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.

Defining a universal measurement unit and scale for gross motor development.

Introduction: The ability of children to accomplish progressively more difficult gross motor tasks follows a predictable sequence that has been well documented as part of development. Current existing instruments were developed independently using classical test theory methods which led to the lack of a universal measurement scale and unit. The purpose of this study was to test a specification equation, anchored to commonly accepted and reproducible tasks in gross motor development, to generate a universal measurement scale and unit of measurement, called the Gross Motor (GM) unit. Methods: We rated component measures for each of the gross motor development tasks on the Gross Motor Function Measure-66 (GMFM). The GMFM is a gross motor development measure created with Rasch measurement theory to quantify observed difficulty levels measured on an interval scale. Component measures for body position, movement, and support were based on hypothesized contributions to gross motor development based on theory. Forward stepwise linear regression was used to test a specification equation. The specification equation was anchored to reference points to fix a unit size. Results: Our specification equation explained 87% of the variance in observed gross motor task difficulty. Predicted difficulty for gross motor tasks was strongly associated with observed task difficulty (r = 0.94, p < 0.0001). Our specification equation was anchored to 1) lying supine (0 GM units) and 2) walking unsupported (100 GM units) setting the size of the GM unit to 1/100 of the distance between lying supine and unsupported walking. Discussion: Our specification equation allows for experimental testing of gross motor development theories. This approach provides a framework for refining our understanding and measurement of gross motor development and creates a universal scale and unit. We expect that this will facilitate placing many, if not all, current gross motor development instruments on the same measurement scale.

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.

Equity Concerns Across Pediatric Research Recruitment: An Analysis of Research Staff Interviews.

BACKGROUND AND OBJECTIVES: Difficulty recruiting individuals from minoritized and underserved populations for clinical research is well documented and has health equity implications. Previously, we reported findings from interviews with research staff about pediatric research recruitment processes. Respondents raised equity concerns related to recruitment and enrollment of participants from minoritized, low resourced, and underserved populations. We therefore decided to perform a secondary coding of the transcripts to examine equity-related issues systematically. METHODS: We conducted a process of secondary coding and analysis of interviews with research staff involved in recruitment for pediatric clinical research. Through consensus we identified codes relevant to equity and developed a conceptual framework including 5 stages of research. RESULTS: We analyzed 28 interviews and coded equity-related items. We report 6 implications of our findings. First, inequitable access to clinical care is an upstream barrier to research participation. Second, there is a need to increase research opportunities where underserved and under-represented populations receive care. Third, increasing research team diversity can build trust with patients and families, but teams must ensure adequate support of all research team members. Fourth, issues related to consent processes raise institutional-level opportunities for improvement. Fifth, there are numerous study procedure-related barriers to participation. Sixth, our analysis illustrates that individuals who speak languages other than English face barriers across multiple stages. CONCLUSIONS: Research staff members identified equity-related concerns and recommended potential solutions across 5 stages of the research process, which may guide those endeavoring to improve research recruitment for pediatric patients from minoritized and underserved populations.

Systematic identification of disease-causing promoter and untranslated region variants in 8,040 undiagnosed individuals with rare disease.

Background: Both promoters and untranslated regions (UTRs) have critical regulatory roles, yet variants in these regions are largely excluded from clinical genetic testing due to difficulty in interpreting pathogenicity. The extent to which these regions may harbour diagnoses for individuals with rare disease is currently unknown. Methods: We present a framework for the identification and annotation of potentially deleterious proximal promoter and UTR variants in known dominant disease genes. We use this framework to annotate de novo variants (DNVs) in 8,040 undiagnosed individuals in the Genomics England 100,000 genomes project, which were subject to strict region-based filtering, clinical review, and validation studies where possible. In addition, we performed region and variant annotation-based burden testing in 7,862 unrelated probands against matched unaffected controls. Results: We prioritised eleven DNVs and identified an additional variant overlapping one of the eleven. Ten of these twelve variants (82%) are in genes that are a strong match to the individual's phenotype and six had not previously been identified. Through burden testing, we did not observe a significant enrichment of potentially deleterious promoter and/or UTR variants in individuals with rare disease collectively across any of our region or variant annotations. Conclusions: Overall, we demonstrate the value of screening promoters and UTRs to uncover additional diagnoses for previously undiagnosed individuals with rare disease and provide a framework for doing so without dramatically increasing interpretation burden.

Social Determinants of Health Screening at an Urban Emergency Department Urgent Care During COVID-19.

INTRODUCTION: Social determinants of health (SDoH) impact patients' health outcomes, yet screening methods in emergency departments (ED) are not consistent or standardized. The SDoH-related health disparities may have widened during the coronavirus 2019 (COVID-19) pandemic, especially among patients who primarily receive their medical care in EDs. We sought to identify SDoH among ED urgent care patients during the COVID-19 pandemic at an urban safety-net hospital, assess the impact of the pandemic on their SDoH, study the feasibility of SDoH screening and resource referrals, and identify preferred methods of resource referrals and barriers to accessing resources. METHODS: Research assistants screened ED urgent care patients using a validated SDoH screener, inquiring about the impact of COVID-19 on their SDoH. A printed resource guide was provided. Two weeks later, a follow-up telephone survey assessed for barriers to resource connection and patients' preferred methods for resource referrals. This study was deemed exempt by our institutional review board. RESULTS: Of the 418 patients presented with a screener, 414 (99.0%) patients completed the screening. Of those screened, 296 (71.5%) reported at least one adverse SDoH, most commonly education (38.7%), food insecurity (35.3%), and employment (31.0%). Housing insecurity was reported by 21.0%. Over half of patients (57.0%) endorsed COVID-19 affecting their SDoH. During follow-up, 156 of 234 (67%) attempted calls were successful and 36/156 (23.1%) reported attempting to connect with a resource, with most attempts made for stable housing (11.0%) and food (7.7%). Reasons for not contacting the provided resources included lack of time (37.8%) and forgetting to do so (26.3%). Patients preferred resource guides to be printed (34.0%) and sent via text message to their mobile devices (25.6%). CONCLUSION: Many urgent care patients of this urban ED reported at least one adverse SDoH, the majority of which were exacerbated by the COVID-19 pandemic. This finding further emphasizes the need to allocate more resources to standardize and expand SDoH screening in EDs. Additionally, hospitals should increase availability of printed or electronic SDoH resource guides, resource navigators, and interpreters both during and after ED visits.

An Experience Sampling Analysis of the Impact of Video Monitoring Technology and In-Person Sitters on Nurse Burnout: The Moderating Effect of Nurse Commitment and Mediating Effect of Emotional Labor.

BACKGROUND: While it is established that video monitoring technology (compared with the use of in-person sitters) is a safe and cost-effective solution for hospitals, little is known about the impact of these approaches on nurses' stress and well-being. PURPOSE: To compare the use of video monitoring technology and in-person sitters (likely a resource reallocated from nurses) for monitoring patients on nurses' emotional labor and burnout. METHOD: An experience sampling method was conducted by surveying nurses twice a day for 3 weeks, resulting in 524 survey administrations provided by 74 nurses. The surveys included measures of daily video monitoring technology and in-person sitter use, emotional labor, emotional exhaustion, and nurse career commitment. FINDINGS: There were positive effects from video monitoring technology and negative effects of in-person sitters on emotional labor and emotional exhaustion, particularly for nurses lower in commitment. DISCUSSION: Hospital adoption of video monitoring technology has a positive impact on nurses compared with in-person sitter use.

Inclusive, engaged, and accountable institutional review boards.

In February 2023, the U.S. Government Accountability Office (GAO) released another report acknowledging that we still lack meaningful, validated, widely-accepted measures for evaluating institutional review board (IRB) quality and effectiveness. This challenge is well known to the Consortium to Advance Effective Research Ethics Oversight (www.AEREO.org), a collaborative group of human research protection (HRP) professionals, researchers, and research ethicists founded in 2018 to do precisely what GAO recommends: examine approaches for measuring IRB effectiveness in protecting human subjects, and implement the approaches as appropriate. Two underlying tenets have been central to AEREO's as approach to thinking about IRB quality and effectiveness: (1) IRBs exist to protect participants and thus the participant perspective should be central to all IRBs do; and (2) because IRBs are tasked with applying subjective ethical and regulatory standards about which people may disagree, their approach and decisions should at least meet the basic standard of reasonableness in terms of accounting for relevant perspectives, considering key factors, and providing defensible justifications. Critical to each of these tenets, IRBs should include diverse perspectives in their deliberations, find ways to meaningfully engage with relevant communities about their views regarding ethical research and appropriate participant protections, and be accountable to the public.

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.

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 Cross Sectional Survey of Recruitment Practices, Supports, and Perceived Roles for Unaffiliated and Non-scientist Members of IRBs.

BACKGROUND: Institutional Review Boards (IRBs) are federally mandated to include both nonscientific and unaffiliated representatives in their membership. Despite this, there is no guidance or policy on the selection of unaffiliated or non-scientist members and reports indicate a lack of clarity regarding members' roles. In the present study we sought to explore processes of recruitment, training, and the perceived roles for unaffiliated and non-scientist members of IRBs. METHODS: We distributed a self-administered REDCap survey of members of the Association for the Accreditation of Human Research Protection Programs familiar with IRB member recruitment. The survey included closed and open-ended questions regarding: the operation of the HRPP/IRB(s), how unaffiliated and non-scientist members are recruited, whether they had faced challenges recruiting for these roles, and training and mentorship offered. The survey also collected information regarding the perceived value and roles of unaffiliated and non-scientist members. RESULTS: 76 responses were included in the analysis (38% completion rate). The most common approach for recruitment was referral from current IRB members, with almost half of respondents indicating challenges recruiting unaffiliated members. Over 75% indicated no additional training was provided to unaffiliated or non-scientist members compared to affiliated or scientist members. Most common supports provided were travel/parking expenses and honoraria. Commonly perceived roles were to provide an independent voice from the participant perspective, notably regarding consent processes and materials. CONCLUSIONS: Respondents indicated challenges in defining unaffiliated and non-scientist members and limited practices toward recruitment and support. Future work should more closely examine the challenges in defining these roles and applying the definitions in practice, as well as strategies that may improve recruitment and retention of unaffiliated and non-scientist members.

Decolonizing Global Health Research: Perspectives from US and International Global Health Trainees.

Background: "Decolonizing global health" (DGH) may help global health trainees understand and remediate the effects of historical colonialism on global health, but little is known regarding how trainees perceive DGH. Understanding their perspectives is critical for designing educational interventions tailored to their needs. Objectives: To understand how trainees perceive DGH research and to determine if perspectives differ between trainees from high- (HICs) versus low- and middle-income countries (LMICs). Methods: An online survey of all 2017-2022 pre-doctoral and post-doctoral trainees (n = 111) and mentors (n = 91) within a multi-university program that supports US and international investigators in one-year mentored global health research. The survey evaluated individuals' self-reported knowledge and attitudes toward DGH and their perceptions of historical colonialism's impact on eight aspects of global health. Findings: The response rate to trainee surveys was 56%. Trainees from LMICs were less aware of the concept of DGH; 5/25 (20%) had never heard of DGH and 16/25 (64%) reported that they "know a little," whereas all HIC trainees had heard of DGH and 29/36 (81%) reported that they "know a little" (p = 0.019). For three aspects of global health (i.e., which research questions get asked; development of collaborative relationships; and data/statistical analyses), trainees from LMICs were more likely to report positive effects of colonialism. However, in open-ended responses, no thematic differences existed between how LMIC and HIC trainees defined DGH (i.e., actively eliminating power imbalances; prioritizing local needs; promoting local leadership; providing equitable opportunities; and ensuring programs are culturally appropriate). Conclusions: Different perspectives surrounding what DGH means suggest a shared understanding may be needed and is arguably prerequisite to designing educational interventions to help global health trainees recognize, understand, and act in global health. Future research is needed to understand perspectives on decolonization across diverse contexts with attention to constructs such as race, ethnicity, and gender.

Evaluating a social risk screening and referral program in an urban safety-net hospital emergency department.

Objective: The emergency department (ED) is an opportune venue to screen for unmet social needs and connect patients with social services. This quality improvement study incorporates both qualitative and quantitative data to examine unmet social needs among ED patients and program implementation. Methods: From September 2020 to December 2021, an urban safety-net hospital adult ED implemented a social needs screening and referral program. Trained emergency staff screened eligible patients for 5 social needs (housing, food, transportation, utilities, employment), giving resource guides to patients who screened positive (THRIVE+). We collected screening data from the electronic health record, conducted semi-structured interviews with THRIVE+ patients and clinical staff, and directly observed discharge interactions. Results: Emergency staff screened 58.5% of eligible patients for social risk. Of the screened patients, 27.0% reported at least 1 unmet social need. Of those, 74.8% requested assistance. Screened patients reported housing insecurity (16.3%) as the most prevalent unmet social need followed by food insecurity (13.3%) and unemployment (8.7%). Among interviewed patients, 57.1% recalled being screened, but only 24.5% recalled receiving resource guides. Patients who received guides reported little success connecting with resources and supported universal guide dissemination. Staff expressed preference for warm handoff to social services. Of 13 observed discharge interactions, clinical staff only discussed guides with 2 patients, with no positive endorsement of the guides in any observed interactions. Conclusions: An ED social needs screening program can be moderately feasible and accepted. We identified housing as the most prevalent need. Significant gaps exist between screening and referral, with few patients receiving resources. Further training and workflow optimization are underway.

Perspectives of mental health professionals on the delivery of embedded mental health services for U.S. Air Force airmen.

United States Air Force (USAF) leadership implemented the integrated operational support care model, which involves embedding mental health professionals directly within operational units to meet the mental health needs of airmen. The present study evaluated perspectives of embedded mental health professionals on the delivery of embedded care services for airmen assigned to various units and installations. We conducted semistructured interviews with 26 embedded mental health professionals. Interviews were audio-recorded and transcribed verbatim for qualitative analysis, involving thematic content analysis to identify and tabulate key themes emergent from the data. The most commonly reported barriers to delivering embedded mental health services were overcoming stigma associated with seeking mental health care, low staffing, insufficient training, and disconnected relationships between medical treatment facility and other support agencies. Interviewees described numerous strategies for effectively delivering embedded mental health services to include fully understanding and being able to communicate levels of mental health care services, reducing stigma, facilitating coordination of care/resources, and developing initiatives to target population needs. This is the first in-depth, systematic exploration of provider perspectives on embedded mental health services in the USAF. Future research should focus on how best to support embedded care programs to sustain this invaluable service for airmen and other military communities over time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

What Can State Medical Boards Do to Effectively Address Serious Ethical Violations?

State Medical Boards (SMBs) can take severe disciplinary actions (e.g., license revocation or suspension) against physicians who commit egregious wrongdoing in order to protect the public. However, there is noteworthy variability in the extent to which SMBs impose severe disciplinary action. In this manuscript, we present and synthesize a subset of 11 recommendations based on findings from our team's larger consensus-building project that identified a list of 56 policies and legal provisions SMBs can use to better protect patients from egregious wrongdoing by physicians.

A Novel CRISPR Interference Effector Enabling Functional Gene Characterization with Synthetic Guide RNAs.

While CRISPR interference (CRISPRi) systems have been widely implemented in pooled lentiviral screening, there has been limited use with synthetic guide RNAs for the complex phenotypic readouts enabled by experiments in arrayed format. Here we describe a novel deactivated Cas9 fusion protein, dCas9-SALL1-SDS3, which produces greater target gene repression than first or second generation CRISPRi systems when used with chemically modified synthetic single guide RNAs (sgRNAs), while exhibiting high target specificity. We show that dCas9-SALL1-SDS3 interacts with key members of the histone deacetylase and Swi-independent three complexes, which are the endogenous functional effectors of SALL1 and SDS3. Synthetic sgRNAs can also be used with in vitro-transcribed dCas9-SALL1-SDS3 mRNA for short-term delivery into primary cells, including human induced pluripotent stem cells and primary T cells. Finally, we used dCas9-SALL1-SDS3 for functional gene characterization of DNA damage host factors, orthogonally to small interfering RNA, demonstrating the ability of the system to be used in arrayed-format screening.

All-Cause Severe Maternal Morbidity (SMM) and Transfusion-Only SMM Are Independently Associated with a Lower Likelihood of Exclusive Breastfeeding.

Background: The rates of severe maternal morbidity (SMM) including blood transfusions after delivery are rising, yet little is known about the impact of these experiences on breastfeeding. Materials and Methods: This is a single-institution retrospective cohort study examining breastfeeding rates at three time points for 1,857 first-time parents delivered at term between July 1, 2016 and June 30, 2019. Our exposure of interest was SMM, which was subdivided into SMM where transfusion was the only indicator (transfusion-only SMM) and SMM where another indicator (diagnostic or procedural) was met, which may also include transfusion (all-cause SMM). Association between transfusion-only SMM and all-cause SMM with feeding method was determined using multinomial regression modeling and adjusting for relevant sociodemographic characteristics. Results: The majority of those with uncomplicated deliveries were exclusively breastfeeding at the 2- to 4-week and 2- to 3-month time points (59.6% and 53.6%, respectively), in contrast to 46.3% and 42.0% of those who had experienced transfusion-only SMM, and 40.9% and 30% of those who had experienced all-cause SMM. In adjusted models, receipt of a blood transfusion was found to be associated with greater risk of exclusive formula feeding at all time points. Experience of all-cause SMM was significantly associated with increased likelihood of exclusive formula feeding at hospital discharge and the 2- to 3-month time point. Conclusions: We identified that experience of all-cause SMM and transfusion-only SMM are independently associated with a lower likelihood of exclusive breastfeeding after adjusting for sociodemographic factors. Perinatal clinicians should be aware of these risks and offer increased support to these couplets.