penguin CBD’s gummies come in just one flavor, but it’s a classic. They are coated in a sweet and sour sugar, bright and cheerful like the jar they come in. Each gummy is tender, tangy, and tastes incredible.Because they are made kamagra for sale with a CBD isolate, much of the pungent “earthy” flavor typical of hemp products is eliminated.

What’s left is delicious, fruit-flavored gummies that pack 10 mg of CBD in each serving—perfect for snacking!. They’re also one of the highest rated CBD gummies on the market now. Just take a look at what sources such as kamagra for sale Cannabis Culture and Merry Jane have said about them in their reviews.3.

Medterra Sleep Tight GummiesMedterra’s products are all made based on the latest scientific research, and their philosophy is that outstanding CBD does not have to drain your wallet.Many companies claim that their products are more expensive because they use naturally and domestically grown hemp, or that they employ extensive third-party testing to confirm their purity and potency.However, Medterra has managed to give you all the quality and assurance while keeping down the cost to you.The Sleep Tight Gummies are made with 25 mg of broad-spectrum CBD, with melatonin and additional botanicals like lemon balm and chamomile thrown in to support the best sleep you can get.They are vegan, flavored with strawberry extract (so no corn syrup or artificial flavors or colors), and the package they come in was made with 20 percent post-consumer recycled products. Great-tasting, healthy kamagra for sale for you, and easy on the environment as well as your bank account. That’s the kind of gummy anyone can get behind.4.

Leaf RemedysLeaf Remedys kamagra for sale Gummies are infused with Full Spectrum oil extracted from extremely high quality organically grown Colorado hemp. With 50mg of CBD each, Leaf Remedys Gummies are one of the strongest on the market and are very reasonably priced at $49.99 for a 30 Pack a total of 1500mg. These gummies kamagra for sale will help you drift off to sleep, without the groggy nest morning.

Although very potent, the texture and flavor are not compromised at all. They feel and taste exactly like a Gummy should taste, but with a potent CBD twist kamagra for sale to them. They come in 3 delicious flavors (blue Raspberry, Strawberry, and Lime) and are only 8 calories each.

Leaf Remedys is a brand dedicated to the cause and proud to offer an all-American product at a very fair price. They offer free shipping within the kamagra for sale united states. 20% with discount code.

DM205. Sunday ScariesSunday Scaries is a CBD company with a sense of humor. With the brand name referring to those anxious feelings you get when you aren’t looking forward to Monday, these gummies aim to take it all away and make you smile in the moment.Sunday Scaries’ regular CBD gummies are a cool take on the classic original gummy bears.

Fruit-flavored and made with 10 mg of CBD each, they are free of THC and a perfect snack any time, day or night. Choose between the standard recipe and the Vegan AF recipe.One of the great things about the Sunday Scaries brand is their unique gummies meant to celebrate their community and their chosen causes.Their Rainbow Jerky contains 10 mg of CBD as well, but comes in bite-sized rainbow-colored pieces that are coated in sweet and sour sugar. The best thing about these is that $1 from every purchase goes to The Trevor Project, an organization with a mission of preventing suicide among LGBTQ+ youth.You can also choose for your purchase to go toward helping to fund breast cancer research.

For every order you place of the latest addition, Bra Berries (strawberry-flavored CBD gummies with vitamin C infused), Sunday Scaries will donate $2 to The Pink Agenda.6. R+R MedicinalsR+R Medicinals is the brand that finally makes the CBD gummy right - with their 25mg Full-Spectrum Gummies, you can really feel the difference. Vegan, sugar coated, no artificial flavors or colors, and simple ingredients make this gummy option a clear winner compared to other gummies on the market.

Each gummy is packed with 25mg of Full-Spectrum CBD and other minor cannabinoids from their CO2 extracted, USDA Certified Organic, proprietary Cherry strain of hemp. R+R partnered with a local candy manufacturer to create these one-of-a-kind gummies. Unlike most other ‘sprayed’ gummies, they truly infuse their CBD into the formula and ensure the hemp flavor doesn’t overpower the deliciousness of each piece.

Each jar has 30 gummies at 25mg each - 750mg total for the jar, with a mix of peach, strawberry, and green apple flavors. This is an outstanding bang for your buck for a Full-Spectrum product at only $46.99. Full-battery certificates of analysis are available for each batch on their website along with a 30-Day Risk Free Trial.

New customers can use the code "RRWORKS20" for 20% off their first order!. 7. Evn CBD GummiesEvn CBD understands that, while CBD oil is the most direct route to hemp-based wellness, CBD gummies are a lot tastier and more fun.Evn uses 100 percent THC-free CBD extracted from organically grown hemp plants, to ensure that professionals and athletes can get their daily dose in worry-free.Pop them into your gym bag or your briefcase and enjoy them as a discreet snack any time you’re feeling the strain throughout the day.When you want to get a great night’s sleep, take 1-3 of these 10 mg CBD gummies and feel yourself start to relax.Choose between a classic sweet gummy bear flavor, gummies with a sour punch, or order a package of both.

After all, variety is the spice of life!. 8. Charlotte’s Web Sleep CBD GummiesWhile full-spectrum CBD gummies have a more pungent flavor than their CBD isolate counterparts, there are some benefits to getting a gummy made with a more robust formula.Charlotte’s Web CBD gummies are made with the full-spectrum CBD that made the brand famous.

They include a potent combination of additional cannabinoids like CBC, CBG, and CBN, and are made with some of the best hemp grown in the United States.One thing that may make the sleep CBD gummies a little more palatable is the fact that the CBD used to make them is CO2 extracted. The flavor is milder than it is in the oil made with an ethanol extraction, and you may find you appreciate the way they taste.These CBD gummies are infused with 3 mg of melatonin in addition to their 10 mg of CBD. They are flavored with natural flavorings and contain no artificial colors.We like that you can choose different sizes.

Go with a 30-count jar if you are just giving them a try. Or if you know what you are looking for, order the 90-count jar to take you through a couple of months.9. ElixinolElixinol has been involved in the hemp industry since before it was an industry in the US.

For 25 years, the company has been doing research, educating the public, and perfecting the products it offers.The brand is a partner of the Realm of Caring, which is an organization dedicated to advocacy, research, and education, for individuals with conditions that can be improved with the use of CBD and cannabis products.These CBD gummies may have a strong, bitter aftertaste because they are made with full-spectrum CBD, but they are vegan, cruelty-free, and naturally flavored.Choose between mixed berry, passionfruit, or pineapple flavors, or order an assortment of flavors if you’re having trouble picking just one.When you are just getting started and you aren’t sure which kinds of gummies are right for you, you can try a 4-pack of any of the flavors you want. Otherwise, go for a jar of 30 to get quality sleep all through the month.10. Bluebird BotanicalsAnother great company with a conscience, Bluebird Botanicals puts its heart and soul into every batch of CBD it makes.The CBD gummies are no exception.

Made with 15 mg of full-spectrum hemp extract each, these gummies are sweetened with pure organic cane sugar. They contain no artificial flavors or colors.Bluebird Botanicals is on a mission to make CBD radically accessible to everyone, through education, support and advocacy.The company is a certified B Corporation, meaning that it lives up to its reputation of care and concern for its customers, its employees, its community, and the environment.11. Joy OrganicsJoy Organics has quickly made a name for itself in the CBD industry because of its careful attention to quality, its consistent products, and its focus in putting the customer first.Joy Organics is one of the few CBD companies out there that you can just call anytime you have a question.

Service agents genuinely care about the consumer, and it is evident in the fact that they work until your questions are answered and you are satisfied. The CBD gummies from Joy Organics are flavored naturally, and they come in green apple and strawberry lemonade.They are made with 10 mg of THC-free broad-spectrum CBD each, and customers give their flavor rave reviews. All Joy Organics products come with a 30-day money back guarantee, and you are encouraged to try the whole product before requesting a refund.Bonus.

Infinite CBD GummiesInfinite CBD makes a variety of CBD-infused gummies, and you are certain to find something you absolutely love from this creative company.We think it’s a blast that all of its products are outer-space themed, and the asteroid gummies are out of this world.Choose between classic-flavored or sour CBD asteroids made with CBD isolate for a milder flavor, broad-spectrum CBD gummies for a THC-free entourage effect, or the seasonal flavor, warm apple pie.This article contains affiliate links to products. Discover may receive a commission for purchases made through these links.Our liver plays a major role in supporting our overall health, including helping with the metabolic process, digestion, and proper blood circulation, as well as cleansing the body of harmful toxins. However, most people damage their livers without even knowing it, with things like drinking too much alcohol, eating processed or fried foods, or even being just a little overweight.

That’s why many people have been turning to natural liver health supplements. A good quality liver supplement is an effective solution to help repair liver damage and optimize liver functioning. Ranking the Best Liver Health Supplements On The Market We reviewed the top brands and found the best 5 liver supplements on the market today.

See our full list below. 1MD LiverMD Live Conscious LiverWell Gaia Herbs Liver Cleanse 1. 1MD LiverMD LiverMD delivers 6 powerful, clinically studied ingredients in one groundbreaking, exclusive 1MD formula to help purify and optimize liver function for better energy, metabolism, and overall health.

This doctor-formulated liver support stands out because it includes EvnolMax, which is a clinical strength tocotrienol, and Siliphos, the bioavailable active ingredient in milk thistle. LiverMD is also made with zinc, selenium, and other ingredients that work to help detox and repair your liver. Additionally, 1MD offers a 90-day, risk-free, money-back guarantee, proving the company stands behind its products.

BUY HERE 2. Live Conscious LiverWell LiverWell’s formula combines optimal liver health ingredients, including clinically studied milk thistle, NAC, and alpha lipoic acid to name a few. Their product is shown to aid liver function, metabolism, and whole-body detoxification.

LiverWell is best for those who need to reduce the effects of environmental toxins and struggle with metabolic issues. LiverWell’s use of powerful antioxidants has also been shown to reduce and repair damage done to liver and kidney health from free radicals in the body. Beyond that, LiveWell offers a comprehensive 365-day return policy, so everyone can try their products completely risk-free.

BUY HERE 3. Gaia Herbs Liver Cleanse Liver Cleanse’s unique proprietary blend covers a vast range of liver supporting nutrients that are all-natural and entirely herbal. While it does contain milk thistle, it lacks several key ingredients, such as zinc, selenium, or any form of Vitamin E.

This limits its ability to support your liver health. The transparent labeling showcases all the ingredients included in its proprietary formula. Gaia Herbs takes a simple approach to producing a good quality liver support supplement for a low price range.Ask any nutritionist and they'll tell you that our health is a reflection of the lifestyle we lead and what we put on our plates.

The food we eat not only satisfies our hunger. It also fuels our bodies with energy to carry on. In today’s fast-paced life, there's limited time to make elaborate home-cooked meals.

It's no wonder that 80 percent of Americans' total calorie consumption is thought to come from store-bought foods and beverages. Many of these food items are considered ua-processed, causing a growing rate of concern for human health among scientists.Breaking Down Ua-Processed FoodsYou may be wondering what exactly ua-processed foods are. The concept of processing refers to changing food from its natural state, according to Harvard Health Publishing.

Methods of accomplishing this include canning, smoking, pasteurizing and drying. Ua-processed foods take processing one step further by adding multiple ingredients such as sugar, preservatives and artificial flavors and colors. Commercially prepared cookies, chips and sodas are just a few of many examples of foods that fall into the highly processed category.

In order to further understand ua-processed foods, we must first explore the different levels of food processing. The term ua-processed was first coined by Carlos Monteiro, a professor of nutrition and public health at the University of Sao Paulo, Brazil. Monteiro also created a food classification system called NOVA that has become a popular tool in categorizing different food items.

The NOVA Food Classification system contains four different groups:Unprocessed/Minimally Processed Foods. Think 100 percent natural and healthy. This group includes foods such as fruits, vegetables, eggs, meats and milk.

Unprocessed foods are considered completely natural and are typically obtained directly from plants and animals. Minimally processed foods are also natural foods that have had very minor changes such as removal of inedible parts, fermentation, cooling, freezing, and any other processes that won't add extra ingredients or substances to the original product.Processed Culinary Ingredients. This group has everything to do with flavor and typically contains ingredients such as fats and aromatic herbs that are extracted from natural foods.

These ingredients are then used in homes and restaurants to season and cook items such as soups, salads and sweets. Many of these extracted ingredients can also be stored for later use. Processed Foods.

Most processed foods contain at least two or three added ingredients such as salt, sugar and oil. Think of this group as a combination of the first two groups. In other words, processed culinary ingredients or flavors that are added to natural foods.

Examples include fruits in sugar syrup, bacon, beef jerky and salted nuts. Ua-Processed Foods. Last and least healthy on the NOVA scale are ua-processed foods.

This group is considered highly processed due to a large amount of added ingredients. Nova typically classifies this group as industrial formulations made entirely or mostly from substances such as oils, fats, sugar, starch and proteins as well as flavor enhancers and artificial colors that make these foods appear more attractive. Frozen items such as pre-prepared burgers or pizzas, candies, sodas, chips and ice cream are a few examples.

On a daily basis, the ua-processed category is not the best source of your nutritional intake. But there's still hope for our frozen pizza and chocolate lovers. Caroline Passerrello, spokesperson for the Academy of Nutrition and Dietetics, suggests that there may be a place on our plates for processed foods.

Everything in ModerationIt's often said that most things are OK in moderation. But does this saying ring true for ua-processed foods?. According to Passerrello, ua-processed foods like cookies, chips and sodas are more energy than nutrient-dense.

This means that while the energy and calories are present, the nutrients we require like vitamins and minerals are often lacking. This can become a cause for concern because our bodies require both energy and nutrients to function properly.A 2017 study that followed the dietary intakes of 9,317 participants found that Americans were eating ua-processed foods at alarming rates. Foods, in this case, were classified according to the NOVA scale.

The results of the study showed that on average more than half of the calories of the participants came from ua-processed foods. These foods failed to deliver proper nutrients. Participants that consumed more ua-processed food lacked proper protein, calcium, fiber, potassium, and vitamins A, C, D and E in their diets.

In contrast, participants that consumed higher amounts of unprocessed or minimally processed foods had a better overall diet with adequate amounts of the different nutrients.So, a balanced diet of the different food groups may just be the way to go. But what happens when we overindulge in ua-processed foods on a regular basis?. Because ua-processed foods are typically filled with sugar and fat, they've been linked to numerous health risks including obesity, heart disease and stroke, type-2 diabetes, cancer and depression.Passerrello explains that overconsumption of highly processed foods over time can also lead to vitamin and mineral deficiencies.

In addition, processed foods tend to have higher amounts of sodium, which is often used to extend their shelf life. Consuming too much sodium can lead to feelings of dehydration and cause muscle twitches.The health risks associated with overconsumption of ua-processed foods can easily pile up, but luckily, there are some healthy alternatives that we can choose to incorporate into our diet. Eat This Not ThatCutting down on ua-processed foods definitely seems like a good start to a healthy and balanced diet, but it's only the first step.

"It's not just the ua-processed food itself that is the concern, but what else we are, or are not, eating — as well as what our bodies need and ultimately, what foods we have access to on a regular basis," says Passerrello.Health and nutrition can vary from person to person, so there is definitely no hard and fast rule as to what goes and what stays. However, Passerrello advises that if you are in a position in life with your time, taste and budget to make a choice between an ua-processed food item and a minimally processed food item, you should typically opt for the minimally processed food.Yes, frozen dinners may be an easy option after a long day of work. However, an easy alternative that can save time could be meal prepping in advance.

A homemade alternative such as a simple rice dish or burritos can be easy to make in batches and store away for the week. Another simple way to slowly decrease your intake of processed foods is to check food labels for excess amounts of salt or sugar. Instead of sodas, Passerrello suggests opting for orange juice or milk that are fortified with calcium and vitamin D.Ultimately, choosing healthy foods is a matter of providing your body with the proper nutrients it needs while also incorporating your personal tastes and preferences.

A handful of chips and a frozen pizza may not be the healthiest treat, but they won't do serious damage as long as ua-processed foods aren't your main and only form of nutrients..

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Patients are more likely to experience preventable harm during perioperative care than in kamagra green pills any other type of healthcare encounter.1 2 For several decades, a hallmark of surgical quality and safety has been the use of checklists to prevent errors (eg, wrong site surgery) and assure that key tasks have been or will be performed. The most widely used approach globally is the Surgical Safety Checklist (SSC) kamagra green pills recommended by the WHO.3 It is divided into preinduction (or sign in, consisting of seven items performed by anaesthesia and nursing), preincision (timeout, 10 items performed by the entire team) and postsurgery (sign out, five items by the entire team).4 5 Most hospitals in the developed world perform the SSC or an equivalent timeout prior to surgical incision. However, preinduction briefings, and postcase debriefings in particular, are much less commonly performed.6 7There are widely disseminated arguments recommending the use of checklists in healthcare8 but also recognised limitations.9 Checklist-based preincision timeouts appear to improve surgical outcomes in many settings,4 5 yet, in other hospitals, the introduction of the SSC failed to improve outcomes.10 Like all tools or processes intended to improve safety, ineffective implementation will reduce the desired benefits.

For example, there is appreciable evidence showing that surgical teams skip or do not meaningfully respond to timeout checklist items.11 12 Even with a robust implementation, effectiveness can be weakened by contextual factors, failure of leadership or deficient safety culture.Despite numerous studies, gaps in the evidence to kamagra green pills guide optimal checklist use persist. For example, we do not know whether checklist-based timeouts only decrease the occurrence of the undesirable events targeted by the checklist or, as many hypothesise, whether their use also facilitates teamwork and interprofessional communication. Although there is increasing guidance on how to optimally implement checklists kamagra green pills at the local level, many questions remain.13 Moreover, we still do not understand the circumstances in which checklist use facilitates the detection, reporting and correction of errors.In this issue of the journal, Muensterer and colleagues14 describe a clever study in which the attending surgeon intentionally introduced errors during the preincision timeout while a medical student in the operating theatre surreptitiously noted whether the error was detected and reported by one or more members of the surgical team.

If the error was not verbalised, the attending surgeon corrected the error before the timeout was complete. The single error embedded in each of 120 of 1800 paediatric operations kamagra green pills was randomly chosen from among wrong patient name, age, gender, allergy or surgical procedure, side or site. Overall, only about half (65.

54%) of all errors were detected and reported kamagra green pills by a team member prior to surgeon correction. Of these, errors were most commonly reported by the anaesthesiologist (64%) and almost never by residents in training (6%) or medical students (1%).This study also has important limitations. Because the investigators were leading the kamagra green pills timeouts as part of a research study, adherence to all of the checklist items was reportedly 100%.

Yet, few organisations consistently attain timeout adherence above 90%.11 Since you are less likely to catch an error if you do not address that item during the timeout, in institutions with lower adherence, the proportion of missed errors may be even higher.The authors, with input from their institutional review board, designed the study to be feasible and compliant with established human subjects protection principles. As such, kamagra green pills the attending surgeon always corrected the error after the anaesthesiologist’s component of the timeout but before the nurses’ component. By excluding the part of the timeout when the nurses address their checklist items (eg, instruments are sterile,) followed by a final opportunity as the timeout ends to note any errors or concerns, the study may have underestimated the rate of error reporting.Because the study did not query team members individually after the timeout, we also do not know how many errors were detected but not annunciated.

For example, recognised errors that were attributed to ‘misspeaking’ and/or kamagra green pills had no clinical significance may not have been verbally challenged. Moreover, as is discussed by the authors, there was an unequivocal hierarchy effect—individuals with the least ‘power’ (ie, low in hierarchy within the current healthcare culture) were the least likely to report the error.This study highlights two important safety relevant questions on which I will elaborate. First, why and how kamagra green pills should we change healthcare culture to facilitate ‘speaking up’?.

Second, how can we best design and implement checklists and other safety interventions to yield more consistent and sustained clinician behaviour change?. The continued problem kamagra green pills of hierarchical culture in healthcareThe significant influence of hierarchy on the incidence of error reporting in Muensterer et al’s14 study is consistent with substantial prior evidence that lower hierarchy clinical providers are less likely to ‘speak up’, even when they are aware of major safety violations.15–17Failure of a subordinate copilot to challenge or speak up to the captain in the 1977 Tenerife disaster was the impetus for the aviation industry’s adoption of crew resource management (CRM). Healthcare team-training initiatives like the Agency for Healthcare Research and Quality’s TeamSTEPPS now include tools such as the ‘two-challenge rule’ and emphasise speaking up.18 Flattened hierarchies and reliance on expertise rather than seniority, especially during crisis or stress, are an integral component of high-reliability organisations.

In contrast, the persistent kamagra green pills hierarchical culture of healthcare is anathema to positive safety attitudes and behaviours. This is particularly problematic in operating theatres where surgeons view themselves as ‘captain of the ship’ and where uncivil behaviour is tolerated.19 The insidious effects of hierarchy will impair effectiveness of checklist use and predispose to safety issues in all aspects of routine and emergency care.20 While team-oriented training designed to enhance the ability of lower hierarchy clinicians to ‘speak up’ can be effective,21 22 evidence to guide the design and implementation of these interventions is still sparse. Single training exposures have generally had limited effects,17 23 in part likely due to inadequate ‘potency’ to achieve the desired effect24 in a clinical environment contaminated by the hierarchical culture and in part because most interventions kamagra green pills have focused on ‘assertiveness’ training for the less powerful members of the team rather than, or in addition to, sensitivity or receptivity training of the most powerful (eg, surgical attendings).17Discussions of power hierarchy to date have largely focused on clinicians’ professional roles (ie, nurse vs physician) and level of experience (eg, resident vs attending).

Even with two attending physicians, for example, a surgeon and anaesthesiologist, power dynamics can degrade communication and decrease team performance. In a multicentre study of experienced anaesthesiologists managing simulated crisis events, the anaesthesiologists’ failure to challenge the surgeon to initiate life-saving interventions (eg, to kamagra green pills open the abdomen in the presence of an enlarging retroperitoneal haematoma during laparoscopic surgery, or to halt surgery to cardiovert an unstable patient) was associated with lower overall scenario performance scores as determined by trained blinded anaesthesiologist video raters.25In fact, hierarchy is much more complex and this may explain in part the variable and generally weak results seen in ‘speaking up’ intervention studies to date. When considering hierarchical effects on communication assertiveness, one must also consider individual characteristics including gender, race/ethnicity, language, personal cultural background and personality, as well as the personality of those in higher power roles, microclimate factors of the team and care unit, and overall organisational culture.17 22 An interesting direction for future study is the facilitation of more positive communication (eg, expressions of gratitude or encouragement).26In a single-site intervention study to improve the quality of handovers from anaesthesia professionals to postanaesthesia care unit (PACU) nurses,27 simulation-based training emphasised specific dyadic communication behaviours—assertiveness for the nurses when their needs were not being met and ‘sensitivity’ (or receptiveness) for the anaesthesia professionals when the nurses raised concerns.

In poststudy interviews, this behavioural focus was kamagra green pills considered an important contributor to the resulting sustained improvement in the quality of actual handovers. As part of this study, we explicitly taught participants to CUSS. CUSS is a kamagra green pills graduated approach to facilitate speaking up.

The acronym stands for ‘I’m Concerned’, ‘I’m Uncomfortable’, ‘This is a Safety issue’ and ‘Stop!. €™. The intended learners were taught these ‘triggers’ for eliciting desired behaviours (ie, to stop what they are doing and have a conversation with the initiator) and this approach creates an environment where the initiating individual can receive support from others who overhear the conversation—‘Doctor, I hear that Maria is CUSSing at you?.

How can I help to resolve this situation?. €™ Such a graded assertiveness approach to ‘stop the line’, developed in other industries, is increasingly being used throughout healthcare.28Designing and implementing more effective safety tools and processesSSCs are just one tool used to advance overall perioperative system safety. Similarly, in commercial aviation, checklists are one tool used as part of CRM to assure operational safety.

CRM is a philosophy or construct that includes explicit values and principles, procedures supported by purpose-designed checklists and other tools, and regularly scheduled mandatory simulation-based training and assessment that together contribute to an existing safety culture in pilots and across the organisation.29 CRM and most of the existing aviation safety system were iteratively designed by pilots (the front-line workers) in collaboration with other stakeholders (including regulators). Healthcare must employ similar human-centred design approaches to re-engineer our safety systems.For commercial aviation to be completely safe, no planes would fly. Similarly, safety will never be the foremost system objective in healthcare.

The primary goal is to efficiently deliver cost-effective care. Instead, in any high-consequence industry, safety is a desirable by-product (an ‘emergent feature’) of a system designed to achieve primary operational goals. In healthcare, sick patients must be treated and there is inherent risk in doing so.30 Achieving societally acceptable levels of safety will stem from a deliberately designed system founded on a strong safety culture and truly committed leadership.With this as background, it is not surprising that so many hospitals struggle to garner reliable and sustained benefit from the use of checklists and other safety tools.

To understand what is required, I would like to draw parallels with anaesthesiology’s experience of implementing another type of checklist.The Food and Drug Administration Anesthesia Machine Pre-Use ChecklistThe earliest checklist used in healthcare to reduce adverse events is the anaesthesia equipment preuse checklist, developed in 1987 by the US Food and Drug Administration (FDA) in collaboration with the Anesthesia Patient Safety Foundation and the American Society of Anesthesiologists.31 After more than three decades of use, lessons learnt from the use of the FDA checklist parallel more recent experiences with SSCs, and are instructive to a more general understanding of the role of safety tools in healthcare (see table 1).View this table:Table 1 Lessons learnt from 30 years of personal experience with and reflection about the Anesthesia Equipment Pre-Use Checklist*A checklist alone is insufficient to achieve optimal resultsHospitals that get the best results from an SSC implementation are often well-resourced organisations that already have safety-oriented committed leadership, a strong safety culture, educated and engaged front-line clinicians and an established track record of successfully implementing other safety interventions.32 That said, any hospital, given adequate commitment, resources and expertise, can implement an SSC or other substantive safety intervention successfully. In doing so, it will educate and engage its workers, improve its safety culture and set the stage for further safety and quality improvements.A multimodal approach to safety interventions is more effective. Hospitals that were able to successfully implement all three components of the SSC saw greater reductions in postoperative complications.33 Similarly, the combination of the SSC with a complementary approach that more fully addresses preoperative and postoperative issues, the Surgical Patient Safety System, was associated with better postoperative outcomes than use of the WHO SSC alone.34 The most effective interventions are those that are based on an integrated conceptual framework and follow human factor principles, especially when the safety goals are multiple or diverse.35In our PACU handover improvement project mentioned earlier,27 the multimodal intervention produced a fourfold improvement in observed clinician behaviours (ie, conduct of actual handovers) that was sustained for at least 3 years after the intervention ceased.

The project began by getting perioperative leadership buy-in, conducting observations of the current handover process and engaging front-line clinicians in all phases of study development. The criteria for an ‘acceptable handover’ were chosen by an independent team of clinicians. Front-line clinicians first completed a multimedia introductory webinar that included key principles and a knowledge assessment.

To attend the 2-hour simulation training session, both anaesthesia professionals and PACU nurses were relieved from regular clinical duties (a strong message that this was an organisational priority). A custom patient-specific electronic form was available at every bedside in the PACU to reinforce the training during actual handovers. Performance feedback was provided to individuals, units and perioperative leadership.

The number of components needed for successful safety interventions will depend on the behaviour change desired, the existing safety culture, current experience and expertise of the intended end users and the priority articulated by organisational leaders. Regardless, design and implementation must be based on a solid conceptual framework, consider the full life-cycle of the intervention (from conceptualisation to obsolescence) and employ human factors engineering and implementation science principles and tools.13ConclusionChecklists and other safety tools are potentially valuable tools to advance perioperative safety. However, when used in isolation or implemented incorrectly, checklists have significant limitations.

Safety initiatives that take a systems-oriented multimodal approach to design and implementation can, with organisational leadership and determination, produce both targeted and more general safety improvement.Ethics statementsPatient consent for publicationNot required.Many patients admitted to hospital require venous access to infuse medications and fluids. The most commonly used device, the peripheral venous catheter, ranges from 2.5 to 4.5 cm in length, and is typically used for less than 5 days. The midline, a relatively newer peripheral venous catheter, is up to 20 cm in length, but does not reach the central veins, and may be used for up to 2 weeks.

A peripherally inserted central venous catheter (PICC) is a longer catheter that is placed in one of the arm veins and extends to reach the central veins. The PICC is used for longer periods of time compared with peripheral intravenous devices, and initially gained popularity as a convenient vascular access device used in the outpatient and home settings. Its premise has been to provide access that lasts for weeks, that is fairly safe and easily manageable.

Patients often require central venous access when hospitalised, with more than half of patients in intensive care, and up to 20% in those cared for in the non-intensive care wards.1 Common indications for PICC use in the acute care setting include the requirement for multiple and frequent infusions (eg, antibiotics, parenteral nutrition), the administration of medications incompatible with peripheral infusion, invasive haemodynamic monitoring in critically ill patients, very poor venous access and frequent need for blood draws.2 Specially trained healthcare workers place PICCs, often nurses from a vascular access team (VAT), or interventional radiologists. The VAT is comprised of skilled nurses, with either medical/surgical, emergency department or intensive care unit backgrounds. Contrary to other healthcare workers that place PICCs, the VAT’s primary function is to place PICCs, and optimise the infusion delivery, through a safe and effective process.

Its scope includes assessment for need, peripheral and central device insertion, monitoring of use and removal.3In their study of five hospitals within the Veterans Administration (VA) healthcare systems in the USA, Krein et al4 underscore the importance of a formal VAT to formulate and implement explicit appropriateness criteria, ensure timely insertion and safe management and direct patient education around PICC use. They found that team structures supporting line placement vary across hospitals from a dedicated team, to individual nurses trained in placement, to hospitals where only interventional radiologists insert PICCs. The presence of a VAT was associated with more defined criteria for PICC use, but a recurrent theme was inadequate interdisciplinary dialogue.

Although qualitative data were gathered at five VA hospitals only, the study’s findings reflect the variation in PICC placement and use, whether in academic or community, small or large hospitals.An important factor in variation in the approach to PICC line placement and management is the availability of resources and expertise at the hospital site. For example, if healthcare workers have suboptimal skills to place peripheral venous catheters, including midlines,5 clinicians may resort to ordering more PICCs unnecessarily to fill that void. Furthermore, as revealed in Krein’s study, a hospital that does not have the expertise to learn about alternative devices, such as those with lower risks and shorter dwell times (eg, midlines), may resort to using more PICCs than necessary.

Similarly, hospitals without clinicians skilled or comfortable placing other central lines6 may rely more on using PICCs. In addition, the lack of an available VAT to place PICCs using uasound guidance may result in more referrals to interventional radiology for placement, potentially exposing the patient to avoidable radiation during fluoroscopy.7We propose an approach to improve the appropriate and safe use of PICCs by focusing on three elements that address the findings by Krein and colleagues. Establishing a structure powered by a VAT.

Anchoring a standardised process for line selection, insertion and care. And promoting adoption by engagement with the key stakeholders.Establishing a structure to support placement and management of PICCs depends on whether the number of devices placed is enough to support the creation of a dedicated vascular access programme. Leadership plays a critical role to invest the resources for a functional VAT, understanding the financial and quality benefits associated.8 Not realising its value, hospital leaders may view the VAT as a non-revenue-generating service, putting it at risk when considering cost reduction strategies.

The value of the VAT expands from mitigating preventable events (eg, deep venous thrombosis, ) to enhancing patient experience (eg, less attempts to place a peripheral device).9 In addition, better outcomes help curb the financial risks (eg, hospital-acquired condition penalties)8 and improve hospital ratings. The VAT’s role encompasses placing PICCs and guaranteeing the proper selection of the intravascular device and its appropriate use.2The second element involves standardising processes for line selection and care, regardless of who is taking care of the device. Implementing policies to address indications, placement and maintenance and using standardised kits help minimise variation.

The creation of policies should be achieved through a multidisciplinary approach with VAT, nurses and physicians. The VAT can act as the ‘gate keeper’ evaluating whether the reason for PICC placement is aligned with indications. In addition, the VAT plays a critical role supporting nurses’ competencies for venous catheter use (eg, aseptic access and maintenance, addressing complications and mitigating risk)10 to reduce mechanical11 and infectious complications.12 The VAT performs regular rounds to mitigate process gaps (eg, dressing site intactness) and to identify complications (eg, PICC site erythema or drainage, arm swelling), and provides timely feedback on clinical performance.

The VAT can also serve as subject matter experts to the ordering physicians for the appropriate device type, based on vessel size and indications for use, how many lumens, site selection and a de-escalation plan for the patient prior to discharge. It also provides services should a device-related complication occur (eg, clotting), and works with clinicians to remedy the issue and salvage the device, thereby preventing a patient from losing their vascular access and/or having to replace it.The last element, and perhaps most significant, is to enhance the adoption of best practices through a partnership with the key stakeholders. PICC-associated outcomes are not only owned by the VAT, rather it is the responsibility of the clinicians, physicians and nurses to achieve those goals (table 1).

Physicians are an essential stakeholder group to engage as they are the ones responsible for ordering the PICC. An identified physician champion who partners and empowers the VAT will help resolve any barriers and be a liaison with the local physician community.13 The ideal physician champion should have the respect of peers, understand process optimisation and promote quality improvement. They need to be well versed on the appropriate indications for PICC use, the associated complications and risks and alternatives to the device.

The physician champion engages the leaders of the key disciplines responsible for requesting a PICC, educating them on the appropriate indications for use, the outcomes associated with PICC use, inviting them to be partners and responding to any of their concerns.View this table:Table 1 Disciplines and their support to mitigate PICC harmWhat about the key physician disciplines to engage?. Physicians can play an active role in enhancing PICC use through avoiding the unnecessary use of infusions. The consultation of infectious diseases specialists for intravenous antibiotic use appropriateness has been associated with less PICC use and lower complications.14 Similarly, having a surgeon support the decision for whether enteral or parenteral nutrition is needed will help reduce unnecessary device use.15 Disciplines like hospitalists or general internists care for a large number of patients and often order PICCs for venous access,16 while nephrologists may advocate avoiding the use of PICCs in the chronic kidney disease population in an effort for vein preservation.17 In hospitals with teaching programmes, the VAT and its physician champion may educate physicians in training on device choice, placement and duration of use, and address with their faculty competencies for line management.18 Engaging these disciplines, elucidating the indications for appropriate use and providing feedback and local data on the potential harm ensure accountability and further attention to PICC safety.In summary, the PICC is one of the primary solutions to achieve vascular access.

With up to one in five patients at risk for developing complications,19 it is incumbent on us to ensure that these devices are properly used and maintained. Identifying and overcoming system barriers are key to delivering sustainable safe outcomes. As a first step, clinical and administrative leaders, realising the financial and quality benefits, need to support the structure reflected by the VAT to enhance PICC care.

Second, the VAT must partner with disciplines (particularly nursing) to promote and ensure adequate competencies for placement and maintenance. Finally, clinical disciplines caring for the patient should instil a collaborative environment for better decision-making on when central access is required, and what device provides the safest and most effective delivery of care.Ethics statementsPatient consent for publicationNot required..

Patients are more likely to experience preventable harm during perioperative care than in any other type of healthcare encounter.1 2 For several decades, a hallmark of surgical quality and safety has kamagra for sale been the use of checklists to prevent errors (eg, wrong site surgery) and assure that key tasks have been or will be performed. The most widely used approach globally is the Surgical Safety Checklist (SSC) recommended by the WHO.3 It is divided into preinduction (or sign in, consisting of seven items performed by anaesthesia and nursing), preincision (timeout, 10 items performed by the entire team) and postsurgery (sign out, five items by the entire team).4 5 Most hospitals in the developed world perform the SSC or an equivalent timeout prior to surgical incision kamagra for sale. However, preinduction briefings, and postcase debriefings in particular, are much less commonly performed.6 7There are widely disseminated arguments recommending the use of checklists in healthcare8 but also recognised limitations.9 Checklist-based preincision timeouts appear to improve surgical outcomes in many settings,4 5 yet, in other hospitals, the introduction of the SSC failed to improve outcomes.10 Like all tools or processes intended to improve safety, ineffective implementation will reduce the desired benefits. For example, there is appreciable evidence showing that surgical teams skip or do not meaningfully respond to timeout checklist items.11 12 Even with a robust implementation, effectiveness can be weakened by contextual factors, failure of leadership or deficient safety culture.Despite numerous studies, gaps in the evidence kamagra for sale to guide optimal checklist use persist. For example, we do not know whether checklist-based timeouts only decrease the occurrence of the undesirable events targeted by the checklist or, as many hypothesise, whether their use also facilitates teamwork and interprofessional communication.

Although there is kamagra for sale increasing guidance on how to optimally implement checklists at the local level, many questions remain.13 Moreover, we still do not understand the circumstances in which checklist use facilitates the detection, reporting and correction of errors.In this issue of the journal, Muensterer and colleagues14 describe a clever study in which the attending surgeon intentionally introduced errors during the preincision timeout while a medical student in the operating theatre surreptitiously noted whether the error was detected and reported by one or more members of the surgical team. If the error was not verbalised, the attending surgeon corrected the error before the timeout was complete. The single error embedded in each of 120 of 1800 paediatric operations was randomly kamagra for sale chosen from among wrong patient name, age, gender, allergy or surgical procedure, side or site. Overall, only about half (65. 54%) of all errors were detected and reported by a team member kamagra for sale prior to surgeon correction.

Of these, errors were most commonly reported by the anaesthesiologist (64%) and almost never by residents in training (6%) or medical students (1%).This study also has important limitations. Because the investigators were leading the timeouts as part of a research study, adherence to kamagra for sale all of the checklist items was reportedly 100%. Yet, few organisations consistently attain timeout adherence above 90%.11 Since you are less likely to catch an error if you do not address that item during the timeout, in institutions with lower adherence, the proportion of missed errors may be even higher.The authors, with input from their institutional review board, designed the study to be feasible and compliant with established human subjects protection principles. As such, the attending surgeon always corrected the error after the kamagra for sale anaesthesiologist’s component of the timeout but before the nurses’ component. By excluding the part of the timeout when the nurses address their checklist items (eg, instruments are sterile,) followed by a final opportunity as the timeout ends to note any errors or concerns, the study may have underestimated the rate of error reporting.Because the study did not query team members individually after the timeout, we also do not know how many errors were detected but not annunciated.

For example, recognised errors that kamagra for sale were attributed to ‘misspeaking’ and/or had no clinical significance may not have been verbally challenged. Moreover, as is discussed by the authors, there was an unequivocal hierarchy effect—individuals with the least ‘power’ (ie, low in hierarchy within the current healthcare culture) were the least likely to report the error.This study highlights two important safety relevant questions on which I will elaborate. First, why and how kamagra for sale should we change healthcare culture to facilitate ‘speaking up’?. Second, how can we best design and implement checklists and other safety interventions to yield more consistent and sustained clinician behaviour change?. The continued problem of hierarchical culture in healthcareThe significant influence of hierarchy on the incidence of error reporting in Muensterer et al’s14 study is consistent with substantial prior evidence that lower hierarchy clinical providers are less likely to ‘speak up’, even when they are aware of major safety violations.15–17Failure of a subordinate copilot to challenge or speak up to the captain in the 1977 Tenerife disaster was kamagra for sale the impetus for the aviation industry’s adoption of crew resource management (CRM).

Healthcare team-training initiatives like the Agency for Healthcare Research and Quality’s TeamSTEPPS now include tools such as the ‘two-challenge rule’ and emphasise speaking up.18 Flattened hierarchies and reliance on expertise rather than seniority, especially during crisis or stress, are an integral component of high-reliability organisations. In contrast, the persistent hierarchical culture of healthcare is anathema to positive safety attitudes and kamagra for sale behaviours. This is particularly problematic in operating theatres where surgeons view themselves as ‘captain of the ship’ and where uncivil behaviour is tolerated.19 The insidious effects of hierarchy will impair effectiveness of checklist use and predispose to safety issues in all aspects of routine and emergency care.20 While team-oriented training designed to enhance the ability of lower hierarchy clinicians to ‘speak up’ can be effective,21 22 evidence to guide the design and implementation of these interventions is still sparse. Single training exposures have generally had limited effects,17 23 in part likely due to inadequate ‘potency’ to achieve the desired effect24 in a clinical environment contaminated by the hierarchical culture and in part because most interventions have focused on ‘assertiveness’ training for kamagra for sale the less powerful members of the team rather than, or in addition to, sensitivity or receptivity training of the most powerful (eg, surgical attendings).17Discussions of power hierarchy to date have largely focused on clinicians’ professional roles (ie, nurse vs physician) and level of experience (eg, resident vs attending). Even with two attending physicians, for example, a surgeon and anaesthesiologist, power dynamics can degrade communication and decrease team performance.

In a multicentre kamagra for sale study of experienced anaesthesiologists managing simulated crisis events, the anaesthesiologists’ failure to challenge the surgeon to initiate life-saving interventions (eg, to open the abdomen in the presence of an enlarging retroperitoneal haematoma during laparoscopic surgery, or to halt surgery to cardiovert an unstable patient) was associated with lower overall scenario performance scores as determined by trained blinded anaesthesiologist video raters.25In fact, hierarchy is much more complex and this may explain in part the variable and generally weak results seen in ‘speaking up’ intervention studies to date. When considering hierarchical effects on communication assertiveness, one must also consider individual characteristics including gender, race/ethnicity, language, personal cultural background and personality, as well as the personality of those in higher power roles, microclimate factors of the team and care unit, and overall organisational culture.17 22 An interesting direction for future study is the facilitation of more positive communication (eg, expressions of gratitude or encouragement).26In a single-site intervention study to improve the quality of handovers from anaesthesia professionals to postanaesthesia care unit (PACU) nurses,27 simulation-based training emphasised specific dyadic communication behaviours—assertiveness for the nurses when their needs were not being met and ‘sensitivity’ (or receptiveness) for the anaesthesia professionals when the nurses raised concerns. In poststudy kamagra for sale interviews, this behavioural focus was considered an important contributor to the resulting sustained improvement in the quality of actual handovers. As part of this study, we explicitly taught participants to CUSS. CUSS is a graduated approach to facilitate speaking up kamagra for sale.

The acronym stands for ‘I’m Concerned’, ‘I’m Uncomfortable’, ‘This is a Safety issue’ and ‘Stop!. €™. The intended learners were taught these ‘triggers’ for eliciting desired behaviours (ie, to stop what they are doing and have a conversation with the initiator) and this approach creates an environment where the initiating individual can receive support from others who overhear the conversation—‘Doctor, I hear that Maria is CUSSing at you?. How can I help to resolve this situation?. €™ Such a graded assertiveness approach to ‘stop the line’, developed in other industries, is increasingly being used throughout healthcare.28Designing and implementing more effective safety tools and processesSSCs are just one tool used to advance overall perioperative system safety.

Similarly, in commercial aviation, checklists are one tool used as part of CRM to assure operational safety. CRM is a philosophy or construct that includes explicit values and principles, procedures supported by purpose-designed checklists and other tools, and regularly scheduled mandatory simulation-based training and assessment that together contribute to an existing safety culture in pilots and across the organisation.29 CRM and most of the existing aviation safety system were iteratively designed by pilots (the front-line workers) in collaboration with other stakeholders (including regulators). Healthcare must employ similar human-centred design approaches to re-engineer our safety systems.For commercial aviation to be completely safe, no planes would fly. Similarly, safety will never be the foremost system objective in healthcare. The primary goal is to efficiently deliver cost-effective care.

Instead, in any high-consequence industry, safety is a desirable by-product (an ‘emergent feature’) of a system designed to achieve primary operational goals. In healthcare, sick patients must be treated and there is inherent risk in doing so.30 Achieving societally acceptable levels of safety will stem from a deliberately designed system founded on a strong safety culture and truly committed leadership.With this as background, it is not surprising that so many hospitals struggle to garner reliable and sustained benefit from the use of checklists and other safety tools. To understand what is required, I would like to draw parallels with anaesthesiology’s experience of implementing another type of checklist.The Food and Drug Administration Anesthesia Machine Pre-Use ChecklistThe earliest checklist used in healthcare to reduce adverse events is the anaesthesia equipment preuse checklist, developed in 1987 by the US Food and Drug Administration (FDA) in collaboration with the Anesthesia Patient Safety Foundation and the American Society of Anesthesiologists.31 After more than three decades of use, lessons learnt from the use of the FDA checklist parallel more recent experiences with SSCs, and are instructive to a more general understanding of the role of safety tools in healthcare (see table 1).View this table:Table 1 Lessons learnt from 30 years of personal experience with and reflection about the Anesthesia Equipment Pre-Use Checklist*A checklist alone is insufficient to achieve optimal resultsHospitals that get the best results from an SSC implementation are often well-resourced organisations that already have safety-oriented committed leadership, a strong safety culture, educated and engaged front-line clinicians and an established track record of successfully implementing other safety interventions.32 That said, any hospital, given adequate commitment, resources and expertise, can implement an SSC or other substantive safety intervention successfully. In doing so, it will educate and engage its workers, improve its safety culture and set the stage for further safety and quality improvements.A multimodal approach to safety interventions is more effective. Hospitals that were able to successfully implement all three components of the SSC saw greater reductions in postoperative complications.33 Similarly, the combination of the SSC with a complementary approach that more fully addresses preoperative and postoperative issues, the Surgical Patient Safety System, was associated with better postoperative outcomes than use of the WHO SSC alone.34 The most effective interventions are those that are based on an integrated conceptual framework and follow human factor principles, especially when the safety goals are multiple or diverse.35In our PACU handover improvement project mentioned earlier,27 the multimodal intervention produced a fourfold improvement in observed clinician behaviours (ie, conduct of actual handovers) that was sustained for at least 3 years after the intervention ceased.

The project began by getting perioperative leadership buy-in, conducting observations of the current handover process and engaging front-line clinicians in all phases of study development. The criteria for an ‘acceptable handover’ were chosen by an independent team of clinicians. Front-line clinicians first completed a multimedia introductory webinar that included key principles and a knowledge assessment. To attend the 2-hour simulation training session, both anaesthesia professionals and PACU nurses were relieved from regular clinical duties (a strong message that this was an organisational priority). A custom patient-specific electronic form was available at every bedside in the PACU to reinforce the training during actual handovers.

Performance feedback was provided to individuals, units and perioperative leadership. The number of components needed for successful safety interventions will depend on the behaviour change desired, the existing safety culture, current experience and expertise of the intended end users and the priority articulated by organisational leaders. Regardless, design and implementation must be based on a solid conceptual framework, consider the full life-cycle of the intervention (from conceptualisation to obsolescence) and employ human factors engineering and implementation science principles and tools.13ConclusionChecklists and other safety tools are potentially valuable tools to advance perioperative safety. However, when used in isolation or implemented incorrectly, checklists have significant limitations. Safety initiatives that take a systems-oriented multimodal approach to design and implementation can, with organisational leadership and determination, produce both targeted and more general safety improvement.Ethics statementsPatient consent for publicationNot required.Many patients admitted to hospital require venous access to infuse medications and fluids.

The most commonly used device, the peripheral venous catheter, ranges from 2.5 to 4.5 cm in length, and is typically used for less than 5 days. The midline, a relatively newer peripheral venous catheter, is up to 20 cm in length, but does not reach the central veins, and may be used for up to 2 weeks. A peripherally inserted central venous catheter (PICC) is a longer catheter that is placed in one of the arm veins and extends to reach the central veins. The PICC is used for longer periods of time compared with peripheral intravenous devices, and initially gained popularity as a convenient vascular access device used in the outpatient and home settings. Its premise has been to provide access that lasts for weeks, that is fairly safe and easily manageable.

Patients often require central venous access when hospitalised, with more than half of patients in intensive care, and up to 20% in those cared for in the non-intensive care wards.1 Common indications for PICC use in the acute care setting include the requirement for multiple and frequent infusions (eg, antibiotics, parenteral nutrition), the administration of medications incompatible with peripheral infusion, invasive haemodynamic monitoring in critically ill patients, very poor venous access and frequent need for blood draws.2 Specially trained healthcare workers place PICCs, often nurses from a vascular access team (VAT), or interventional radiologists. The VAT is comprised of skilled nurses, with either medical/surgical, emergency department or intensive care unit backgrounds. Contrary to other healthcare workers that place PICCs, the VAT’s primary function is to place PICCs, and optimise the infusion delivery, through a safe and effective process. Its scope includes assessment for need, peripheral and central device insertion, monitoring of use and removal.3In their study of five hospitals within the Veterans Administration (VA) healthcare systems in the USA, Krein et al4 underscore the importance of a formal VAT to formulate and implement explicit appropriateness criteria, ensure timely insertion and safe management and direct patient education around PICC use. They found that team structures supporting line placement vary across hospitals from a dedicated team, to individual nurses trained in placement, to hospitals where only interventional radiologists insert PICCs.

The presence of a VAT was associated with more defined criteria for PICC use, but a recurrent theme was inadequate interdisciplinary dialogue. Although qualitative data were gathered at five VA hospitals only, the study’s findings reflect the variation in PICC placement and use, whether in academic or community, small or large hospitals.An important factor in variation in the approach to PICC line placement and management is the availability of resources and expertise at the hospital site. For example, if healthcare workers have suboptimal skills to place peripheral venous catheters, including midlines,5 clinicians may resort to ordering more PICCs unnecessarily to fill that void. Furthermore, as revealed in Krein’s study, a hospital that does not have the expertise to learn about alternative devices, such as those with lower risks and shorter dwell times (eg, midlines), may resort to using more PICCs than necessary. Similarly, hospitals without clinicians skilled or comfortable placing other central lines6 may rely more on using PICCs.

In addition, the lack of an available VAT to place PICCs using uasound guidance may result in more referrals to interventional radiology for placement, potentially exposing the patient to avoidable radiation during fluoroscopy.7We propose an approach to improve the appropriate and safe use of PICCs by focusing on three elements that address the findings by Krein and colleagues. Establishing a structure powered by a VAT. Anchoring a standardised process for line selection, insertion and care. And promoting adoption by engagement with the key stakeholders.Establishing a structure to support placement and management of PICCs depends on whether the number of devices placed is enough to support the creation of a dedicated vascular access programme. Leadership plays a critical role to invest the resources for a functional VAT, understanding the financial and quality benefits associated.8 Not realising its value, hospital leaders may view the VAT as a non-revenue-generating service, putting it at risk when considering cost reduction strategies.

The value of the VAT expands from mitigating preventable events (eg, deep venous thrombosis, ) to enhancing patient experience (eg, less attempts to place a peripheral device).9 In addition, better outcomes help curb the financial risks (eg, hospital-acquired condition penalties)8 and improve hospital ratings. The VAT’s role encompasses placing PICCs and guaranteeing the proper selection of the intravascular device and its appropriate use.2The second element involves standardising processes for line selection and care, regardless of who is taking care of the device. Implementing policies to address indications, placement and maintenance and using standardised kits help minimise variation. The creation of policies should be achieved through a multidisciplinary approach with VAT, nurses and physicians. The VAT can act as the ‘gate keeper’ evaluating whether the reason for PICC placement is aligned with indications.

In addition, the VAT plays a critical role supporting nurses’ competencies for venous catheter use (eg, aseptic access and maintenance, addressing complications and mitigating risk)10 to reduce mechanical11 and infectious complications.12 The VAT performs regular rounds to mitigate process gaps (eg, dressing site intactness) and to identify complications (eg, PICC site erythema or drainage, arm swelling), and provides timely feedback on clinical performance. The VAT can also serve as subject matter experts to the ordering physicians for the appropriate device type, based on vessel size and indications for use, how many lumens, site selection and a de-escalation plan for the patient prior to discharge. It also provides services should a device-related complication occur (eg, clotting), and works with clinicians to remedy the issue and salvage the device, thereby preventing a patient from losing their vascular access and/or having to replace it.The last element, and perhaps most significant, is to enhance the adoption of best practices through a partnership with the key stakeholders. PICC-associated outcomes are not only owned by the VAT, rather it is the responsibility of the clinicians, physicians and nurses to achieve those goals (table 1). Physicians are an essential stakeholder group to engage as they are the ones responsible for ordering the PICC.

An identified physician champion who partners and empowers the VAT will help resolve any barriers and be a liaison with the local physician community.13 The ideal physician champion should have the respect of peers, understand process optimisation and promote quality improvement. They need to be well versed on the appropriate indications for PICC use, the associated complications and risks and alternatives to the device. The physician champion engages the leaders of the key disciplines responsible for requesting a PICC, educating them on the appropriate indications for use, the outcomes associated with PICC use, inviting them to be partners and responding to any of their concerns.View this table:Table 1 Disciplines and their support to mitigate PICC harmWhat about the key physician disciplines to engage?. Physicians can play an active role in enhancing PICC use through avoiding the unnecessary use of infusions. The consultation of infectious diseases specialists for intravenous antibiotic use appropriateness has been associated with less PICC use and lower complications.14 Similarly, having a surgeon support the decision for whether enteral or parenteral nutrition is needed will help reduce unnecessary device use.15 Disciplines like hospitalists or general internists care for a large number of patients and often order PICCs for venous access,16 while nephrologists may advocate avoiding the use of PICCs in the chronic kidney disease population in an effort for vein preservation.17 In hospitals with teaching programmes, the VAT and its physician champion may educate physicians in training on device choice, placement and duration of use, and address with their faculty competencies for line management.18 Engaging these disciplines, elucidating the indications for appropriate use and providing feedback and local data on the potential harm ensure accountability and further attention to PICC safety.In summary, the PICC is one of the primary solutions to achieve vascular access.

With up to one in five patients at risk for developing complications,19 it is incumbent on us to ensure that these devices are properly used and maintained. Identifying and overcoming system barriers are key to delivering sustainable safe outcomes. As a first step, clinical and administrative leaders, realising the financial and quality benefits, need to support the structure reflected by the VAT to enhance PICC care. Second, the VAT must partner with disciplines (particularly nursing) to promote and ensure adequate competencies for placement and maintenance. Finally, clinical disciplines caring for the patient should instil a collaborative environment for better decision-making on when central access is required, and what device provides the safest and most effective delivery of care.Ethics statementsPatient consent for publicationNot required..

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E/e′, mitral E wave max/average diastolic tissue Doppler velocity from the septal and http://joehuser.com/buy-kamagra-now/ lateral kamagra oral jelly ingredients annulus. ICC, intraclass correlation coefficient. NT-proBNP, N-terminal pro-B-type natriuretic peptide." data-icon-position data-hide-link-title="0">Figure 1 Reproducibility, validity and time efficiency of the index-beat approach for E/e′. Comparison of the index-beat method verses averaging of 5 and 10 consecutive beats kamagra oral jelly ingredients for.

(1) reproducibility (ICC and 95% CI for within-beat, intraoperator and interoperator variability). (2) validity (beta coefficient for NT-proBNP with 95% CI). And (3) time taken to kamagra oral jelly ingredients measure E/e′ (mean seconds, with 95% CI). E/e′, mitral E wave max/average diastolic tissue Doppler velocity from the septal and lateral annulus.

ICC, intraclass correlation coefficient. NT-proBNP, N-terminal pro-B-type natriuretic peptide.Minners and Jander4 comment that this data convincingly shows that kamagra oral jelly ingredients the index-beat approach is more reproducible and quicker than averaging several consecutive beats. However, they caution that ventricular function may be underestimated if the index beat is not representative of overall heart rate. On the other hand, ‘In clinical practice, the vast majority of echocardiography departments (including our own) assesses a ‘typical’ or representative beat whereby the echocardiographer chooses a single beat considered characteristic of the patient’s haemodynamic situation.’ ‘Further work, such as the one presented by Bunting et al3 is clearly required to improve parameters of reproducibility, validity, as well as clinical applicability and relevance in our commitment to optimise care in patients with AF and heart failure.’Balloon aortic valvuloplasty (BAV) continues to be performed in a small subset of patients, particularly those who require stabilisation prior to transcatheter aortic valve implantation (TAVI).

Tumscitz and colleagues5 report the safety, efficacy and impact of frailty on outcomes after BAV using a minimally invasive radial artery approach kamagra oral jelly ingredients (figure 2). The essential frailty toolset (EFT) provides a composite score from 0 to 5 based a chair test, cognition, haemoglobin and albumin. An EFT score of three or higher is associated with increased mortality.Cumulative survival of patients bridged to TAVI stratified according to EFT baseline and 1-month values. EFT, essential kamagra oral jelly ingredients frailty toolset.

TAVI, transcatheter aortic valve replacement." data-icon-position data-hide-link-title="0">Figure 2 Cumulative survival of patients bridged to TAVI stratified according to EFT baseline and 1-month values. EFT, essential frailty toolset. TAVI, transcatheter aortic valve kamagra oral jelly ingredients replacement.Commenting on this study, Bongiovanni and Presbitero6 raise the question of whether BAV still has a place in the TAVI era. Their answer is.

€˜Certainly, it will be an important procedure in different settings. First, to evaluate the clinical impact of transvalvular gradient reduction in patients with kamagra oral jelly ingredients reduced ejection fraction and unclear functional reserve before definitive TAVI therapy. Second, to allow urgent major surgery in severely ill patients with unclear prognosis. Third, as a bridge to decision or to definitive surgical or percutaneous treatment in countries with limited technologies and budget.’The Education in Heart article in this issue summarises the approach to anti-thrombotic therapy in patients with chronic coronary syndromes.7 Key steps in the rather complex decision-making process are the presence of atrial fibrillation.

Prior myocardial infarction, revascularisation or definite coronary kamagra oral jelly ingredients artery disease on imaging. Bleeding risk. And ischaemic risk (figure 3).Decision algorithm summarising the approach to determining an optimum regimen of antithrombotic regimen suggested in the ESC 2019 CCS guidelines. APT, antiplatelet kamagra oral jelly ingredients therapy.

BD, twice daily. CAD, coronary artery disease. CCS, chronic coronary syndrome. CrCl, creatinine kamagra oral jelly ingredients clearance.

DAPT, dual antiplatelet therapy. DATT low-dose dual antithrombotic therapy. ESC, European Society of Cardiology kamagra oral jelly ingredients. HF, heart failure.

MI, myocardial infarction. NOAC, non-vitamin K antagonist oral kamagra oral jelly ingredients anticoagulant. OAC, oral anticoagulant. OD, once daily.

PAD, peripheral artery kamagra oral jelly ingredients disease. PCI, percutaneous coronary intervention. SAPT, single antiplatelet therapy. TIA, transient ischaemic attack kamagra oral jelly ingredients.

VKA, vitamin K antagonist." data-icon-position data-hide-link-title="0">Figure 3 Decision algorithm summarising the approach to determining an optimum regimen of antithrombotic regimen suggested in the ESC 2019 CCS guidelines. APT, antiplatelet therapy. BD, twice kamagra oral jelly ingredients daily. CAD, coronary artery disease.

CCS, chronic coronary syndrome. CrCl, creatinine kamagra oral jelly ingredients clearance. DAPT, dual antiplatelet therapy. DATT low-dose dual antithrombotic therapy.

ESC, European Society of kamagra oral jelly ingredients Cardiology. HF, heart failure. MI, myocardial infarction. NOAC, non-vitamin K antagonist oral anticoagulant kamagra oral jelly ingredients.

OAC, oral anticoagulant. OD, once daily. PAD, peripheral artery disease.

In addition, sexism limited opportunities for professional advancement in 33% of female cardiologists compared to 2% of male cardiologists.In the accompanying editorial, Babu-Narayan and Ray2 discuss the perceived and actual barriers to improved representation of women in kamagra for sale cardiology. €˜There is no doubt that cardiology requires drive, dedication and commitment, but these should not be conflated with a requirement for excessively long working hours, ‘presenteeism’ and the exclusion of outside interests and family life either for men or for women.’ Underrepresentation of women does matter. €˜Lack of diversity of the leadership stifles creativity and innovation and gender inequality may help sexism or sexual harassment go unchallenged. Missing out on talent could cost lives.’ As they conclude ‘Effective strategies proven to mitigate the unwanted effects of gender or other stereotypes kamagra for sale on women or men in cardiology are needed.

These must address structural barriers to entry, to pay and to career progression in cardiology including in academic cardiology, and may include continued and robust analysis of gender-related and intersectional pay disparity, transparency of metrics for and access to promotion, fair performance evaluation for assessment for additional renumeration, investment in childcare, centralised budgets for parental leave and incentives to existing leaders to address the imbalance. Sexism and sexual harassment by women or men are no more acceptable in cardiology than anywhere else and must no longer be tolerated.’Heart failure (HF) is present or will develop in up to 50% of patients with atrial fibrillation (AF). However, the echocardiographic diagnosis of HF in patients with AF is complicated by kamagra for sale the beat-to-beat variability in measures of ventricular function with an irregular heart rhythm. In a series of 160 patients with AF, Bunting and colleagues3 found that measurements of LV function based on a single index beat improved reproducibility and saved time compared to averaging 5–10 consecutive beats, with no effect on validity compared to natriuretic peptide levels (figure 1).

The index beat approach is simply to measure a single cardiac cycle that follows two preceding R–R intervals of similar duration.Reproducibility, validity and time efficiency of the index-beat approach for E/e′. Comparison of the index-beat method verses averaging of 5 kamagra for sale and 10 consecutive beats for. (1) reproducibility (ICC and 95% CI for within-beat, intraoperator and interoperator variability). (2) validity (beta coefficient for NT-proBNP with 95% CI).

And (3) time taken to kamagra for sale measure E/e′ (mean seconds, with 95% CI). E/e′, mitral E wave max/average diastolic tissue Doppler velocity from the septal and lateral annulus. ICC, intraclass correlation coefficient. NT-proBNP, N-terminal pro-B-type natriuretic peptide." data-icon-position data-hide-link-title="0">Figure 1 Reproducibility, validity and kamagra for sale time efficiency of the index-beat approach for E/e′.

Comparison of the index-beat method verses averaging of 5 and 10 consecutive beats for. (1) reproducibility (ICC and 95% CI for within-beat, intraoperator and interoperator variability). (2) validity kamagra for sale (beta coefficient for NT-proBNP with 95% CI). And (3) time taken to measure E/e′ (mean seconds, with 95% CI).

E/e′, mitral E wave max/average diastolic tissue Doppler velocity from the septal and lateral annulus. ICC, intraclass correlation coefficient kamagra for sale. NT-proBNP, N-terminal pro-B-type natriuretic peptide.Minners and Jander4 comment that this data convincingly shows that the index-beat approach is more reproducible and quicker than averaging several consecutive beats. However, they caution that ventricular function may be underestimated if the index beat is not representative of overall heart rate.

On the other hand, ‘In clinical practice, the vast majority of echocardiography departments (including our own) assesses a ‘typical’ or representative beat whereby the echocardiographer chooses a single beat considered characteristic of the patient’s haemodynamic situation.’ ‘Further work, such as the one presented by kamagra for sale Bunting et al3 is clearly required to improve parameters of reproducibility, validity, as well as clinical applicability and relevance in our commitment to optimise care in patients with AF and heart failure.’Balloon aortic valvuloplasty (BAV) continues to be performed in a small subset of patients, particularly those who require stabilisation prior to transcatheter aortic valve implantation (TAVI). Tumscitz and colleagues5 report the safety, efficacy and impact of frailty on outcomes after BAV using a minimally invasive radial artery approach (figure 2). The essential frailty toolset (EFT) provides a composite score from 0 to 5 based a chair test, cognition, haemoglobin and albumin. An EFT score of three or higher is associated with increased mortality.Cumulative survival of patients bridged to TAVI stratified according kamagra for sale to EFT baseline and 1-month values.

EFT, essential frailty toolset. TAVI, transcatheter aortic valve replacement." data-icon-position data-hide-link-title="0">Figure 2 Cumulative survival of patients bridged to TAVI stratified according to EFT baseline and 1-month values. EFT, essential frailty toolset. TAVI, transcatheter aortic valve replacement.Commenting on this study, Bongiovanni and Presbitero6 raise the question of whether BAV kamagra for sale still has a place in the TAVI era.

Their answer is. €˜Certainly, it will be an important procedure in different settings. First, to evaluate the clinical impact of transvalvular kamagra for sale gradient reduction in patients with reduced ejection fraction and unclear functional reserve before definitive TAVI therapy. Second, to allow urgent major surgery in severely ill patients with unclear prognosis.

Third, as a bridge to decision or to definitive surgical or percutaneous treatment in countries with limited technologies and budget.’The Education in Heart article in this issue summarises the approach to anti-thrombotic therapy in patients with chronic coronary syndromes.7 Key steps in the rather complex decision-making process are the presence of atrial fibrillation. Prior myocardial kamagra for sale infarction, revascularisation or definite coronary artery disease on imaging. Bleeding risk. And ischaemic risk (figure 3).Decision algorithm summarising the approach to determining an optimum regimen of antithrombotic regimen suggested in the ESC 2019 CCS guidelines.

APT, antiplatelet kamagra for sale therapy. BD, twice daily. CAD, coronary artery disease. CCS, chronic kamagra for sale coronary syndrome.

CrCl, creatinine clearance. DAPT, dual antiplatelet therapy. DATT low-dose dual antithrombotic therapy kamagra for sale. ESC, European Society of Cardiology.

HF, heart failure. MI, myocardial infarction kamagra for sale. NOAC, non-vitamin K antagonist oral anticoagulant. OAC, oral anticoagulant.

OD, once daily kamagra for sale. PAD, peripheral artery disease. PCI, percutaneous coronary intervention. SAPT, single kamagra for sale antiplatelet therapy.

TIA, transient ischaemic attack. VKA, vitamin K antagonist." data-icon-position data-hide-link-title="0">Figure 3 Decision algorithm summarising the approach to determining an optimum regimen of antithrombotic regimen suggested in the ESC 2019 CCS guidelines. APT, antiplatelet therapy.

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A key consideration in timing of aortic valve replacement (AVR) for patients with aortic stenosis (AS) is whether there is an increased risk of sudden cardiac death (SCD) that might be is kamagra good reduced by relief of outflow obstruction. Minners and colleagues1 addressed this issue in a retrospective analysis of outcomes in 1840 patients with mild to moderate AS (aortic maximum velocity 2.5–4.0 m/s) is kamagra good in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Overall the annualised rate of SCD was 0.39% per year with 27 events in asymptomatic patients. The most is kamagra good recent echocardiogram prior to SCD showed mild–moderate AS in most (80%) of these patients with no difference in SCD event rates in those who progressed to severe AS compared to those who did not develop severe valve obstruction.

On Cox regression analysis, the only independent risk factors for SCD were age (HR 1.06, 95% CI 1.01 to 1.11 per year, p=0.02), increased left ventricular mass index (HR 1.20, 95% CI 1.10 to 1.32 per 10 g/m2, p<0.001) and lower body mass index (HR 0.87, 95% CI 0.79 to 0.97 per kg/m2, is kamagra good p=0.01) but not the severity of valve obstruction (figure 1).Univariate (top) and multivariate (bottom) Cox regression analyses for SCD during 46.1±14.6 months of follow-up in the Simvastatin and Ezetimibe in Aortic Stenosis study. The number of events for each variable is reflected by the dark, horizontal bars with separation at the median for continuous variables. A forest plot visualisation of HRs for SCD is provided on is kamagra good the right. LVED, left ventricular enddiastolic is kamagra good diameter.

LVES, left ventricular endsystolic diameter. LVM, left ventricular mass is kamagra good. SCD, sudden cardiac death." data-icon-position data-hide-link-title="0">Figure 1 Univariate (top) and multivariate (bottom) Cox regression analyses for SCD during 46.1±14.6 months of follow-up in the Simvastatin and is kamagra good Ezetimibe in Aortic Stenosis study. The number of events for each variable is reflected by the dark, horizontal bars with separation at the median for continuous variables.

A forest plot visualisation of HRs for SCD is provided on is kamagra good the right. LVED, left ventricular enddiastolic diameter. LVES, left ventricular endsystolic is kamagra good diameter. LVM, left ventricular is kamagra good mass.

SCD, sudden cardiac death.The lack of association between AS severity and the risk of SCD in the SEAS study is thought-provoking and challenges the conventional wisdom that early AVR would prevent SCD in asymptomatic patients with AS.2 In the past, syncope and SCD in patients with AS were thought to be due to mechanisms such as left ventricle (LV) baroreceptor malfunction, hypotension secondary to peripheral vasodilation in the face of fixed valve obstruction, or a shortened diastolic filling interval at high heart rates leading to a reduced stroke volume. However, it is doubtful that any of these mechanisms would is kamagra good account for SCD when AS is only mild to moderate in severity. €˜It is increasingly recognised is kamagra good that that AS is not simply a mechanical problem of the valve leaflets not opening fully. Instead, AS compromises a complex interplay between the valve, ventricle and vasculature with abnormal function of all three components of the disease process.’ As I conclude in an editorial, ‘It is unlikely that early AVR will reduce the risk of sudden death when severe valve obstruction is not present.

Perhaps it is time to turn our attention to mitigating the non-valvular disease processes in adults with calcific valve disease.’In another interesting paper in this issue of Heart, Williams and Brown3 hypothesised that the apparent benefit of fractional flow reserve (FFR) guidance of percutaneous coronary intervention (PCI) in patients with chronic coronary syndromes (CCS) might simply be due to utilisation of fewer stents rather than to knowledge about the physiological severity of the is kamagra good coronary lesions. In a Monte Carlo simulation using data from the PCI strata of the Bypass Angioplasty Revascularization Investigation 2 Diabetes study, random deferral of PCI progressively reduced the risk of death and myocardial infarction at 1 year, suggesting that FFR-guided deferral of PCI improves outcomes simply because fewer stents are placed.In an editorial, Weintraub and Boden4 put this data into the context of 30 years of clinical trials comparing PCI with optimal medical therapy from CCS and conclude ‘In contrast to patients with acute coronary syndrome, there remains no convincing evidence that PCI will prevent events in patients with stable angina and chronic ischaemic is kamagra good heart disease. We know that, if needed, PCI will ameliorate severe angina, but we also know that this may not be a durable effect. By contrast, for the great majority of patients who are is kamagra good not disabled by angina, PCI can be safely deferred in both diabetic and non-diabetic patients, with revascularisation reserved only for those with unacceptable angina or who develop an acute coronary syndrome during follow-up.

The role of FFR remains uncertain at best and need not be performed routinely in all patients with CCS, though it may is kamagra good be useful where the visual estimation of angiographical severity is uncertain.’Cardiac involvement in patients with sepsis contributes to adverse outcomes with most previous studies focusing on left ventricular dysfunction. In order to assess the impact of right ventricular involvement on outcomes in sepsis Kim and colleagues5 performed a retrospective cohort study of 778 patients with septic shock with echocardiographic imaging. Sepsis-induced cardiac dysfunction was present in 34.7% is kamagra good of the entire cohort, affecting the LV in 67.3% and the right ventricle (RV) in 40.7% of these patients. Any type of sepsis-induced cardiac dysfunction was associated with a significantly higher 28-day mortality (35.9 vs 26.8%.

P<0.01), longer intensive care unit length of stay and longer duration is kamagra good of mechanical ventilator, compared with those without cardiac dysfunction. Isolated RV dysfunction was rare (24/270, 8.9%) but was associated with a higher risk of is kamagra good 28-day mortality (adjusted OR 2.77, 95% CI 1.20 to 6.40, p=0.02) (figure 2).Comparisons of survival curves between each type of dysfunction. LV, left ventricle. RV, right ventricle." data-icon-position data-hide-link-title="0">Figure 2 is kamagra good Comparisons of survival curves between each type of dysfunction.

LV, left is kamagra good ventricle. RV, right ventricle.The mechanisms of cardiac dysfunction in patients with sepsis are summarised in an editorial by Dugar and Vallabhajosyula6 (figure 3). They also point out the challenges in understanding cardiac involvement in patients with sepsis including the effect of timing of imaging on detection, is kamagra good difficulties in measuring RV systolic performance, and differing definitions of RV dysfunction. They conclude is kamagra good.

€˜there is a crucial need to understand the how to identify RV dysfunction in sepsis and the causative mechanisms associated with higher mortality in this population, which will significantly influence how we prevent and manage this disease process.’Mechanism of RV dysfunction associated organ failure and mortality in sepsis. RV, right ventricular." data-icon-position data-hide-link-title="0">Figure 3 Mechanism is kamagra good of RV dysfunction associated organ failure and mortality in sepsis. RV, right ventricular.The Education-in-Heart article in this issue by Steiner and is kamagra good Kirkpatrick7 focuses on palliative care in management of pateints with cardiovascular disease. Palliative care now encompasses much more than end-of-life comfort measures.

Instead, ‘Palliative care is a specialised type of medical care that focuses on improving communication about goals of care, maximising quality of life is kamagra good and reducing symptoms’ and thus applies to many of our patients at many time points in their disease course. Each of you will want to read the entire article yourself which includes several useful tools, such as the one shown in figure 4, to improve conversations with patients about treatment options, goals of care and planning for adverse outcomes.Ask-Tell-Ask tool to guide difficult conversations." data-icon-position data-hide-link-title="0">Figure 4 Ask-Tell-Ask tool to guide difficult conversations.Be sure to try the two Image Challenge questions in this issue.8 9 Over 150 board-review format multiple choice questions based on all types of cardiac images can be found in our online archive on the Heart homepage (https://heart.bmj.com/pages/collections/image_challenges/)..

A key consideration in timing of aortic valve replacement (AVR) for patients with kamagra for sale aortic stenosis (AS) is whether there is an increased risk of sudden cardiac death (SCD) that might be reduced by relief of outflow obstruction. Minners and colleagues1 addressed this issue in a retrospective analysis of outcomes in 1840 patients with mild to moderate AS (aortic maximum kamagra for sale velocity 2.5–4.0 m/s) in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Overall the annualised rate of SCD was 0.39% per year with 27 events in asymptomatic patients.

The most recent echocardiogram prior to SCD showed mild–moderate AS in most (80%) of these patients with no difference in SCD event rates in those who progressed to severe AS compared to kamagra for sale those who did not develop severe valve obstruction. On Cox regression analysis, the only independent risk factors for SCD were age (HR 1.06, 95% CI 1.01 to 1.11 per year, p=0.02), increased left ventricular mass index (HR 1.20, 95% CI 1.10 to 1.32 per 10 g/m2, p<0.001) and lower body mass index (HR 0.87, 95% CI 0.79 to 0.97 per kg/m2, p=0.01) but not the severity of valve obstruction (figure 1).Univariate (top) and multivariate (bottom) Cox regression analyses for SCD during 46.1±14.6 months of follow-up in the Simvastatin and Ezetimibe in Aortic kamagra for sale Stenosis study. The number of events for each variable is reflected by the dark, horizontal bars with separation at the median for continuous variables.

A forest plot visualisation of HRs for SCD is kamagra for sale provided on the right. LVED, left ventricular enddiastolic diameter kamagra for sale. LVES, left ventricular endsystolic diameter.

LVM, left kamagra for sale ventricular mass. SCD, sudden cardiac death." data-icon-position data-hide-link-title="0">Figure 1 Univariate (top) and multivariate (bottom) Cox regression analyses for SCD during kamagra for sale 46.1±14.6 months of follow-up in the Simvastatin and Ezetimibe in Aortic Stenosis study. The number of events for each variable is reflected by the dark, horizontal bars with separation at the median for continuous variables.

A forest plot visualisation of HRs for SCD is provided kamagra for sale on the right. LVED, left ventricular enddiastolic diameter. LVES, left ventricular endsystolic kamagra for sale diameter.

LVM, left kamagra for sale ventricular mass. SCD, sudden cardiac death.The lack of association between AS severity and the risk of SCD in the SEAS study is thought-provoking and challenges the conventional wisdom that early AVR would prevent SCD in asymptomatic patients with AS.2 In the past, syncope and SCD in patients with AS were thought to be due to mechanisms such as left ventricle (LV) baroreceptor malfunction, hypotension secondary to peripheral vasodilation in the face of fixed valve obstruction, or a shortened diastolic filling interval at high heart rates leading to a reduced stroke volume. However, it is doubtful that any of these mechanisms would kamagra for sale account for SCD when AS is only mild to moderate in severity.

€˜It is increasingly recognised that that AS is not simply a mechanical problem of kamagra for sale the valve leaflets not opening fully. Instead, AS compromises a complex interplay between the valve, ventricle and vasculature with abnormal function of all three components of the disease process.’ As I conclude in an editorial, ‘It is unlikely that early AVR will reduce the risk of sudden death when severe valve obstruction is not present. Perhaps it is time to turn our attention to mitigating the non-valvular disease processes in adults with calcific valve disease.’In another interesting paper in this issue of Heart, Williams and Brown3 hypothesised that the apparent benefit kamagra for sale of fractional flow reserve (FFR) guidance of percutaneous coronary intervention (PCI) in patients with chronic coronary syndromes (CCS) might simply be due to utilisation of fewer stents rather than to knowledge about the physiological severity of the coronary lesions.

In a Monte Carlo simulation using data from the PCI kamagra for sale strata of the Bypass Angioplasty Revascularization Investigation 2 Diabetes study, random deferral of PCI progressively reduced the risk of death and myocardial infarction at 1 year, suggesting that FFR-guided deferral of PCI improves outcomes simply because fewer stents are placed.In an editorial, Weintraub and Boden4 put this data into the context of 30 years of clinical trials comparing PCI with optimal medical therapy from CCS and conclude ‘In contrast to patients with acute coronary syndrome, there remains no convincing evidence that PCI will prevent events in patients with stable angina and chronic ischaemic heart disease. We know that, if needed, PCI will ameliorate severe angina, but we also know that this may not be a durable effect. By contrast, for the great majority of patients who are not disabled by angina, PCI can be safely deferred in both diabetic and non-diabetic patients, with kamagra for sale revascularisation reserved only for those with unacceptable angina or who develop an acute coronary syndrome during follow-up.

The role of FFR remains uncertain at best and need not be performed routinely in all patients with CCS, though it may be useful where the visual estimation of angiographical severity is uncertain.’Cardiac involvement in patients with sepsis kamagra for sale contributes to adverse outcomes with most previous studies focusing on left ventricular dysfunction. In order to assess the impact of right ventricular involvement on outcomes in sepsis Kim and colleagues5 performed a retrospective cohort study of 778 patients with septic shock with echocardiographic imaging. Sepsis-induced cardiac dysfunction was present kamagra for sale in 34.7% of the entire cohort, affecting the LV in 67.3% and the right ventricle (RV) in 40.7% of these patients.

Any type of sepsis-induced cardiac dysfunction was associated with a significantly higher 28-day mortality (35.9 vs 26.8%. P<0.01), longer intensive care unit length of stay and longer duration of mechanical ventilator, compared kamagra for sale with those without cardiac dysfunction. Isolated RV dysfunction was rare (24/270, 8.9%) but was associated with a higher risk of 28-day mortality (adjusted OR kamagra for sale 2.77, 95% CI 1.20 to 6.40, p=0.02) (figure 2).Comparisons of survival curves between each type of dysfunction.

LV, left ventricle. RV, right ventricle." data-icon-position data-hide-link-title="0">Figure 2 Comparisons of survival curves kamagra for sale between each type of dysfunction. LV, left kamagra for sale ventricle.

RV, right ventricle.The mechanisms of cardiac dysfunction in patients with sepsis are summarised in an editorial by Dugar and Vallabhajosyula6 (figure 3). They also point out the challenges in understanding cardiac involvement in patients with sepsis including the effect kamagra for sale of timing of imaging on detection, difficulties in measuring RV systolic performance, and differing definitions of RV dysfunction. They conclude kamagra for sale.

€˜there is a crucial need to understand the how to identify RV dysfunction in sepsis and the causative mechanisms associated with higher mortality in this population, which will significantly influence how we prevent and manage this disease process.’Mechanism of RV dysfunction associated organ failure and mortality in sepsis. RV, right ventricular." data-icon-position data-hide-link-title="0">Figure 3 Mechanism kamagra for sale of RV dysfunction associated organ failure and mortality in sepsis. RV, right ventricular.The Education-in-Heart article in this issue by Steiner and Kirkpatrick7 focuses on palliative care in management of kamagra for sale pateints with cardiovascular disease.

Palliative care now encompasses much more than end-of-life comfort measures. Instead, ‘Palliative care is a specialised type of medical care that focuses on improving communication about goals kamagra for sale of care, maximising quality of life and reducing symptoms’ and thus applies to many of our patients at many time points in their disease course. Each of you will want to read the entire article yourself which includes several useful tools, such as the one shown in figure 4, to improve conversations with patients about treatment options, goals of care and planning for adverse outcomes.Ask-Tell-Ask tool to guide difficult conversations." data-icon-position data-hide-link-title="0">Figure 4 Ask-Tell-Ask tool to guide difficult conversations.Be sure to try the two Image Challenge questions in this issue.8 9 Over 150 board-review format multiple choice questions based on all types of cardiac images can be found in our online archive on the Heart homepage (https://heart.bmj.com/pages/collections/image_challenges/)..

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Start Authority kamagra safe Sec. 101(e), Pub. L. 114-10, 129 kamagra safe Stat.

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Award recipients will collaborate with regional and local partners to ensure a broad geographic reach with the goal of getting as many people vaccinated as possible. €œTrusted messengers play an essential role in sharing information about erectile dysfunction treatments, kamagra for sale answering questions, and ultimately convincing people to get vaccinated,” said Acting HRSA Administrator Diana Espinosa. €œThis funding will support national, regional, and local organizations that will work directly with hard-hit, underserved, and high-risk communities to help bolster erectile dysfunction treatment vaccination rates.” For a list of awards recipients, see www.hrsa.gov/erectile dysfunction/community-based-workforce. HRSA has also released a second notice of funding opportunity targeting smaller community-based organizations, with awards expected to be released in July 2021. Contact CBOtreatmentOutreach@hrsa.gov with any questions kamagra for sale.

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Letters of nomination and resumes should be submitted no later than July 16, 2021, to ensure adequate opportunity for review and consideration of nominees prior to appointment. Appointments will kamagra for sale be made in October 2021. Submit letters of nomination and resumes to PTACcommittee@gao.gov. Start Further Info Greg Giusto at (202) 512-8268 or giustog@gao.gov if you do not receive an acknowledgement within a week of submission or you need additional kamagra for sale information. For general information, contact GAO's Office of Public Affairs at (202) 512-4800.

Start Authority Sec kamagra for sale. 101(e), Pub. L. 114-10, 129 kamagra for sale Stat. 87, 115 (2015).

End Authority Start Signature Gene kamagra for sale L. Dodaro, Comptroller General of the United States. End Signature End Further Info End Preamble [FR kamagra for sale Doc. 2021-12145 Filed 6-11-21. 8:45 am]BILLING CODE 1610-02-P.

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