BACKGROUND:Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely ...tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.
METHODS:Utilizing an evidence-based framework, 3 gene curation teams blinded to each other’s work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.
RESULTS:Of 17 genes reported as being causative for LQTS, 9 (AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (KCNQ1, KCNH2, SCN5A) were curated as definitive genes for typical LQTS. Another 4 genes (CALM1, CALM2, CALM3, TRDN) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (CACNA1C) had moderate level evidence for causing LQTS.
CONCLUSIONS:More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
Sialic acids are nine-carbon sugars that frequently cap glycans at the cell surface in cells of vertebrates as well as cells of certain types of invertebrates and bacteria. The nine-carbon backbone ...of sialic acids can undergo extensive enzymatic modification in nature and O-acetylation at the C-4/7/8/9 position in particular is widely observed. In recent years, the detection and analysis of O-acetylated sialic acids have advanced, and sialic acid-specific O-acetyltransferases (SOATs) and O-acetylesterases (SIAEs) that add and remove O-acetyl groups, respectively, have been identified and characterized in mammalian cells, invertebrates, bacteria, and viruses. These advances now allow us to draw a more complete picture of the biosynthetic pathway of the diverse O-acetylated sialic acids to drive the generation of genetically and biochemically engineered model cell lines and organisms with altered expression of O-acetylated sialic acids for dissection of their roles in glycoprotein stability, development, and immune recognition, as well as discovery of novel functions. Furthermore, a growing number of studies associate sialic acid O-acetylation with cancer, autoimmunity, and infection, providing rationale for the development of selective probes and inhibitors of SOATs and SIAEs. Here, we discuss the current insights into the biosynthesis and biological functions of O-acetylated sialic acids and review the evidence linking this modification to disease. Furthermore, we discuss emerging strategies for the design, synthesis, and potential application of unnatural O-acetylated sialic acids and inhibitors of SOATs and SIAEs that may enable therapeutic targeting of this versatile sialic acid modification.
Physical activity levels of children with disabilities are low, as these children and their parents face a wide variety of both personal and environmental barriers. Behavior change techniques support ...pediatric physical therapists to address these barriers together with parents and children. We developed the What Moves You?! intervention Toolkit (WMY Toolkit) filled with behavioral change tools for use in pediatric physical therapy practice. To evaluate the feasibility of using the WMY Toolkit in daily pediatric physical therapy practice. We conducted a feasibility study with a qualitative approach using semi-structured interviews with pediatric physical therapists (n = 11). After one day of training, the pediatric physical therapists used the WMY Toolkit for a period of 9 weeks, when facilitating physical activity in children with disabilities. We analyzed the transcripts using an inductive thematic analysis followed by a deductive analysis using a feasibility framework. For acceptability, pediatric physical therapists found that the toolkit facilitated conversation about physical activity in a creative and playful manner. The working mechanisms identified were in line with the intended working mechanisms during development of the WMY Toolkit, such as focusing on problem solving, self-efficacy and independence. For demand, the pediatric physical therapists mentioned that they were able to use the WMY Toolkit in children with and without disabilities with a broad range of physical activity goals. For implementation, education is important as pediatric physical therapists expressed the need to have sufficient knowledge and to feel confident using the toolkit. For practicality, pediatric physical therapists were positive about the ease of which tools could be adapted for individual children. Some of the design and materials of the toolkit needed attention due to fragility and hygiene. The WMY Toolkit is a promising and innovative way to integrate behavior change techniques into pediatric physical therapy practice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This article explores differences in the pattern of political participation between immigrants and the majority population in Western Europe. Using data from the European Social Survey, I find that ...for immigrants the pattern of political participation is less distinct, that is, participation types are more strongly related than for the majority population; and that this cannot be explained by differences in levels of resources and engagement, but by differences in the importance of mobilization and by the amount of time spent in the new country of residence. This indicates that the explanatory mechanisms operate differently for immigrants than the majority, impacting not only on the decision on whether not to participate, but also on how. These findings are important, not only for what they tell us about the process of political integration, but also for how we study political participation more broadly.
Purpose
Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding ...affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues.
Methods and results
In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC
50
values in the nanomolar range. Interestingly,
177
LuLu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed
177
LuLu-PSMA-617 to have the lowest binding to these healthy organs compared with
177
LuLu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of
177
LuLu-PSMA-617 and
177
LuLu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However,
177
LuLu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio.
Conclusion
177
LuLu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with
177
LuLu-PSMA-I&T and
177
LuLu-JVZ-007. Based on our preclinical evaluation,
177
LuLu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.
We advance the debate about the impact of political disagreement in social networks on electoral participation by addressing issues of causal inference common in network studies, focusing on voters' ...most important context of interpersonal influence: the household. We leverage a randomly assigned spillover experiment conducted in the United Kingdom, combined with a detailed database of pretreatment party preferences and public turnout records, to identify social influence within heterogeneous and homogeneous partisan households. Our results show that intrahousehold mobilization effects are larger as a result of campaign contact in heterogeneous than in homogeneous partisan households, and larger still when the partisan intensity of the message is exogenously increased, suggesting discussion rather than behavioral contagion as a mechanism. Our results qualify findings from influential observational studies and suggest that within intimate social networks, negative correlations between political heterogeneity and electoral participation are unlikely to result from political disagreement.
To analyze needs and requirements of Pediatric Physical Therapists (PPTs), parents, children and adolescents with and without developmental disabilities in the future use of an activity monitor ...prototype (AM-p) in everyday clinical practice. Qualitative exploratory study with a thematic analysis approach, based on Braun and Clarke's six steps. Codes derived from the analysis and central themes were collated, based on Fleuren et al.'s groupings of determinants. We interviewed 25 PPTs, 12 parents, and 12 children and adolescents. Within four groupings of determinants, we found nine themes: 1) development of information materials; 2) application: output visualization and ease of use; 3) design; 4) relevance and acceptance; 5) shared decision-making; 6) compatibility in daily living; 7) finances, 8) time, and 9) legislation and regulations. End-users have similar basic needs, with individual fine-tuning to be addressed during further development of the AM-p. A child-friendly design, information material, and an easy-to-use application to read and interpret results, need to be developed. Efficient training for PPTs is important for the use of the AM-p and analysis of results. Communication between PPTs and children as well as parents enhances shared decision-making. We recommend involving diverse end-users to enable maximum customization of the AM-p.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This review appraises evidence on the difference between single- and double-embryo transfer (SET, DET) in assisted reproductive technology (ART) regarding the four healthcare quality dimensions most ...important to fertility patients and doctors. Regarding safety, not only does DET create the uncontested perinatal risks of twin pregnancies, but compelling evidence has added that singleton pregnancies after a vanishing twin also have poorer perinatal outcomes. SET is as effective as DET, as shown by meta-analyses of randomized controlled trials, comparing two cycles of SET versus DET and shown by cumulative live birth rates of entire ART trajectories of up to six cycles. Proposing SET, which is safer than DET and as effective, as the gold standard is not irreconcilable with patient-centred care if patients are thoroughly informed on the reasoning behind the proposition and welcomed to challenge whether it fits their personal values. The cost-efficiency of SET is clearly higher, which has even induced certain countries to start reimbursing ART on the condition that SET is used. In conclusion, SET should be the gold standard offered to all patients. The question is not whether to apply SET but how to apply it in terms of patient selection, patient-centred counselling and coverage of treatment.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) and short QT syndrome (SQTS) are inherited arrhythmogenic disorders that can cause sudden death. Numerous genes have been reported to ...cause these conditions, but evidence supporting these gene-disease relationships varies considerably. To ensure appropriate utilization of genetic information for CPVT and SQTS patients, we applied an evidence-based reappraisal of previously reported genes.
Three teams independently curated all published evidence for 11 CPVT and 9 SQTS implicated genes using the ClinGen gene curation framework. The results were reviewed by a Channelopathy Expert Panel who provided the final classifications. Seven genes had definitive to moderate evidence for disease causation in CPVT, with either autosomal dominant (RYR2, CALM1, CALM2, CALM3) or autosomal recessive (CASQ2, TRDN, TECRL) inheritance. Three of the four disputed genes for CPVT (KCNJ2, PKP2, SCN5A) were deemed by the Expert Panel to be reported for phenotypes that were not representative of CPVT, while reported variants in a fourth gene (ANK2) were too common in the population to be disease-causing. For SQTS, only one gene (KCNH2) was classified as definitive, with three others (KCNQ1, KCNJ2, SLC4A3) having strong to moderate evidence. The majority of genetic evidence for SQTS genes was derived from very few variants (five in KCNJ2, two in KCNH2, one in KCNQ1/SLC4A3).
Seven CPVT and four SQTS genes have valid evidence for disease causation and should be included in genetic testing panels. Additional genes associated with conditions that may mimic clinical features of CPVT/SQTS have potential utility for differential diagnosis.
Prostate specific membrane antigen (PSMA) has become a major focus point in the research and development of prostate cancer (PCa) imaging and therapeutic strategies using radiolabeled tracers. PSMA ...has shown to be an excellent target for PCa theranostics because of its high expression on the membrane of PCa cells and the increase in expression during disease progression. Therefore, numerous PSMA-targeting tracers have been developed and (pre)clinically studied with promising results. However, many of these PSMA-targeting tracers show uptake in healthy organs such as the salivary glands, causing radiotoxicity. Furthermore, not all patients respond to PSMA-targeted radionuclide therapy (TRT). This created the necessity of additional preclinical research studies in which existing tracers are reevaluated and new tracers are developed in order to improve PSMA-TRT by protecting the (PSMA-expressing) healthy organs and improving tumor uptake. In this review we will give an overview of the recent preclinical research projects regarding PCa-TRT using PSMA-specific radiotracers, which will give an indication of where the PSMA-TRT research movement is going and what we can expect in future clinical trials.
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