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Summary: Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: −22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models. Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case–control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions. Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: −17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: −17.9% to 89.6%), and further increased to 80.9% (95% CI: −17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker. Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen. Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV.

Abstract Marine heatwaves are increasing in frequency and duration, threatening tropical reef ecosystems through intensified coral bleaching events. We examined a strikingly variable spatial pattern of bleaching in Moorea, French Polynesia following a heatwave that lasted from November 2018 to July 2019. In July 2019, four months after the onset of bleaching, we surveyed > 5000 individual colonies of the two dominant coral genera, Pocillopora and Acropora, at 10 m and 17 m water depths, at six forereef sites around the island where temperature was measured. We found severe bleaching increased with colony size for both coral genera, but Acropora bleached more severely than Pocillopora overall. Acropora bleached more at 10 m than 17 m, likely due to higher light availability at 10 m compared to 17 m, or greater daily temperature fluctuation at depth. Bleaching in Pocillopora corals did not differ with depth but instead varied with the interaction of colony size and Accumulated Heat Stress (AHS), in that larger colonies (> 30 cm) were more sensitive to AHS than mid-size (10–29 cm) or small colonies (5–9 cm). Our findings provide insight into complex interactions among coral taxa, colony size, and water depth that produce high spatial variation in bleaching and related coral mortality.

Background: Pain is often a significant symptom in patients with head and neck cancer (HNC). The objective of this study was to determine the prevalence of pain, factors limiting effective pain management, and whether differences in pain management exist between the public and private health sectors in South Africa in HNC patients after they have completed treatment. Methods: A cross-sectional survey using the Brief Pain Inventory was performed on adults over the age of 18 years treated for HNC of any subsite in both a public and private hospital in Cape Town, South Africa. Results: Overall pain scores indicated mild levels of pain and impact on daily activities. The domains of life most affected by pain were general activity, sleep and mood. There was no difference in pain scores between public hospital patients versus those with private insurance. Less than half of the patients reported receiving all their necessary medications. Most of the postoperative pain was managed with paracetamol, tramadol and ibuprofen, with only 12.8% of patients using morphine. Conclusion: This study provides a survey of pain experiences in HNC patients in a middle-income country. Insurance status did not significantly impact pain experiences, indicating equitable access to pain management resources. However, the overall utilisation of morphine and medications used to treat neuropathic pain is low. Further research is needed into the complex factors associated with pain in HNC patients. Contribution: This article is an example of a standard clinical study on patient-reported outcome measures.

Background Access to sample-level metadata is important when selecting public metagenomic sequencing datasets for reuse in new biological analyses. The Standards, Precautions, and Advances in Ancient Metagenomics community (SPAAM, https://spaam-community.org) has previously published AncientMetagenomeDir, a collection of curated and standardised sample metadata tables for metagenomic and microbial genome datasets generated from ancient samples. However, while sample-level information is useful for identifying relevant samples for inclusion in new projects, Next Generation Sequencing (NGS) library construction and sequencing metadata are also essential for appropriately reprocessing ancient metagenomic data. Currently, recovering information for downloading and preparing such data is difficult when laboratory and bioinformatic metadata is heterogeneously recorded in prose-based publications. Methods Through a series of community-based hackathon events, AncientMetagenomeDir was updated to provide standardised library-level metadata of existing and new ancient metagenomic samples. In tandem, the companion tool 'AMDirT' was developed to facilitate rapid data filtering and downloading of ancient metagenomic data, as well as improving automated metadata curation and validation for AncientMetagenomeDir. Results AncientMetagenomeDir was extended to include standardised metadata of over 6000 ancient metagenomic libraries. The companion tool 'AMDirT' provides both graphical- and command-line interface based access to such metadata for users from a wide range of computational backgrounds. We also report on errors with metadata reporting that appear to commonly occur during data upload and provide suggestions on how to improve the quality of data sharing by the community. Conclusions Together, both standardised metadata reporting and tooling will help towards easier incorporation and reuse of public ancient metagenomic datasets into future analyses.

Abstract Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline CAG expansions, somatic repeat expansions in neurons also contribute to HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as a genetic modifier of HD onset and progression, promotes somatic CAG expansions, and thus presents a potential therapeutic target. However, what extent of MSH3 protein reduction is needed to attenuate somatic CAG expansions and elicit therapeutic benefits in HD disease models is less clear. In our study, we employed potent di-siRNAs to silence mouse Msh3 mRNA expression in a dose-dependent manner in HdhQ111/+ mice and correlated somatic Htt CAG instability with MSH3 protein levels from simultaneously isolated DNA and protein after siRNA treatment. Our results reveal a linear correlation with a proportionality constant of ~ 1 between the prevention of somatic Htt CAG expansions and MSH3 protein expression in vivo, supporting MSH3 as a rate-limiting step in somatic expansions. Intriguingly, despite a 75% reduction in MSH3 protein levels, striatal nuclear HTT aggregates remained unchanged. We also note that evidence for nuclear Msh3 mRNA that is inaccessible to RNA interference was found, and that MSH6 protein in the striatum was upregulated following MSH3 knockdown in HdhQ111/+ mice. These results provide important clues to address critical questions for the development of therapeutic molecules targeting MSH3 as a potential therapeutic target for HD.

Abstract The COVID-19 pandemic has highlighted the importance of understanding what contributes to individual variability in experiences of stress. Increases in stress related to the pandemic have been especially pronounced in parents, indicating a need for research examining what factors contribute to parents’ perceptions of stress. Here, we assessed the relationship between parents’ perceptions of stress, control, loneliness, and experiences of childhood trauma in two populations of caregivers. In Study 1, we examined the relationship between perceptions of stress, control, loneliness, and history of early stress, along with indices of socioeconomic risk and resting parasympathetic nervous systema activity, which has been linked to variability in perceptions of stress, in caregivers of young children. Perceived control, loneliness, childhood stress, and resting parasympathetic nervous system activity predicted caregivers’ stress. In Study 2, we replicated these initial findings in a second sample of caregivers. Additionally, we examined how these processes change over time. Caregivers demonstrated significant changes in perceptions of control, loneliness, and stress, and changes in control and childhood trauma history were associated with changes in perceptions of stress. Together these results indicate the importance of assessing how caregivers perceive their environment when examining what contributes to increased risk for stress. Additionally, they suggest that caregivers’ stress-related processes are malleable and provide insight into potential targets for interventions aimed at reducing parents’ stress.

Purpose: The profession of genetic counselors has existed for over 50 years. This article provides an update on the global state of the genetic counseling (GC) profession in 2022 and 2023. Methods: We used a survey approach to collect data from individuals who were identified as being leaders in GC practice and/or education around the world. Results: Based on responses provided between October 2023 and January 2024, we estimate that there are over 10,250 genetic counselors in over 45 countries around the world. These numbers have increased significantly in the past 5 years, when there were ∼7000 genetic counselors. Key factors identified as driving the increase in genetic counselors are the number of training programs that have developed (>130 globally, mostly at a master’s degree level) and a growing number of national biobanks and/or population screening programs that require GC as part of the process. There is tremendous variability in how genetic counselors are regulated, with only a few countries holding national statutory regulation processes. There are many commonalities, but the GC profession appears nuanced to their specific country and its wider socio-political context and history. Conclusion: We hope that genetic counselors internationally will come together to assist each other in all aspects: training, statutory regulation, developing the workforce, and establishing GC as an academic discipline. We envision that establishing an international organization for the profession of genetic counselors might maintain such international connections and provide relevant data in future years.

Trauma is a common cause of morbidity and mortality in humans and companion animals. Recent efforts in procedural development, training, quality systems, data collection, and research have positively impacted patient outcomes; however, significant unmet need still exists. Coordinated efforts by collaborative, translational, multidisciplinary teams to advance trauma care and improve outcomes have the potential to benefit both human and veterinary patient populations. Strategic use of veterinary clinical trials informed by expertise along the research spectrum (i.e., benchtop discovery, applied science and engineering, large laboratory animal models, clinical veterinary studies, and human randomized trials) can lead to increased therapeutic options for animals while accelerating and enhancing translation by providing early data to reduce the cost and the risk of failed human clinical trials. Active topics of collaboration across the translational continuum include advancements in resuscitation (including austere environments), acute traumatic coagulopathy, trauma-induced coagulopathy, traumatic brain injury, systems biology, and trauma immunology. Mechanisms to improve funding and support innovative team science approaches to current problems in trauma care can accelerate needed, sustainable, and impactful progress in the field. This review article summarizes our current understanding of veterinary and human trauma, thereby identifying knowledge gaps and opportunities for collaborative, translational research to improve multispecies outcomes. This translational trauma group of MDs, PhDs, and DVMs posit that a common understanding of injury patterns and resulting cellular dysregulation in humans and companion animals has the potential to accelerate translation of research findings into clinical solutions.

BACKGROUND: While health data sharing for research purposes is strongly supported in principle, it can be challenging to implement in practice. Little is known about the actual bottlenecks to health data sharing in Switzerland. AIMS OF THE STUDY: This study aimed to assess the obstacles to Swiss health data sharing, including legal, ethical and logistical bottlenecks. METHODS: We identified 37 key stakeholders in data sharing via the Swiss Personalised Health Network ecosystem, defined as being an expert on sharing sensitive health data for research purposes at a Swiss university hospital (or a Swiss disease cohort) or being a stakeholder in data sharing at a public or private institution that uses such data. We conducted semi-structured interviews, which were transcribed, translated when necessary, and de-identified. The entire research team discussed the transcripts and notes taken during each interview before an inductive coding process occurred. RESULTS: Eleven semi-structured interviews were conducted (primarily in English) with 17 individuals representing lawyers, data protection officers, ethics committee members, scientists, project managers, bioinformaticians, clinical trials unit members, and biobank stakeholders. Most respondents felt that it was not the actual data transfer that was the bottleneck but rather the processes and systems around it, which were considered time-intensive and confusing. The templates developed by the Swiss Personalised Health Network and the Swiss General Consent process were generally felt to have streamlined processes significantly. However, these logistics and data quality issues remain practical bottlenecks in Swiss health data sharing. Areas of legal uncertainty include privacy laws when sharing data internationally, questions of “who owns the data”, inconsistencies created because the Swiss general consent is perceived as being implemented differently across different institutions, and definitions and operationalisation of anonymisation and pseudo-anonymisation. Many participants desired to create a “culture of data sharing” and to recognise that data sharing is a process with many steps, not an event, that requires sustainability efforts and personnel. Some participants also stressed a desire to move away from data sharing and the current privacy focus towards processes that facilitate data access. CONCLUSIONS: Facilitating a data access culture in Switzerland may require legal clarifications, further education about the process and resources to support data sharing, and further investment in sustainable infrastructureby funders and institutions.

Background: Inter-individual differences in opioid sensitivity may underlie different opioid risk profiles but have often been researched in persons who have current or past opioid use disorder or physical dependence. This study examined how opioid sensitivity manifests across various assessments of opioid effects in a primarily opioid-naïve population. Procedures: Data were harmonized from two within-subject, double-blind trials wherein healthy participants (N = 123) received placebo and 4 mg oral hydromorphone. Demographics, self-report ratings, observer ratings, physiological, and cold pressor measures were collected. Participants were categorized as being responsive or nonresponsive to the opioid dose tested and compared using mixed-models, Pearson product correlations, and paired t-tests. Findings: Participants were 49.6% female, mean 33.0 (SD=9.3) years old, and 44.7% Black/African American and 41.5% White, with 89.4% reporting no prior exposure to opioids. Within-subject sensitivity to opioids varied depending on the measure. One in five participants did not respond subjectively to the 4 mg hydromorphone dose based on their “Drug Effects” rating. Persons who were responsive showed more evidence of drug-dependent effects than did persons who were not responsive on ratings of Bad Effects (p= .03), feeling High (p= .01), Nausea (p= .03), pupil diameter (p< 0.01), and on the circular lights task (p< 0.001). Conclusions: This study provides initial evidence that the experience of opioids may be domain specific. Data suggest potentially clinically meaningful differences exist regarding opioid response patterns, evident following one dose among opioid inexperienced individuals.

Women with a family history of breast cancer have an increased lifetime risk of the disease. Delay in symptom presentation can lead to poorer outcomes. Low awareness of breast cancer symptoms and help-seeking barriers have been associated with delay in presentation in the general population. Symptom awareness and help-seeking barriers among women at increased risk of breast cancer are unknown. We conducted analysis of survey data which included women with moderate and high risk of breast cancer from 20 secondary and tertiary care clinics in England (n = 408). Women completed a validated survey assessing breast cancer symptom awareness, barriers to help-seeking and anticipated delay in help-seeking. Women recognised an average of 9.1/11 breast cancer symptoms (SD = 2.1). Nipple rash was the least recognised symptom (51.0%). Women educated to at least degree level had higher awareness than those with lower education (β = 0.14, 95% CI 0.13, 0.99, p = 0.011). Women at lower socioeconomic status (SES) had lower awareness than those at higher SES (β = -0.13, 95% CI −1.09, −0.07, p = 0.027). Women reported several anticipated help-seeking barriers (mean = 4.0/11, SD = 2.8). Waiting to see if a symptom will pass was the most commonly reported barrier to help-seeking (71.5%). Most women (376/408; 92.2%) reported that they would seek medical help within 2 weeks of discovering a breast cancer symptom. Interventions to increase awareness of non-lump breast cancer symptoms and reduce help-seeking barriers are needed, with considerations of appropriate reading levels and modalities for women with lower education and SES.

Abstract Pyrimidine catabolism is implicated in hepatic steatosis. Dihydropyrimidine dehydrogenase (DPYD) is an enzyme responsible for uracil and thymine catabolism, and DPYD human genetic variability affects clinically observed toxicity following 5-Fluorouracil administration. In an in vitro model of fatty acid-induced steatosis, the pharmacologic inhibition of DPYD resulted in protection from lipid accumulation. Additionally, a gain-of-function mutation of DPYD, created through clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) engineering, led to an increased lipid burden, which was associated with altered mitochondrial functionality in a hepatocarcionma cell line. The studies presented herein describe a novel role for DPYD in hepatocyte metabolic regulation as a modulator of hepatic steatosis.

Summary: Background: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. Methods: The case–control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. Findings: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. Interpretation: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. Funding: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.

Abstract Poor quality medical research causes serious harms by misleading healthcare professionals and policymakers, decreasing trust in science and medicine, and wasting public funds. Here we outline underlying problems including insufficient transparency, dysfunctional incentives, and reporting biases. We make the following recommendations to address these problems: Journals and funders should ensure authors fulfil their obligation to share detailed study protocols, analytical code, and (as far as possible) research data. Funders and journals should incentivise uptake of registered reports and establish funding pathways which integrate evaluation of funding proposals with initial peer review of registered reports. A mandatory national register of interests for all those who are involved in medical research in the UK should be established, with an expectation that individuals maintain the accuracy of their declarations and regularly update them. Funders and institutions should stop using metrics such as citations and journal’s impact factor to assess research and researchers and instead evaluate based on quality, reproducibility, and societal value. Employers and non-academic training programmes for health professionals (clinicians hired for patient care, not to do research) should not select based on number of research publications. Promotions based on publication should be restricted to those hired to do research.

We detected Eurasian-origin highly pathogenic avian influenza A(H5N1) virus belonging to the Gs/GD lineage, clade 2.3.4.4b, in wild waterfowl in 2 Atlantic coastal states in the United States. Bird banding data showed widespread movement of waterfowl within the Atlantic Flyway and between neighboring flyways and northern breeding grounds.

Abstract Mass thermal bleaching events are a primary threat to coral reefs, yet the sublethal impacts, particularly on energetics and reproduction, are poorly characterized. Given that the persistence of coral populations is contingent upon the reproduction of individuals that survive disturbances, there is an urgent need to understand the sublethal effects of bleaching on reproductive output to accurately predict coral recovery rates. In 2019, the French Polynesian island of Mo’orea experienced a severe mass bleaching event accompanied by widespread coral mortality. At the most heavily impacted sites, we observed Acropora hyacinthus individuals that were resistant to bleaching, alongside colonies that bleached but showed signs of symbiont recovery shortly after the bleaching event. We collected fragments from A. hyacinthus colonies five months post-bleaching and, using energetic assays and histological measurements, examined the physiological and reproductive consequences of these two distinct heat stress responses. Despite healthy appearances in both resistant and recovered corals, we found that recovered colonies had significantly reduced energy reserves compared to resistant colonies. In addition, we detected compound effects of stress on reproduction: recovered colonies displayed both a lower probability of containing gametes and lower fecundity per polyp. Our results indicate that bleaching inflicts an energetic constraint on the concurrent re-accumulation of energy reserves and development of reproductive material, with decreased reproductive potential of survivors possibly hampering overall reef resilience. These findings highlight the presence of intraspecific responses to bleaching and the importance of considering multiple trajectories for individual species when predicting population recovery following disturbance.

Introduction Artificial intelligence (AI) has the potential to transform clinical decision-making as we know it. Powered by sophisticated machine learning algorithms, clinical decision support systems (CDSS) can generate unprecedented amounts of predictive information about individuals’ health. Yet, despite the potential of these systems to promote proactive decision-making and improve health outcomes, their utility and impact remain poorly understood due to their still rare application in clinical practice. Taking the example of AI-powered CDSS in stroke medicine as a case in point, this paper provides a nuanced account of stroke survivors’, family members’, and healthcare professionals’ expectations and attitudes towards medical AI. Methods We followed a qualitative research design informed by the sociology of expectations, which recognizes the generative role of individuals’ expectations in shaping scientific and technological change. Semi-structured interviews were conducted with stroke survivors, family members, and healthcare professionals specialized in stroke based in Germany and Switzerland. Data was analyzed using a combination of inductive and deductive thematic analysis. Results Based on the participants’ deliberations, we identified four presumed roles that medical AI could play in stroke medicine, including an administrative, assistive, advisory, and autonomous role AI. While most participants held positive attitudes towards medical AI and its potential to increase accuracy, speed, and efficiency in medical decision making, they also cautioned that it is not a stand-alone solution and may even lead to new problems. Participants particularly emphasized the importance of relational aspects and raised questions regarding the impact of AI on roles and responsibilities and patients’ rights to information and decision-making. These findings shed light on the potential impact of medical AI on professional identities, role perceptions, and the doctor-patient relationship. Conclusion Our findings highlight the need for a more differentiated approach to identifying and tackling pertinent ethical and legal issues in the context of medical AI. We advocate for stakeholder and public involvement in the development of AI and AI governance to ensure that medical AI offers solutions to the most pressing challenges patients and clinicians face in clinical care.

People living with HIV-1 (PLWH) exhibit more rapid antibody decline following routine immunization and elevated baseline chronic inflammation than people without HIV-1 (PWOH), indicating potential for diminished humoral immunity during SARS-CoV-2 infection. Conflicting reports have emerged on the ability of PLWH to maintain humoral protection against SARS-CoV-2 coinfection during convalescence. It is unknown whether peak COVID-19 severity, along with HIV-1 infection status, associates with the quality and quantity of humoral immunity following recovery. Using a cross-sectional observational cohort from the United States and Peru, adults were enrolled 1–10 weeks after SARS-CoV-2 infection diagnosis or symptom resolution. Serum antibodies were analyzed for SARS-CoV-2–specific response rates, binding magnitudes, ACE2 receptor blocking, and antibody-dependent cellular phagocytosis. Overall, (a) PLWH exhibited a trend toward decreased magnitude of SARS-CoV-2–specific antibodies, despite modestly increased overall response rates when compared with PWOH; (b) PLWH recovered from symptomatic outpatient COVID-19 had comparatively diminished immune responses; and (c) PLWH lacked a corresponding increase in SARS-CoV-2 antibodies with increased COVID-19 severity when asymptomatic versus symptomatic outpatient disease was compared.

Abstract Background The use of proactive genetic screening for disease prevention and early detection is not yet widespread. Professional practice guidelines from the American College of Medical Genetics and Genomics (ACMG) have encouraged reporting pathogenic variants that confer personal risk for actionable monogenic hereditary disorders, but only as secondary findings from exome or genome sequencing. The Centers for Disease Control and Prevention (CDC) recognizes the potential public health impact of three Tier 1 actionable disorders. Here, we report results of a large multi-center cohort study to determine the yield and potential value of screening healthy individuals for variants associated with a broad range of actionable monogenic disorders, outside the context of secondary findings. Methods Eligible adults were offered a proactive genetic screening test by health care providers in a variety of clinical settings. The screening panel based on next-generation sequencing contained up to 147 genes associated with monogenic disorders within cancer, cardiovascular, and other important clinical areas. Sequence and intragenic copy number variants classified as pathogenic, likely pathogenic, pathogenic (low penetrance), or increased risk allele were considered clinically significant and reported. Results were analyzed by clinical area and severity/burden of disease using chi-square tests without Yates’ correction. Results Among 10,478 unrelated adults screened, 1619 (15.5%) had results indicating personal risk for an actionable monogenic disorder. In contrast, only 3.1 to 5.2% had clinically reportable variants in genes suggested by the ACMG version 2 secondary findings list to be examined during exome or genome sequencing, and 2% had reportable variants related to CDC Tier 1 conditions. Among patients, 649 (6.2%) were positive for a genotype associated with a disease of high severity/burden, including hereditary cancer syndromes, cardiovascular disorders, or malignant hyperthermia susceptibility. Conclusions This is one of the first real-world examples of specialists and primary care providers using genetic screening with a multi-gene panel to identify health risks in their patients. Nearly one in six individuals screened for variants associated with actionable monogenic disorders had clinically significant results. These findings provide a foundation for further studies to assess the role of genetic screening as part of regular medical care.

Summary: Background: The identification of baseline host determinants that associate with robust HIV-1 vaccine-induced immune responses could aid HIV-1 vaccine development. We aimed to assess both the collective and relative performance of baseline characteristics in classifying individual participants in nine different Phase 1-2 HIV-1 vaccine clinical trials (26 vaccine regimens, conducted in Africa and in the Americas) as High HIV-1 vaccine responders. Methods: This was a meta-analysis of individual participant data, with studies chosen based on participant-level (vs. study-level summary) data availability within the HIV-1 Vaccine Trials Network. We assessed the performance of 25 baseline characteristics (demographics, safety haematological measurements, vital signs, assay background measurements) and estimated the relative importance of each characteristic in classifying 831 participants as High (defined as within the top 25th percentile among positive responders or above the assay upper limit of quantification) versus Non-High responders. Immune response outcomes included HIV-1-specific serum IgG binding antibodies and Env-specific CD4+ T-cell responses assessed two weeks post-last dose, all measured at central HVTN laboratories. Three variable importance approaches based on SuperLearner ensemble machine learning were considered. Findings: Overall, 30.1%, 50.5%, 36.2%, and 13.9% of participants were categorized as High responders for gp120 IgG, gp140 IgG, gp41 IgG, and Env-specific CD4+ T-cell vaccine-induced responses, respectively. When including all baseline characteristics, moderate performance was achieved for the classification of High responder status for the binding antibody responses, with cross-validated areas under the ROC curve (CV-AUC) of 0.72 (95% CI: 0.68, 0.76) for gp120 IgG, 0.73 (0.69, 0.76) for gp140 IgG, and 0.67 (95% CI: 0.63, 0.72) for gp41 IgG. In contrast, the collection of all baseline characteristics yielded little improvement over chance for predicting High Env-specific CD4+ T-cell responses [CV-AUC: 0.53 (0.48, 0.58)]. While estimated variable importance patterns differed across the three approaches, female sex assigned at birth, lower height, and higher total white blood cell count emerged as significant predictors of High responder status across multiple immune response outcomes using Approach 1. Of these three baseline variables, total white blood cell count ranked highly across all three approaches for predicting vaccine-induced gp41 and gp140 High responder status. Interpretation: The identified features should be studied further in pursuit of intervention strategies to improve vaccine responses and may be adjusted for in analyses of immune response data to enhance statistical power. Funding: National Institute of Allergy and Infectious Diseases (UM1AI068635 to YH, UM1AI068614 to GDT, UM1AI068618 to MJM, and UM1 AI069511 to MCK), the Duke CFAR P30 AI064518 to GDT, and National Institute of Dental and Craniofacial Research (R01DE027245 to JJK). This work was also supported by the Bill and Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding sources.

Abstract Objectives Dall’s sheep (Ovis dalli dalli) are important herbivores in the mountainous ecosystems of northwestern North America, and recent declines in some populations have sparked concern. Our aim was to improve capabilities for fecal metabarcoding diet analysis of Dall’s sheep and other herbivores by contributing new sequence data for arctic and alpine plants. This expanded reference library will provide critical reference sequence data that will facilitate metabarcoding diet analysis of Dall’s sheep and thus improve understanding of plant-animal interactions in a region undergoing rapid climate change. Data description We provide sequences for the chloroplast rbcL gene of 16 arctic-alpine vascular plant species that are known to comprise the diet of Dall’s sheep. These sequences contribute to a growing reference library that can be used in diet studies of arctic herbivores.

Abstract Background Genetic information is increasingly relevant across healthcare. Traditional genetic counseling (GC) may limit access to genetic information and may be more information and support than some individuals need. We report on the application and clinical implications of a framework to consistently integrate genetics expertise where it is most useful to patients. Methods The Clinical Genome Resource’s (ClinGen) Consent and Disclosure Recommendations (CADRe) workgroup designed rubrics to guide pre- and post-genetic test communication. Using a standard set of testing indications, pre- and post-test rubrics were applied to 40 genetic conditions or testing modalities with diverse features, including variability in levels of penetrance, clinical actionability, and evidence supporting a gene-disease relationship. Final communication recommendations were reached by group consensus. Results Communication recommendations were determined for 478 unique condition-indication or testing-indication pairs. For half of the conditions and indications (238/478), targeted discussions (moderate communication depth) were the recommended starting communication level for pre- and post-test conversations. Traditional GC was recommended pre-test for adult-onset neurodegenerative conditions for individuals with no personal history and post-test for most conditions when genetic testing revealed a molecular diagnosis as these situations are likely higher in complexity and uncertainty. A brief communication approach was recommended for more straightforward conditions and indications (e.g., familial hypercholesterolemia; familial variant testing). Conclusions The CADRe recommendations provide guidance for clinicians in determining the depth of pre- and post-test communication, strategically aligning the anticipated needs of patients with the starting communication approach. Shorter targeted discussions or brief communications are suggested for many tests and indications. Longer traditional GC consultations would be reserved for patients with more complex and uncertain situations where detailed information, education, and psychological support can be most beneficial. Future studies of the CADRe communication framework will be essential for determining if CADRe-informed care supports quality patient experience while improving access to genetic information across healthcare.

Abstract Studies have shown that the presence of tumor infiltrating lymphocytes (TILs) in Triple Negative Breast Cancer (TNBC) is associated with better prognosis. However, the molecular mechanisms underlying these immune cell differences are not well delineated. In this study, analysis of hematoxylin and eosin images from The Cancer Genome Atlas (TCGA) breast cancer cohort failed to show a prognostic benefit of TILs in TNBC, whereas CIBERSORT analysis, which quantifies the proportion of each immune cell type, demonstrated improved overall survival in TCGA TNBC samples with increased CD8 T cells or CD8 plus CD4 memory activated T cells and in Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) TNBC samples with increased gamma delta T cells. Twenty-five genes showed mutational frequency differences between the TCGA high and low T cell groups, and many play important roles in inflammation or immune evasion (ATG2B, HIST1H2BC, PKD1, PIKFYVE, TLR3, NOTCH3, GOLGB1, CREBBP). Identification of these mutations suggests novel mechanisms by which the cancer cells attract immune cells and by which they evade or dampen the immune system during the cancer immunoediting process. This study suggests that integration of mutations with CIBERSORT analysis could provide better prediction of outcomes and novel therapeutic targets in TNBC cases.

Abstract BRCA-mutant cancers often develop therapeutic resistance through several mechanisms. Here, we report a case of pathogenic germline BRCA2-driven breast cancer monitored for disease progression and acquired resistance using longitudinal multi-tissue genomic testing. Briefly, genomic testing was performed throughout the course of disease on tumor tissue from multiple sites, circulating tumor DNA from blood plasma, and matched normal tissue. Genomic analyses identified actionable variants for targeted therapies, as well as emerging resistance mutations over time. Two unique BRCA2 somatic alterations (p.N255fs and p.D252fs) were identified upon resistance to PARP inhibitor and platinum treatment, respectively. Both alterations restored the open reading frame of the original germline alteration, likely accounting for acquired resistance. This case exemplifies the evolution of multiple subclonal BRCA reversion alterations over time and demonstrates the value of longitudinal multi-tissue genomic testing for monitoring disease progression, predicting measures of response, and evaluating treatment outcomes in oncology patients.

Background: Stigma is a barrier to the treatment of opioid use disorder (OUD) in the criminal legal system. Staff sometimes have negative attitudes about medications for OUD (i.e., MOUD), but there is little research on what drives these attitudes. How staff think about criminal involvement and addiction may explain their attitudes toward MOUD. Methods: A convenience sample of U.S. criminal legal staff (e.g., correctional/probation officers, nurses, psychologists, court personnel) were recruited via online methods (N = 152). Participants completed an online survey of their attitudes about justice-involved people and addiction, and these were entered as predictors of an adapted version of the Opinions about Medication Assisted Treatment survey (OAMAT) in a linear regression, controlling for sociodemographics (cross-sectional design). Results: At the bivariate level, measures capturing more stigmatizing attitudes toward justice-involved people, believing addiction represents a moral weakness, and believing people with addiction are responsible for their actions and their recovery were related to more negative attitudes about MOUD, whereas higher educational attainment and believing addiction has a genetic basis were related to more positive attitudes about MOUD. In a linear regression, only stigma toward justice-involved people significantly predicted negative attitudes about MOUD (B = -.27, p = .010). Conclusion: Criminal legal staff's stigmatizing attitudes about justice-involved people, such as believing they are untrustworthy and cannot be rehabilitated, contributed significantly to negative attitudes about MOUD, above their beliefs about addiction. The stigma tied to criminal involvement needs to be addressed in attempts to increase MOUD adoption in the criminal legal system.

We describe coronavirus disease (COVID-19) among US food manufacturing and agriculture workers and provide updated information on meat and poultry processing workers. Among 742 food and agriculture workplaces in 30 states, 8,978 workers had confirmed COVID-19; 55 workers died. Racial and ethnic minority workers could be disproportionately affected by COVID-19.

Most human pegivirus 2 (HPgV-2) infections are associated with past or current hepatitis C virus (HCV) infection. HPgV-2 is thought to be a bloodborne virus: higher prevalence of active infection has been found in populations with a history of parenteral exposure to viruses. We evaluated longitudinally collected blood samples obtained from injection drug users (IDUs) for active and resolved HPgV-2 infections using a combination of HPgV-2–specific molecular and serologic tests. We found evidence of HPgV-2 infection in 11.2% (22/197) of past or current HCV-infected IDUs, compared with 1.9% (4/205) of an HCV-negative IDU population. Testing of available longitudinal blood samples from HPgV-2–positive participants identified 5 with chronic infection (>6 months viremia in >3 timepoints); 2 were identified among the HCV-positive IDUs and 3 among the HCV-negative IDUs. Our findings indicate that HPgV-2 can establish chronic infection and replicate in the absence of HCV.

By 13,000 BP human populations were present across North America, but the exact date of arrival to the continent, especially areas south of the continental ice sheets, remains unclear. Here we examine patterns in the stratigraphic integrity of early North American sites to gain insight into the timing of first colonization. We begin by modeling stratigraphic mixing of multicomponent archaeological sites to identify signatures of stratigraphic integrity in vertical artifact distributions. From those simulations, we develop a statistic we call the Apparent Stratigraphic Integrity Index (ASI), which we apply to pre- and post-13,000 BP archaeological sites north and south of the continental ice sheets. We find that multiple early Beringian sites dating between 13,000 and 14,200 BP show excellent stratigraphic integrity. Clear signs of discrete and minimally disturbed archaeological components do not appear south of the ice sheets until the Clovis period. These results provide support for a relatively late date of human arrival to the Americas.

Pseudogymnoascus destructans is a fungal pathogen responsible for a deadly disease among North American bats known as white-nose syndrome (WNS). Since detection of WNS in the United States in 2006, its rapid spread and high mortality has challenged development of treatment and prevention methods, a significant objective for wildlife management agencies. In an effort to mitigate precipitous declines in bat populations due to WNS, we have developed and implemented a multi-year mitigation strategy at Black Diamond Tunnel (BDT), Georgia, singly known as one of the most substantial winter colony sites for tricolored bats (Perimyotis subflavus), with pre-WNS abundance exceeding 5000 individuals. Our mitigation approach involved in situ treatment of bats at the colony level through aerosol distribution of antifungal volatile organic compounds (VOCs) that demonstrated an in vitro ability to inhibit P. destructans conidia germination and mycelial growth through contact-independent exposure. The VOCs evaluated have been identified from microbes inhabiting naturally-occurring fungistatic soils and endophytic fungi. These VOCs are of low toxicity to mammals and have been observed to elicit antagonism of P. destructans at low gaseous concentrations. Cumulatively, our observations resolved no detrimental impact on bat behavior or health, yet indicated a potential for attenuation of WNS related declines at BDT and demonstrated the feasibility of this novel disease management approach.

Background: Heavy alcohol use is associated with increased risk of alcohol-related health consequences. Alcohol consumption has increased in females in the last fifteen years and females are more likely to experience exacerbated health risks due to drinking. Our group identified that females with AUD were more likely to report respiratory conditions or cancers compared to their male counterparts. This analysis sought to further examine relationships between sex and alcohol use on medical conditions by using the new 2020 U.S. Dietary Guidelines risk drinking levels. Methods: Data from the U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC-III; n = 36,309) was used to evaluate associations between sex (female vs. male) and alcohol risk drinking levels (abstainer, binge, heavy, extreme binge vs. moderate drinking) on past year self-reported doctor-confirmed medical conditions). Results: Females were 1.5 to 2 times more likely to have pain, respiratory, or other medical conditions in the past year (odds ratio [OR]=1.46–2.11) vs. males. Significant interactions demonstrated that heavy drinking females or extreme binge drinking females were 2 to 3 times more likely to have cancers or other conditions (OR=1.95–2.69) vs. males at the same risk drinking level. Female abstainers were more likely than male abstainers to have other medical conditions (OR=1.77). Conclusions: Consistent with our previous findings, results identify that higher risk drinking levels are associated with the presence of past year self-reported doctor-confirmed medical conditions spanning organ systems, particularly in females. Treatment for high-risk drinking should be considered in the clinical care of individuals with significant medical conditions.

Defects in how excess nutrients are stored as triglycerides can result in several diseases including obesity, heart disease, and diabetes. Understanding the genes responsible for normal lipid homeostasis will help understand the pathogenesis of these diseases. RNAi screens performed in Drosophila cells identified genes involved in vesicle formation and protein sorting as important for the formation of lipid droplets; however, all of the vesicular trafficking proteins that regulate lipid storage are unknown. Here, we characterize the function of the Drosophila Charged multivesicular protein 1 (Chmp1) gene in regulating fat storage. Chmp1 is a member of the ESCRT-III complex that targets membrane localized signaling receptors to intralumenal vesicles in the multivesicular body of the endosome and then ultimately to the lysosome for degradation. When Chmp1 levels are decreased specifically in the fly fat body, triglyceride accumulates while fat-body-specific Chmp1 overexpression decreases triglycerides. Chmp1 controls triglyceride storage by regulating the number and size of fat body cells produced and not by altering food consumption or lipid metabolic enzyme gene expression. Together, these data uncover a novel function for Chmp1 in controlling lipid storage in Drosophila and supports the role of the endomembrane system in regulating metabolic homeostasis.

Introduction: Voters facing illness or disability are disproportionately under-represented in terms of voter turnout. Earlier research has indicated that enfranchisement of these populations may reinforce the implementation of policies improving health outcomes and equity. Due to the confluence of the coronavirus 2019 (COVID-19) pandemic and the 2020 election, we aimed to assess emergency absentee voting processes, which allow voters hospitalized after regular absentee deadlines to still obtain an absentee ballot, and election changes due to COVID-19 in all 50 states. Methods: We performed a cross-sectional study collecting 34 variables pertaining to emergency voting processes and COVID-19-related election changes, including deadlines, methods of submission for applications and ballots, and specialized services for patients. Data were obtained from, in order of priority, state boards of elections websites, poll worker manuals, application forms, and state legislation. We verified all data through direct correspondence with state boards of elections. Results: Emergency absentee voting processes are in place in 39 states, with the remaining states having universal vote-by-mail (n = 5) or extended regular absentee voting deadlines (n = 6). The emergency absentee period most commonly began within 24 hours following the normal absentee application deadline, which was often seven days before an election (n = 11). Unique aspects of emergency voting processes included patients designating an “authorized agent” to deliver their applications and ballots (n = 38), electronic ballot delivery (n = 5), and in-person teams that deliver ballots directly to patients (n = 18). Documented barriers in these processes nationwide include unavailable online information (n = 11), restrictions mandating agents to be family members (n = 7), physician affidavits or signatures (n = 9), and notary or witness signature requirements (n = 15). For the November 2020 presidential election, 12 states expanded absentee eligibility to allow COVID-19 as a reason to request an absentee ballot, and 18 states mailed absentee ballot applications or absentee ballots to all registered voters. Conclusion: While 39 states operate emergency absentee voting processes for hospitalized voters, there are considerable areas for improvement and heterogeneity in guidelines for these protocols. For future election cycles, information on emergency voting and broader election reforms due to COVID-19 may be useful for emergency providers and patients alike to improve the democratic participation of voters experiencing illness.

Introduction: Rural areas have higher rates of firearm-related unintentional and suicide deaths. Having access to a firearm greatly increases suicide risk. Safe firearm storage can be a major factor in preventing these tragedies. In this study we evaluated firearm exposure and storage practices in rural adolescents’ homes. Methods: An anonymous survey was administered to a convenience sample of attendees at the 2019 Iowa FFA (formerly Future Farmers of America) Leadership Conference. We performed descriptive, bivariate and multivariable logistic regression analyses. Results: A total of 1,382 adolescents participated; 51% were males and 49% were females. Respondents were 13–18 years old, and 53% lived on a farm, 18% in the country/not on a farm, and 29% in town. Almost all (96%) self-identified as White/Caucasian. In their homes, 84% reported having rifles/shotguns, 58% reported having handguns, and 56% reported having both rifles/shotguns and handguns. Males were significantly more likely than females to report having firearms in their home (P

Introduction: This study reviews malpractice, also called medical professional liability (MPL), claims involving adult patients cared for in emergency departments (ED) and urgent care settings. Methods: We conducted a retrospective review of closed MPL claims of adults over 18 years, from the Medical Professional Liability Association’s Data Sharing Project database from 2001–2015, identifying 6,779 closed claims. Data included the total amount, origin, top medical specialties named, chief medical factors, top medical conditions, severity of injury, resolution, average indemnity, and defense costs of closed claims. Results: Of 6,779 closed claims, 65.9% were dropped, withdrawn, or dismissed. Another 22.8% of claims settled for an average indemnity of $297,709. Of the 515 (7.6%) cases that went to trial, juries returned verdicts for the defendant in 92.6% of cases (477/515). The remaining 7.4% of cases (38/515) were jury verdicts for the plaintiff, with an average indemnity of $816,909. The most common resulting medical condition cited in paid claims was cardiac or cardiorespiratory arrest (10.4%). Error in diagnosis was the most common chief medical error cited in closed claims. Death was the most common level of severity listed in closed (38.5%) and paid (42.8%) claims. Claims reporting major permanent injury had the highest paid-to-closed ratio, and those reporting grave injury had the highest average indemnity of $686,239. Conclusion: This retrospective review updates the body of knowledge surrounding medical professional liability and represents the most recent analysis of claims in emergency medicine. As the majority of emergency providers will be named in a MPL claim during their career, it is essential to have a better understanding of the most common factors resulting in MPL claims.

Abstract The contributions of maternal diet and obesity in shaping offspring microbiome remain unclear. Here we employed a mouse model of maternal diet-induced obesity via high-fat diet feeding (HFD, 45% fat calories) for 12 wk prior to conception on offspring gut microbial ecology. Male and female offspring were provided access to control or HFD from weaning until 17 wk of age. Maternal HFD-associated programming was sexually dimorphic, with male offspring from HFD dams showing hyper-responsive weight gain to postnatal HFD. Likewise, microbiome analysis of offspring cecal contents showed differences in α-diversity, β-diversity and higher Firmicutes in male compared to female mice. Weight gain in offspring was significantly associated with abundance of Lachnospiraceae and Clostridiaceae families and Adlercreutzia, Coprococcus and Lactococcus genera. Sex differences in metagenomic pathways relating to lipid metabolism, bile acid biosynthesis and immune response were also observed. HFD-fed male offspring from HFD dams also showed worse hepatic pathology, increased pro-inflammatory cytokines, altered expression of bile acid regulators (Cyp7a1, Cyp8b1 and Cyp39a1) and serum bile acid concentrations. These findings suggest that maternal HFD alters gut microbiota composition and weight gain of offspring in a sexually dimorphic manner, coincident with fatty liver and a pro-inflammatory state in male offspring.

Abstract The Hippo signaling pathway is involved in organ size regulation and tumor suppression. Although inhibition of Hippo leads to tumorigenesis, activation of Hippo may play a role in neurodegeneration. Specifically, activation of the upstream regulator, mammalian sterile 20 (STE20)-like kinase 1 (MST1), reduces activity of the transcriptional co-activator Yes-Associated Protein (YAP), thereby mediating oxidative stress-induced neuronal death. Here, we investigated the possible role of this pathway in Huntington’s disease (HD) pathogenesis. Our results demonstrate a significant increase in phosphorylated MST1, the active form, in post-mortem HD cortex and in the brains of CAG knock-in Hdh Q111/Q111 mice. YAP nuclear localization was also decreased in HD post-mortem cortex and in neuronal stem cells derived from HD patients. Moreover, there was a significant increase in phosphorylated YAP, the inactive form, in HD post-mortem cortex and in Hdh Q111/Q111 brain. In addition, YAP was found to interact with huntingtin (Htt) and the chaperone 14-3-3, however this interaction was not altered in the presence of mutant Htt. Lastly, YAP/TEAD interactions and expression of Hippo pathway genes were altered in HD. Together, these results demonstrate that activation of MST1 together with a decrease in nuclear YAP could significantly contribute to transcriptional dysregulation in HD.

We describe a lethal respiratory outbreak among wild chimpanzees in Uganda in 2013 for which molecular and epidemiologic analyses implicate human rhinovirus C as the cause. Postmortem samples from an infant chimpanzee yielded near-complete genome sequences throughout the respiratory tract; other pathogens were absent. Epidemiologic modeling estimated the basic reproductive number (R0) for the epidemic as 1.83, consistent with the common cold in humans. Genotyping of 41 chimpanzees and examination of 24 published chimpanzee genomes from subspecies across Africa showed universal homozygosity for the cadherin-related family member 3 CDHR3-Y529 allele, which increases risk for rhinovirus C infection and asthma in human children. These results indicate that chimpanzees exhibit a species-wide genetic susceptibility to rhinovirus C and that this virus, heretofore considered a uniquely human pathogen, can cross primate species barriers and threatens wild apes. We advocate engineering interventions and prevention strategies for rhinovirus infections for both humans and wild apes.

Abstract Worldwide, an estimated 5% of hepatitis B virus (HBV) infected people are coinfected with hepatitis delta virus (HDV). HDV infection leads to increased mortality over HBV mono-infection, yet HDV diagnostics are not widely available. Prototype molecular (RNA) and serologic (IgG) assays were developed for high-throughput testing on the Abbott m2000 and ARCHITECT systems, respectively. RNA detection was achieved through amplification of a ribozyme region target, with a limit of detection of 5 IU/ml. The prototype serology assay (IgG) was developed using peptides derived from HDV large antigen (HDAg), and linear epitopes were further identified by peptide scan. Specificity of an HBV negative population was 100% for both assays. A panel of 145 HBsAg positive samples from Cameroon with unknown HDV status was tested using both assays: 16 (11.0%) had detectable HDV RNA, and 23 (15.7%) were sero-positive including the 16 HDV RNA positive samples. Additionally, an archival serial bleed panel from an HDV superinfected chimpanzee was tested with both prototypes; data was consistent with historic testing data using a commercial total anti-Delta test. Overall, the two prototype assays provide sensitive and specific methods for HDV detection using high throughput automated platforms, allowing opportunity for improved diagnosis of HDV infected patients.

Background The 2019 novel coronavirus disease (COVID-19) has created unprecedented medical challenges. There remains a need for validated risk prediction models to assess short-term mortality risk among hospitalized patients with COVID-19. The objective of this study was to develop and validate a 7-day and 14-day mortality risk prediction model for patients hospitalized with COVID-19. Methods We performed a multicenter retrospective cohort study with a separate multicenter cohort for external validation using two hospitals in New York, NY, and 9 hospitals in Massachusetts, respectively. A total of 664 patients in NY and 265 patients with COVID-19 in Massachusetts, hospitalized from March to April 2020. Results We developed a risk model consisting of patient age, hypoxia severity, mean arterial pressure and presence of kidney dysfunction at hospital presentation. Multivariable regression model was based on risk factors selected from univariable and Chi-squared automatic interaction detection analyses. Validation was by receiver operating characteristic curve (discrimination) and Hosmer-Lemeshow goodness of fit (GOF) test (calibration). In internal cross-validation, prediction of 7-day mortality had an AUC of 0.86 (95%CI 0.74–0.98; GOF p = 0.744); while 14-day had an AUC of 0.83 (95%CI 0.69–0.97; GOF p = 0.588). External validation was achieved using 265 patients from an outside cohort and confirmed 7- and 14-day mortality prediction performance with an AUC of 0.85 (95%CI 0.78–0.92; GOF p = 0.340) and 0.83 (95%CI 0.76–0.89; GOF p = 0.471) respectively, along with excellent calibration. Retrospective data collection, short follow-up time, and development in COVID-19 epicenter may limit model generalizability. Conclusions The COVID-AID risk tool is a well-calibrated model that demonstrates accuracy in the prediction of both 7-day and 14-day mortality risk among patients hospitalized with COVID-19. This prediction score could assist with resource utilization, patient and caregiver education, and provide a risk stratification instrument for future research trials.

Introduction Little is known about the effects of HIV reservoir research at the end of life on staff members involved. Staff members’ perceptions and experiences were assessed related to their involvement in the Last Gift, a rapid autopsy study at the University of California San Diego enrolling people living with HIV who are terminally ill and have a desire to contribute to HIV cure-related research. Methods Two focus group discussions consisting of clinical (n = 7) and rapid research autopsy (n = 8) staff members were conducted to understand the perspectives of staff members and the impact the Last Gift rapid autopsy study had on them. The total sample consisted of 66.7% females and 33.3% males and was ethnically diverse (66.7% Caucasian, 6.7% African American, 20.0% Asian descent, 6.7% Hispanic descent and American Indian) with a range of experience in the HIV field from 1 year to 30 years. Results Qualitative focus group data revealed five major themes underlying study staff members’ multilayered mental and practical involvement: 1) positive perceptions of the Last Gift study, with sub-themes including Last Gift study participants’ altruism, fulfillment, and control at the end of life, 2) perceptions of staff members’ close involvement in the Last Gift study, with sub-themes related to staff members’ cognitive processing, self-actualization and fulfillment, stress management and resilience, coping mechanisms, and gratitude toward Last Gift participants and toward the study itself, 3) considerations for successful and sustainable study implementation, such as ethical awareness and sustained community and patient engagement, 4) collaborative learning and organizational processes and the value of interdependence between staff members, and 5) considerations for potential study scale-up at other clinical research sites. Discussion Understanding staff members’ nuanced emotional and procedural experiences is crucial to the Last Gift study’s sustainability and will inform similar cure research studies conducted with people living with HIV at the end of life. The study’s potential reproducibility depends on a robust research infrastructure with established, interdependent clinical and rapid autopsy teams, continuous community engagement, and an ethical and well-informed engagement process with people living with HIV.

Background: Non-motor symptoms such as sleep disturbance, cognitive decline, fatigue, anxiety, and depression in Parkinson’s disease (PD) impact quality of life. Increased levels of pro-inflammatory cytokines in individuals with PD have been reported, which may contribute to non-motor symptoms. A mind-body exercise, Qigong, has demonstrated benefits across different medical conditions. However, a lack of evidence causes clinicians and patients to be uncertain about the effects of Qigong in individuals with PD. This study will examine the effects of Qigong on non-motor symptoms and inflammatory status in individuals with PD. Methods: Sixty individuals with PD will be recruited. Qigong and sham Qigong group (n = 30 for each) will receive a 12-week intervention. Participants will practice their assigned exercise at home (2×/day) and attend routinely group exercise meetings. Results: Clinical questionnaires and neuropsychological tests will measure non-motor symptoms including sleep quality (primary outcome). Biomarker assays will measure inflammatory status. A two-way mixed-design analysis of variance (ANOVA) will be utilized. Conclusions: This study may generate evidence for the benefits of Qigong on non-motor symptoms of PD and the effect on inflammatory status. Findings may lead to the development of a novel, safe, and cost-effective rehabilitation approach for individuals with PD.

Biofilms create an impermeable barrier against antimicrobial treatment and immune cell access, severely complicating treatment and clearance of nosocomial Pseudomonas aeruginosa infections. We recently reported that biofilm also contributes to pathogen virulence by regulating the production of the siderophore pyoverdine. In this study, we investigated the role of PqsA, a key cell-signaling protein, in this regulatory pathway. We demonstrate that PqsA promotes pyoverdine production in a biofilm-dependent manner. Under nutritionally deficient conditions, where biofilm and pyoverdine are decoupled, PqsA is dispensable for pyoverdine production. Interestingly, although PqsA-dependent pyoverdine production does not rely upon Pseudomonas quinolone signal (PQS) biosynthesis, exogenous PQS can also trigger biofilm-independent production of pyoverdine. Adding PQS rapidly induced planktonic cell aggregation. Moreover, these clumps of cells exhibit strong expression of pyoverdine biosynthetic genes and show substantial production of this siderophore. Finally, we surveyed the relationship between biofilm formation and pyoverdine production in various clinical and environmental isolates of P. aeruginosa to evaluate the clinical significance of targeting biofilm during infections. Our findings implicate PqsA in P. aeruginosa virulence by regulating biofilm formation and pyoverdine production.

More diverse communities are thought to be more stable—the diversity–stability hypothesis—due to increased resistance to and recovery from disturbances. For example, high diversity can make the presence of resilient or fast growing species and key facilitations among species more likely. How natural, geographic biodiversity patterns and changes in biodiversity due to human activities mediate community-level disturbance dynamics is largely unknown, especially in diverse systems. For example, few studies have explored the role of diversity in tropical marine communities, especially at large scales. We tested the diversity–stability hypothesis by asking whether coral richness is related to resistance to and recovery from disturbances including storms, predator outbreaks, and coral bleaching on tropical coral reefs. We synthesized the results of 41 field studies conducted on 82 reefs, documenting changes in coral cover due to disturbance, across a global gradient of coral richness. Our results indicate that coral reefs in more species-rich regions were marginally less resistant to disturbance and did not recover more quickly. Coral community resistance was also highly dependent on pre-disturbance coral cover, probably due in part to the sensitivity of fast-growing and often dominant plating acroporid corals to disturbance. Our results suggest that coral communities in biodiverse regions, such as the western Pacific, may not be more resistant and resilient to natural and anthropogenic disturbances. Further analyses controlling for disturbance intensity and other drivers of coral loss and recovery could improve our understanding of the influence of diversity on community stability in coral reef ecosystems.