Web platform vs in-person genetic counselor for return of carrier results from exome sequencing a randomized clinical trial

© 2018 American Medical Association. All rights reserved. IMPORTANCE A critical bottleneck in clinical genomics is the mismatch between large volumes of results and the availability of knowledgeable professionals to return them. OBJECTIVE To test whether a web-based platform is noninferior to a genetic counselor for educating patients about their carrier results from exome sequencing. DESIGN, SETTING, AND PARTICIPANTS A randomized noninferiority trial conducted in a longitudinal sequencing cohort at the National Institutes of Health from February 5, 2014, to December 16, 2016, was used to compare the web-based platform with a genetic counselor. Among the 571 eligible participants, 1 to 7 heterozygous variants were identified in genes that cause a phenotype that is recessively inherited. Surveys were administered after cohort enrollment, immediately following trial education, and 1 month and 6 months later to primarily healthy postreproductive participants who expressed interest in learning their carrier results. Both intention-to-treat and per-protocol analyses were applied. INTERVENTIONS A web-based platform that integrated education on carrier results with personal test results was designed to directly parallel disclosure education by a genetic counselor. The sessions took a mean (SD) time of 21 (10.6), and 27 (9.3) minutes, respectively. MAIN OUTCOMES AND MEASURES The primary outcomes and noninferiority margins (dNI) were knowledge (0 to 8, dNI = -1), test-specific distress (0 to 30, dNI = +1), and decisional conflict (15 to 75, dNI = +6). RESULTS After 462 participants (80.9%) provided consent and were randomized, all but 3 participants (n = 459) completed surveys following education and counseling; 398 (86.1%) completed 1-month surveys and 392 (84.8%) completed 6-month surveys. Participants were predominantly well-educated, non-Hispanic white, married parents; mean (SD) age was 63 (63.1) years and 246 (53.6%) were men. The web platform was noninferior to the genetic counselor on outcomes assessed at 1 and 6 months: knowledge (mean group difference, -0.18; lower limit of 97.5% CI, -0.63; dNI = -1), test-specific distress (median group difference, 0; upper limit of 97.5% CI, 0; dNI = +1), and decisional conflict about choosing to learn results (mean group difference, 1.18; upper limit of 97.5% CI, 2.66; dNI = +6). There were no significant differences between the genetic counselors and web-based platform detected between modes of education delivery in disclosure rates to spouses (151 vs 159; relative risk [RR], 1.04; 95% CI, 0.64-1.69; P > .99), children (103 vs 117; RR, 1.07; 95% CI, 0.85-1.36; P = .59), or siblings (91 vs 78; RR, 1.17; 95% CI, 0.94-1.46; P = .18). CONCLUSIONS AND RELEVANCE This trial demonstrates noninferiority of web-based return of carrier results among postreproductive, mostly healthy adults. Replication studies among younger and more diverse populations are needed to establish generalizability. Yet return of results via a web-based platform may be sufficient for subsets of test results, reserving genetic counselors for return of results with a greater health threat

Self-inflicted penetrating eye injuries using a razor blade: Case report

<p>Abstract</p> <p>Background</p> <p>A 23 year old white male with a history of social and behavioural problems attempted to blind himself chemically, with alcohol, and mechanically, with a razor blade.</p> <p>Methods</p> <p>Observational case report of a patient who self-inflicted bilateral scleral lacerations with a razor blade, after losing his job.</p> <p>Results</p> <p>The patient sustained bilateral inferior scleral perforations, with hypotony and a right traumatic cataract. He received urgent surgical repair, and prophylactic antibiotics. There were no retinal breaks or detachments. He later underwent successful cataract surgery to the right eye.</p> <p>Conclusion</p> <p>Self-inflicted ocular injury may be possible in non-psychotic patients, as a situational response to a life event. Urgent repair can completely restore vision in some cases. Referral for psychiatric counseling is mandatory.</p

Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour

Organizational Stress in High-Level Field Hockey: Examining Transactional Pathways Between Stressors, Appraisals, Coping, and Performance Satisfaction

This study investigated transactional pathways between organizational stressors and their 28 underpinning situational properties, appraisals, coping, perceived coping effectiveness (PCE) 29 and performance satisfaction in athletes. Ten high-level field hockey players were 30 interviewed. Data relating to stressors, situational properties, appraisals and coping were 31 analysed using directed content analysis. Mean PCE scores were calculated and subjective 32 performance satisfaction data were categorised as satisfied, neutral, or dissatisfied. A variety 33 of organizational stressors was reported, which were underpinned by five situational 34 properties. Challenge, threat and harm/loss appraisals were experienced and problem solving 35 was the most commonly reported family of coping. High PCE was not always associated with 36 performance satisfaction. Performance satisfaction was, however, linked to the appraisal 37 experienced. A battery of stress management techniques and ways of coping is useful for 38 optimising appraisals and alleviating negative outcomes of stress

Physicochemical analysis of rotavirus segment 11 supports a 'modified panhandle' structure and not the predicted alternative tRNA-like structure (TRLS)

.Rotaviruses are a major cause of acute gastroenteritis, which is often fatal in infants. The viral genome consists of 11 double-stranded RNA segments, but little is known about their cis-acting sequences and structural elements. Covariation studies and phylogenetic analysis exploring the potential structure of RNA11 of rotaviruses suggested that, besides the previously predicted "modified panhandle" structure, the 5' and 3' termini of one of the isoforms of the bovine rotavirus UKtc strain may interact to form a tRNA-like structure (TRLS). Such TRLSs have been identified in RNAs of plant viruses, where they are important for enhancing replication and packaging. However, using tRNA mimicry assays (in vitro aminoacylation and 3'- adenylation), we found no biochemical evidence for tRNA-like functions of RNA11. Capping, synthetic 3' adenylation and manipulation of divalent cation concentrations did not change this finding. NMR studies on a 5'- and 3'-deletion construct of RNA11 containing the putative intra-strand complementary sequences supported a predominant panhandle structure and did not conform to a cloverleaf fold despite the strong evidence for a predicted structure in this conserved region of the viral RNA. Additional viral or cellular factors may be needed to stabilise it into a form with tRNA-like properties

The devil is in the details: Genomics of transmissible cancers in Tasmanian devils

Cancer poses one of the greatest human health threats of our time. Fortunately, aside from a few rare cases of cancer transmission in immune-suppressed organ transplant recipients or a small number of transmission events from mother to fetus, cancers are not spread from human to human. However, transmissible cancers have been detected in vertebrate and invertebrate animals, sometimes with devastating effects. Four examples of transmissible cancers are now known: 1) canine transmissible venereal tumor (CTVT) in dogs, 2) a tumor in a laboratory population of Syrian hamsters that is no longer cultured, 3) infectious neoplasias in at least four species of bivalve mollusks, and 4) two independently derived transmissible cancers (devil facial tumor disease [DFTD]) in Tasmanian devils (Fig 1A and 1B). The etiologic agents of CTVT, the bivalve cancers, and DFTDare the transplants (allografts) of the neoplastic cells themselves, but the etiologic agent is unknown for the hamster tumor.The effects of these transmissible cancers on their respective host populations vary. CTVT is spread in dogs through sexual contact and is at least 11,000 years old, placing the timing of its origin close to that of the domestication of dogs. Although genomic analyses of the tumor suggest evasion of multiple components of the dog immune system, dogs most commonly survive and often show evidence of spontaneous tumor regression within a year of initial diagnosis. For the infectious bivalve neoplasias, which have existed for at least 40 years, population effects vary from enzootic infections with no noticeable effects on population sizes to evidence of a catastrophic population decline. In Tasmanian devils (Fig 1A), the first infectious tumor discovered (DFT1; Fig 1B) has spread across approximately 95% of the geographic range of Tasmanian devils since 1996 (Fig 1C). DFTD is almost always fatal (Fig 1B), with >90% declines in infected localities and an overall species-wide decline exceeding 80%. Transmission dynamics appear consistent with frequency dependence, with DFTD spread by biting during social interactions, resulting in predictions of extinction from standard epidemiological models. Despite these predictions, long-infected devil populations persist at reduced densities, suggesting that individual-level variability in fecundity and tumor growth rate in infected individuals are key for understanding epidemiological dynamics. Additionally, the origin of the second, independent lineage of DFTD (i.e., DFT2) within 20 years of the discovery of DFT1 suggests that transmissible cancers may be a recurring part of the Tasmanian devils' evolutionary history, without causing extinction

Adapting a Program to Inform African American and Hispanic American Women About Cancer Clinical Trials

The dearth of evidence-based clinical trial education programs may contribute to the underrepresentation of African American and Hispanic American women in cancer research studies. This study used focus group-derived data from 80 women distributed among eight Spanish- and English-language focus groups. These data guided the researchers’ adaptation and refinement of the National Cancer Institute’s various clinical trials education programs into a program that was specifically focused on meeting the information needs of minority women and addressing the barriers to study participation that they perceived. A “sisterhood” theme was adopted and woven throughout the presentation

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders