The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

Applying the theory of behavioral choice to plant-based dietary intentions.

Improving understanding of the intention to choose plant-based food is an important element of climate change mitigation. A cross-sectional survey of 454 North American adults was used to predict their dietary-change intentions from the theory of planned behavior (TPB) and the more-recently proposed theory of behavioral choice (TBC). The TPB accounted for 65 percent of the variance in intentions and the TBC accounted for a significantly greater (80 percent) proportion of variance. The strongest predictors of intention were the TBC's sense of obligation, attitude-values-affect (AVA), and habit, and the TBP's social norms. Five interactions also contributed in small but significant ways toward the accounting of the participants' food-choice intentions. Policy implications are discussed.

Adjuvant conditioning induces an immunosuppressive milieu that delays alloislet rejection through the expansion of myeloid-derived suppressor cells.

Advances in immunosuppression have been relatively stagnant over the past 2 decades, and transplant recipients continue to experience long-term morbidity associated with immunosuppression regimens. Strategies to reduce or eliminate the dosage of immunosuppression medications are needed. We discovered a novel administration strategy using the classic adjuvant alum to condition murine islet transplant recipients, known as adjuvant conditioning (AC), to expand both polymorphonuclear and monocytic myeloid-derived suppressive cells (MDSCs) in vivo. These AC MDSCs potently suppress T cell proliferation when cultured together in vitro. AC MDSCs also facilitate naïve CD4+ T cells to differentiate into regulatory T cells. In addition, we were able to demonstrate a significant delay in alloislet rejection compared with that by saline-treated control following adjuvant treatment in a MDSC-dependent manner. Furthermore, AC MDSCs produce significantly more interleukin (IL)-10 than saline-treated controls, which we demonstrated to be critical for the increased T cell suppressor function of AC MDSCs as well as the observed protective effect of AC against alloislet rejection. Our data suggest that adjuvant-related therapeutics designed to expand MDSCs could be a useful strategy to prevent transplant rejection and curb the use of toxic immunosuppressive regimens currently used in transplant patients.

A comparative evaluation of quality and depth of learning by trainee doctors in regional, rural, and remote locations.

BACKGROUND: An equitable supply and distribution of medical practitioners for all the population is an important issue, especially in Australia where 28% of the population live in rural and remote areas. Research identified that training in rural/remote locations is a predictor for the uptake of rural practice, but training must provide comparable learning and clinical experiences, irrespective of location. Evidence shows GPs in rural and remote areas are more likely to be engaged in complex care. However, the quality of GP registrar education has not been systematically evaluated. This timely study evaluates GP registrar learning and clinical training experiences in regional, rural, and remote locations in Australia using assessment items and independent evaluation. METHODS: The research team retrospectively analysed GP trainee formative clinical assessment reports compiled by experienced medical educators during real-time patient consultations. Written reports were assessed using Bloom's taxonomy classified into low and high cognitive level thinking. Regional, rural, and remotely located trainees were compared using Pearson chi-squared test and Fisher's exact test (for 2 × 2 comparisons) to calculate associations between categorical proportions of learning setting and 'complexity'. RESULTS: 1650 reports (57% regional, 15% rural and 29% remote) were analysed, revealing a statistically significant association between learner setting and complexity of clinical reasoning. Remote trainees were required to use a high level of clinical reasoning in managing a higher proportion of their patient visits. Remotely trained GPs managed significantly more cases with high clinical complexity and saw a higher proportion of chronic and complex cases and fewer simple cases. CONCLUSIONS: This retrospective study showed GP trainees in all locations experienced comparable learning experiences and depth of training. However, learning in rural and remote locations had equal or more opportunities for seeing higher complexity patients and the necessity to apply greater levels of clinical reasoning to manage each case. This evidence supports learning in rural and remote locations is of a similar standard of learning as for regional trainees and in several areas required a superior level of thinking. Training needs to seriously consider utilising rural and remote clinical placements as exceptional locations for developing and honing medical expertise.

Pulmonary arteriovenous malformations may be the only clinical criterion present in genetically confirmed hereditary haemorrhagic telangiectasia.

Pulmonary arteriovenous malformations (PAVMs) result in preventable complications demanding specialty care. Underlying hereditary haemorrhagic telangiectasia (HHT) can be identified by genetic testing, if the diagnosis is considered. Retrospectively reviewing 152 unrelated adults with genetically confirmed HHT due to ACVRL1, ENG or SMAD4, we found that only 104/152 (68%) met a clinical diagnosis of HHT with three Curaçao criteria. The genetic diagnostic rate was similar for patients with three (104/137, 76%) or one to two (48/71, 68%; p=0.25) criteria. Of 83 unrelated probands with PAVM(s) and genetically-confirmed HHT, 20/83 (24%) had few, if any, features of HHT. Enhanced clinical suspicion, as well as HHT genetic testing, is recommended if one or more PAVMs are present.

Obstinate leg ulceration secondary to prolidase deficiency, treated with 5% topical proline.

Prolidase deficiency is a rare cause of chronic ulceration with less than 100 reported cases in the literature. This article highlights to clinicians the features of this uncommon genodermatosis, the challenge of diagnosis, and treatment options.

Perceptions of prescription opioid use among rural farming and ranching communities: Preliminary implications for outreach and treatment.

Background: In 2017, 45% of rural adults reported being directly impacted by the opioid epidemic. While research on the experiences of those using prescription opioids in rural communities is increasing, less is known about a unique sub-population who may have high rates of exposure: rural agricultural workers. The purpose of this study was to explore the prevalence and perceptions related to prescription opioids among rural producers and farmworkers. Methods: A questionnaire was mailed in spring 2019 and spring 2020 to rural residents living in one of two agricultural-based states in the Upper Midwest. Individuals were eligible to participate if any member of their family was involved in the agricultural industry. A total of 1116 questionnaires were returned for a 27.9% response rate. Results: Participants were 68.1 years old on average. The majority identified as white, male, and married. Prescription opioid use was found in 8.2% of households currently, and 15.7% in the past year. There were no gender differences in prevalence of use, but women and older individuals reported significantly more perceived risk than men and younger individuals. Nearly half used alternative pain management, and received most information about prescription opioids from the radio (65.5%) and newsletters (13.5%). Conclusions. Despite their elevated age and working in an occupation at high risk of injury and chronic pain, study participants reported few opioid prescriptions and moderate use of alternative pain management. Perceived risk of prescription opioids may explain low prevalence. Outreach efforts that increase access to healthcare services and alternative pain management treatments for agricultural workers may mitigate the experience of chronic pain that can interfere with their overall quality of life.

Gender-Based Microaggressions in Surgery: A Scoping Review of the Global Literature.

BACKGROUND: In addition to systemic gender disparities, women in surgery encounter interpersonal microaggressions. The objective of this study is to describe the most common forms of microaggressions reported by women in surgery. METHODS: We conducted a scoping review using PubMed/MEDLINE, Ovid, and Web of Science to describe the international, indexed English-language literature on gender-based microaggressions experienced by female surgeons, surgical trainees, and medical students in surgery. After screening by title, abstract, and full-text, 37 articles were retained for data extraction and analysis. Microaggressions were analyzed using the Sexist Microaggression Experience and Stress Scale (MESS) framework and stratified by country of origin. RESULTS: Gender-based microaggression publications most commonly originated from the United States (n = 27 articles), Canada (n = 3), and India (n = 2). Gender-based microaggressions were classified into environmental invalidations (n = 20), being treated like a second-class citizen (n = 18), assumptions of traditional gender roles (n = 12), sexual objectification (n = 11), assumptions of inferiority (n = 10), being forced to leave gender at the door (n = 8), and experiencing sexist language (n = 6). Additionally, attendings were more frequently reported to experience microaggressions than surgical trainees and medical students, but more articles reported data on attendings (n = 16) than surgical trainees (n = 10) or students (n = 4). CONCLUSION: While recent advancements have opened the field of surgery to women, there is still a lack of female representation, and persistent microaggressions may perpetuate this gender disparity. Addressing microaggressions against female surgeons is essential to achieving gender equity in surgical practice.

Occipital teratoma in a neonate with CHARGE syndrome: a case report.

INTRODUCTION: Teratomas of the head and neck region are rare lesions, representing just 5% of all congenital teratomas. Usually found in the pineal region orneurohypophysis, teratomas are uncommonly located in the posterior occiput. CASE PRESENTATION: Herein, we present a case of a female neonate born at 37-week gestation with hydrocephalus, an occipital scalp lesion, and several craniofacial abnormalities consistent with a diagnosis of coloboma, heart defect, atresia choanae, retarded growth, genital abnormality, and ear abnormality (CHARGE) syndrome. The occipital scalp lesion was initially thought to be an encephalocele. On day of life 3, the neonate was taken to the operating room for placement of a ventriculoperitoneal shunt and repair of the occipital lesion. Intra-operatively, the lesion resembled a dural-based meningocele; however, during histologic evaluation, it was found to contain tissue derived from all three germ layers and thus, it was determined to be more consistent with a teratoma. CONCLUSION: We hypothesize that a germline mutation in CHD7 or other similar regulatory gene causative of CHARGE syndrome and craniofacial developmental abnormalities may have contributed to the unusual location of the teratoma in this case.

Hypothalamic hamartomas and inner ear diverticula with X-linked stapes gusher syndrome - new associations?

X-linked stapes gusher syndrome is a genetic form of deafness with distinct radiographic features on temporal bone CT. Hypothalamic hamartoma is a congenital glioneuronal anomaly of the hypothalamus. We report a potential association between these two rare anomalies that, to our knowledge, has not been reported. Two brothers presented with sensorineural hearing loss and almost identical inner ear and hypothalamic abnormalities, consistent with a diagnosis of X-linked stapes gusher syndrome and hypothalamic hamartoma. Genetic testing revealed identical mutations in the POU3F4 gene associated with X-linked stapes gusher syndrome. Furthermore, multiple vestibular diverticula were seen in both brothers, which have also not been reported with X-linked stapes gusher syndrome. This case suggests that POU3F4 mediated X-linked stapes gusher syndrome may also lead to multiple vestibular diverticula and hypothalamic hamartoma and, therefore, brain magnetic resonance imaging (MRI) could be considered in patients presenting with these inner ear findings.

Coping with ageing in rural Australia.

OBJECTIVE: Ageing is a time of change that might involve financial, health and social losses. To maintain well-being, older people need to engage a range of resources to cope with these losses. However, national policies mainly focus on financial resources. This study used Folkman and Lazarus's transactional theory to identify coping methods engaged by older adults living in three rural communities. DESIGN: A qualitative research design was undertaken using an ethnographic case study approach. SETTING: Three rural communities within northern Australia. PARTICIPANTS: Older Australians aged 65 or over, living in their own homes. MAIN OUTCOME MEASURES: Exploration of techniques that older adults use to cope with ageing (including both problem-focused and emotion-focused strategies). RESULTS: People in rural areas planned their ageing journey using both problem-focused and emotion-focused coping strategies, to deal with the uncertainties of ageing. When participants could control the event, problem-focused coping strategies were mainly such as used seeking social support and planful problem-solving. Conversely, emotion-focused strategies were used to deal with uncertainty and emotive issues such as health decline, and the possibility of needing future care. CONCLUSION: There is a need for health community workers to encourage older people to consider initiating a discussion of future care needs with their social network. This is of particular importance in rural areas, which have larger numbers of older residents and limited resources to support ageing in place.

Patient Data-Sharing for AI: Ethical Challenges, Catholic Solutions.

Recent news of Catholic and secular healthcare systems sharing electronic health record (EHR) data with technology companies for the purposes of developing artificial intelligence (AI) applications has drawn attention to the ethical and social challenges of such collaborations, including threats to patient privacy and confidentiality, undermining of patient consent, and lack of corporate transparency. Although the United States Catholic Conference of Bishops' Ethical and Religious Directives for Health Care Services (ERDs) address collaborations between US Catholic healthcare providers and other entities, the ERDs do not adequately address the novel concerns seen in EHR data-sharing for AI development. Neither does the Health Insurance Portability and Accountability Act (HIPAA) privacy rule. This article describes ethical and social problems observed in recent patient data-sharing collaborations with AI companies and analyzes them in light of the guiding principles of the ERDs as well as the 2020 Rome Call to AI Ethics (RCAIE) document recently released by the Vatican. While both the ERDs and RCAIE guiding principles can inform future collaborations, we suggest that the next revision of the ERDs should consider addressing data-sharing and AI more directly. SUMMARY: Electronic health record data-sharing with artificial intelligence developers presents unique ethical and social challenges that can be addressed with updated United States Catholic Conference of Bishops' Ethical and Religious Directives and guidance from the Vatican's 2020 Rome Call to AI Ethics.

Serious Ethical Violations in Medicine: A Statistical and Ethical Analysis of 280 Cases in the United States From 2008-2016.

Serious ethical violations in medicine, such as sexual abuse, criminal prescribing of opioids, and unnecessary surgeries, directly harm patients and undermine trust in the profession of medicine. We review the literature on violations in medicine and present an analysis of 280 cases. Nearly all cases involved repeated instances (97%) of intentional wrongdoing (99%), by males (95%) in nonacademic medical settings (95%), with oversight problems (89%) and a selfish motive such as financial gain or sex (90%). More than half of cases involved a wrongdoer with a suspected personality disorder or substance use disorder (51%). Despite clear patterns, no factors provide readily observable red flags, making prevention difficult. Early identification and intervention in cases requires significant policy shifts that prioritize the safety of patients over physician interests in privacy, fair processes, and proportionate disciplinary actions. We explore a series of 10 questions regarding policy, oversight, discipline, and education options. Satisfactory answers to these questions will require input from diverse stakeholders to help society negotiate effective and ethically balanced solutions.

Sexual Violation of Patients by Physicians: A Mixed-Methods, Exploratory Analysis of 101 Cases.

A mixed-method, exploratory design was used to examine 101 cases of sexual violations in medicine. The study involved content analysis of cases to characterize the physicians, patient-victims, the practice setting, kinds of sexual violations, and consequences to the perpetrator. In each case, a criminal law framework was used to examine how motives, means, and opportunity combined to generate sexual misconduct. Finally, cross-case analysis was performed to identify clusters of causal factors that explain specific kinds of sexual misconduct. Most cases involved a combination of five factors: male physicians (100%), older than the age of 39 (92%), who were not board certified (70%), practicing in nonacademic settings (94%) where they always examined patients alone (85%). Only three factors (suspected antisocial personality, physician board certification, and vulnerable patients) differed significantly across the different kinds of sexual abuse: personality disorders were suspected most frequently in cases of rape, physicians were more frequently board certified in cases of consensual sex with patients, and patients were more commonly vulnerable in cases of child molestation. Drawing on study findings and past research, we offer a series of recommendations to medical schools, medical boards, chaperones, patients, and the national practitioners database.

Caliber and fitness of the axillary artery as a conduit for large-bore cardiovascular procedures.

OBJECTIVES: We sought to describe the caliber and vascular health of the subclavian and axillary arteries as related to their potential utilization in complex cardiovascular procedures. BACKGROUND: Patients referred for advanced catheter-based therapies frequently have lower extremity peripheral vascular disease that may prohibit the use of large bore arterial catheters. Utilization of the upper extremity peripheral vasculature is rarely considered as an alternative access strategy. This may be due in part to a lack of familiarity with the thoracic vasculature. METHODS AND RESULTS: 208 consecutive patients undergoing routine CTA prior to transcatheter aortic valve replacement were retrospectively evaluated in a systematic analysis of upper and lower extremity vasculature. Minimal luminal diameters (MLDs) for the axillary arteries and iliofemoral arteries were 6.0 ± 1.1 mm and 6.6 ± 1.8 mm respectively. Compared to the iliofemoral arteries, the axillary arteries demonstrated substantially lower rates of significant stenosis (2% vs. 12%, p < 0.01) and significantly lower rates of moderate to severe calcification disease (9% vs. 64%, p < 0.01). Diabetes and tobacco use were independently associated with smaller axillary artery caliber by MLD (p < 0.01) but not with significant stenotic disease. CONCLUSIONS: The axillary arteries are slightly smaller but less frequently diseased than the corresponding iliofemoral vessels.

HIV care continuum outcomes of pregnant women living with HIV with and without depression.

Women living with HIV (WLWH) suffer from poor viral suppression and retention postpartum. The effect of perinatal depression on care continuum outcomes during pregnancy and postpartum is unknown. We performed a retrospective cohort analysis using HIV surveillance data of pregnant WLWH enrolled in perinatal case management in Philadelphia and evaluated the association between possible or definite depression with four outcomes: viral suppression at delivery, care engagement within three months postpartum, retention and viral suppression at one-year postpartum. Out of 337 deliveries (2005-2013) from 281 WLWH, 53.1% (n = 179) had no depression; 46.9% had either definite (n = 126) or possible (n = 32) depression during pregnancy. There were no differences by depression status across all four HIV care continuum outcomes in unadjusted and adjusted analyses. The prevalence of possible or definite depression was high among pregnant WLWH. HIV care continuum outcomes did not differ by depression status, likely because of supportive services and intensive case management provided to women with possible or definite depression.

Regression of a nonfunctioning pituitary macroadenoma on the CDK4/6 inhibitor palbociclib: case report.

A 71-year-old female patient was referred in 2013 for evaluation of an asymptomatic nonsecreting pituitary adenoma. The adenoma, measuring 13 mm in height by 10 mm in width, was discovered incidentally on imaging in 2012. Biochemical testing demonstrated a nonfunctioning adenoma. Given the relatively small lesion size and the lack of symptoms, observation was preferred over surgical intervention. The patient was monitored with routine MRI, which until 2016 demonstrated minimal growth. In early 2016, the patient developed recurrence of metastatic breast cancer and was treated with palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor. This inhibitor acts on a pathway believed to be involved in pituitary adenoma tumorigenesis. One year after starting palbociclib, routine imaging demonstrated significant regression of her pituitary adenoma. The authors hypothesize that inhibition of the CDK4/6 pathway by palbociclib contributed to adenoma regression in this patient, and that palbociclib may represent a possible adjuvant therapy for the treatment of nonfunctioning pituitary adenomas.

Genetic diversity and sex ratio of naked mole rat, Heterocephalus glaber, zoo populations.

The naked mole rat, Heterocephalus glaber, is a highly unusual mammal that displays a complex social system similar to that found in eusocial insects. Colonies of H. glaber are commonly maintained in zoo collections because they represent fascinating educational exhibits for the public. However, little is known about the genetic structure or sex ratio of captive populations of H. glaber. In this study, we developed a set of microsatellite markers to examine genetic variation in three captive zoo populations of H. glaber. We also studied sex ratio of these captive populations. Our goal was to determine levels of genetic variation within, and genetic differences between, captive populations of H. glaber. Overall, we found modest levels of genetic variation in zoo populations. We also uncovered little evidence for inbreeding within the captive populations. However, zoo populations did differ genetically, which may reflect the isolation of captive naked mole rat colonies. Finally, we found no evidence of biased sex ratios within colonies. Overall, our study documents levels of genetic variation and sex ratios in a captive eusocial mammalian population. Our results may provide insight into how to manage captive populations of H. glaber.