Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network.

Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic-high risk and benign-no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease-gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that 'national subspecialist multidisciplinary meetings' (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership

Redefining palliative care-a new consensus-based definition

Context: The International Association for Hospice and Palliative Care developed a consensus-based definition of palliative care (PC) that focuses on the relief of serious health-related suffering, a concept put forward by the Lancet Commission Global Access to Palliative Care and Pain Relief. Objective: The main objective of this article is to present the research behind the new definition. Methods: The three-phased consensus process involved health care workers from countries in all income levels. In Phase 1, 38 PC experts evaluated the components of the World Health Organization definition and suggested new/revised ones. In Phase 2, 412 International Association for Hospice and Palliative Care members in 88 countries expressed their level of agreement with the suggested components. In Phase 3, using results from Phase 2, the expert panel developed the definition. Results: The consensus-based definition is as follows: Palliative care is the active holistic care of individuals across all ages with serious health-related suffering due to severe illness and especially of those near the end of life. It aims to improve the quality of life of patients, their families and their caregivers. The definition includes a number of bullet points with additional details as well as recommendations for governments to reduce barriers to PC. Conclusion: Participants had significantly different perceptions and interpretations of PC. The greatest challenge faced by the core group was trying to find a middle ground between those who think that PC is the relief of all suffering and those who believe that PC describes the care of those with a very limited remaining life span

Endophyte Microbiome Diversity in Micropropagated Atriplex canescens and Atriplex torreyi var griffithsii

Microbial diversity associated with micropropagated Atriplex species was assessed using microscopy, isolate culturing, and sequencing. Light, electron, and confocal microscopy revealed microbial cells in aseptically regenerated leaves and roots. Clone libraries and tag-encoded FLX amplicon pyrosequencing (TEFAP) analysis amplified sequences from callus homologous to diverse fungal and bacterial taxa. Culturing isolated some seed borne endophyte taxa which could be readily propagated apart from the host. Microbial cells were observed within biofilm-like residues associated with plant cell surfaces and intercellular spaces. Various universal primers amplified both plant and microbial sequences, with different primers revealing different patterns of fungal diversity. Bacterial and fungal TEFAP followed by alignment with sequences from curated databases revealed 7 bacterial and 17 ascomycete taxa in A. canescens, and 5 bacterial taxa in A. torreyi. Additional diversity was observed among isolates and clone libraries. Micropropagated Atriplex retains a complex, intimately associated microbiome which includes diverse strains well poised to interact in manners that influence host physiology. Microbiome analysis was facilitated by high throughput sequencing methods, but primer biases continue to limit recovery of diverse sequences from even moderately complex communities

2019 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

The International Liaison Committee on Resuscitation has initiated a continuous review of new, peer-reviewed, published cardiopulmonary resuscitation science. This is the third annual summary of the International Liaison Committee on Resuscitation International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. It addresses the most recent published resuscitation evidence reviewed by International Liaison Committee on Resuscitation Task Force science experts. This summary addresses the role of cardiac arrest centers and dispatcher-assisted cardiopulmonary resuscitation, the role of extracorporeal cardiopulmonary resuscitation in adults and children, vasopressors in adults, advanced airway interventions in adults and children, targeted temperature management in children after cardiac arrest, initial oxygen concentration during resuscitation of newborns, and interventions for presyncope by first aid providers. Members from 6 International Liaison Committee on Resuscitation task forces have assessed, discussed, and debated the certainty of the evidence on the basis of the Grading of Recommendations, Assessment, Development, and Evaluation criteria, and their statements include consensus treatment recommendations. Insights into the deliberations of the task forces are provided in the Justification and Evidence to Decision Framework Highlights sections. The task forces also listed priority knowledge gaps for further research

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Clinical Utility of Ventricular Repolarization Dispersion for Real-Time Detection of Non-ST Elevation Myocardial Infarction in Emergency Departments.

BackgroundA specific electrocardiographic (ECG) marker of ischemia would greatly improve the speed and accuracy of detecting and treating non-ST elevation myocardial infarction (NSTEMI). We hypothesize that ischemia induces ventricular repolarization dispersion (VRD), altering the T-wave before any ST segment deviation. We sought to evaluate the clinical utility of VRD to (1) detect NSTEMI cases in the emergency department (ED) and (2) identify NSTEMI cases at high risk for in-hospital major adverse cardiac events (MACEs).Methods and resultsWe continuously recorded 12-lead Holter ECGs from chest pain patients upon their arrival to the ED. VRD was quantified using principal component analysis of the 12-lead ECG to compute a T-wave complexity ratio (ie, ratio of second to first eigenvectors of repolarization). Clinical outcomes were obtained from hospital records. The sample was composed mainly of older males (n=369; ages 63±12 years; 63% males), and 92 (25%) had NSTEMI and 26 (7%) had MACEs. Baseline T-wave complexity ratio modestly correlated with peak troponin levels (r=0.41; P<0.001) and was a good classifier of NSTEMI events (area under the curve=0.70). An increased T-wave complexity ratio on the presenting ECG was strongly associated with NSTEMI (odds ratio [OR]=3.8 [2.1 to 5.8]) and in-hospital MACE (OR=8.2 [3.1 to 21.5]).ConclusionsA simple measure of global VRD on the presenting 12-lead ECG correlates with ischemic myocardial injury and can discriminate NSTEMI cases very early during evaluation. Prospective studies should validate these findings and test whether VRD can guide therapy

Concurrent determination of hepatic bioavailability of salicylamide by three techniques in the dog

Three methods of measuring hepatic first‐pass metabolism of salicylamide in dogs that had undergone portacaval transposition were compared. The drug in both its radiolabeled (0.74 MBq) and unlabeled (20 mg/kg) forms was infused concurrently into forelimb and hindlimb veins, respectively. Because of the transposition, drug from the hindlimb is subject to first‐pass metabolism in the liver. Bioavailability is a complementary measure of the extent of this metabolism. The three methods of determining bioavailability were continuous withdrawal of blood to determine the ratio of the areas under the plasma concentration versus time curves, ratio of specific activities in plasma after all the drug had been administered, and the conventional method, measurement of the ratio of areas determined from sequential plasma concentrations. The three techniques were found to give virtually identical values for bioavailability. Each method has its own advantages, limitations, and possible applications. The continuous withdrawal technique is potentially most applicable for drugs with short half‐lives. The ratio of specific activities may be the preferred method for drugs with long half‐lives. The conventional method is limited by the number of samples needed, but is potentially useful under those conditions in which data following test and intravenous routes of administration are available