A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Environmental DNA as a tool to reconstruct catch composition for longline fisheries vessels.

Global wild-capture fisheries are a large and diverse sector requiring various tools for fisheries-dependant data collection and effective Monitoring, Control and Surveillance (MCS). Here we present a novel protocol to collect eDNA from brine tanks onboard commercial longline vessels to reconstruct catch composition. We collected samples from nine vessels operating out of the Eastern Tuna Billfish Fishery, Australia, validating eDNA results with reliable catch data consisting of seven target and bycatch species. Environmental DNA was highly effective for detecting species retained on vessels without contamination or false positives. For four vessels, logbook data and eDNA were consistent with detections of all species. The remaining vessels detected all species except for rare catches of short-billed spearfish (Tetrapturus angustirostris). Similarities between rank abundance distributions of catch and eDNA reads were observed with logbook data mirrored when eDNA sequences were organised into rank order abundance. The method was effective at identifying highly abundant taxa retained in brine tanks- tuna (Thunnus spp.), swordfish (Xiphias gladius), marlin (Kajijia audax), and Atlantic Pomfret (Brama brama). Further research is required to validate how eDNA and other molecular monitoring tools can be scaled and applied to provide solutions for monitoring challenges in the fisheries sector.

Toward Part-per-Million Precision in the Determination of an Ion's Collision Cross Section Using Multipass Cyclic Ion Mobility.

In cyclic ion mobility (cIMS), ions are permitted to travel multiple passes around the drift cell, increasing the distance traveled and the relative separation between ions. This study tests the hypothesis that multiple passes around the cell can also result in improved precision when measuring an ion's mobility and the collision cross section (TWCCS) derived therefrom. Experiments were performed with a diverse set of compounds, including 16 polycyclic aromatic hydrocarbons using gas chromatographic atmospheric pressure chemical ionization and a set of drug molecules by direct infusion electrospray ionization. The average periodic drift time, viz., the average time required for the ion to travel around the cIMS cell once, shifts dramatically, approaching part-per-million (ppm) precision as the number of passes increases to ∼100. Extrapolation of the precision of the CCS values with respect to the number of passes led to the prediction that the precision will reach 1000 ppm after 50 passes, 100 ppm after 100 passes, and <10 ppm after 150 passes. Experiments wherein the number of passes exceeded 100 produced TWCCS values having within-run precisions ranging between 15 and 117 ppm. The improved precision with an increasing number of passes may be a consequence of mitigating space-charge effects by allowing the ions to occupy a larger region of the cIMS cell. A method is proposed to enable practical measurements of TWCCS with ppm precision and is demonstrated to characterize an unknown drug mixture.

Exotic Dark Matter Search with the Majorana Demonstrator.

With excellent energy resolution and ultralow-level radiogenic backgrounds, the high-purity germanium detectors in the Majorana Demonstrator enable searches for several classes of exotic dark matter (DM) models. In this work, we report new experimental limits on keV-scale sterile neutrino DM via the transition magnetic moment from conversion to active neutrinos ν_{s}→ν_{a}. We report new limits on fermionic dark matter absorption (χ+A→ν+A) and sub-GeV DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), and new exclusion limits for bosonic dark matter (axionlike particles and dark photons). These searches utilize the (1-100)-keV low-energy region of a 37.5-kg y exposure collected by the Demonstrator between May 2016 and November 2019 using a set of ^{76}Ge-enriched detectors whose surface exposure time was carefully controlled, resulting in extremely low levels of cosmogenic activation.

HESI workshop summary: Interpretation of developmental and reproductive toxicity endpoints and the impact on data interpretation of adverse events.

The Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (HESI-DART) group held a hybrid in-person and virtual workshop in Washington, DC, in 2022. The workshop was entitled, "Interpretation of DART in Regulatory Contexts and Frameworks." There were 154 participants (37 in person and 117 virtual) across 9 countries. The purpose of the workshop was to capture key consensus approaches used to assess DART risks associated with chemical product exposure when a nonclinical finding is identified. The decision-making process for determining whether a DART endpoint is considered adverse is critical because the outcome may have downstream implications (e.g., increased animal usage, modifications to reproductive classification and pregnancy labeling, impact on enrollment in clinical trials and value chains). The workshop included a series of webinar modules to train and engage in discussions with federal and international regulators, clinicians, academic investigators, nongovernmental organizations, contract research organization scientists, and private sector scientists on the best practices and principles of interpreting DART and new approach methodologies in the context of regulatory requirements and processes. Despite the differences in regulatory frameworks between the chemical and pharmaceutical sectors, the same foundational principles for data interpretation should be applied. The discussions led to the categorization of principles, which offer guidance for the systematic interpretation of data. Step 1 entails identifying any hazard by closely analyzing the data at the study endpoint level, while Step 2 involves assessing risk using weight of evidence. These guiding principles were derived from the collective outcomes of the workshop deliberations.

Loneliness is associated with mentalizing and emotion recognition abilities in schizophrenia, but only in a cluster of patients with social cognitive deficits.

OBJECTIVE: Loneliness is a concern for patients with schizophrenia. However, the correlates of loneliness in patients with schizophrenia are unclear; thus, the aim of the study is to investigate neuro- and social cognitive mechanisms associated with loneliness in individuals with schizophrenia. METHOD: Data from clinical, neurocognitive, and social cognitive assessments were pooled from two cross-national samples (Poland/USA) to examine potential predictors of loneliness in 147 patients with schizophrenia and 103 healthy controls overall. Furthermore, the relationship between social cognition and loneliness was explored in clusters of patients with schizophrenia differing in social cognitive capacity. RESULTS: Patients reported higher levels of loneliness than healthy controls. Loneliness was linked to increased negative and affective symptoms in patients. A negative association between loneliness and mentalizing and emotion recognition abilities was found in the patients with social-cognitive impairments, but not in those who performed at normative levels. CONCLUSIONS: We have elucidated a novel mechanism which may explain previous inconsistent findings regarding the correlates of loneliness in individuals with schizophrenia.

Improvements in Survival and Clinical Benefit With Gemcitabine as First-Line Therapy for Patients With Advanced Pancreas Cancer: A Randomized Trial.

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Measurement of Electron-Neutrino Charged-Current Cross Sections on

Using an 185-kg NaI[Tl] array, COHERENT has measured the inclusive electron-neutrino charged-current cross section on ^{127}I with pion decay-at-rest neutrinos produced by the Spallation Neutron Source at Oak Ridge National Laboratory. Iodine is one the heaviest targets for which low-energy (≤50 MeV) inelastic neutrino-nucleus processes have been measured, and this is the first measurement of its inclusive cross section. After a five-year detector exposure, COHERENT reports a flux-averaged cross section for electron neutrinos of 9.2_{-1.8}^{+2.1}×10^{-40} cm^{2}. This corresponds to a value that is ∼41% lower than predicted using the MARLEY event generator with a measured Gamow-Teller strength distribution. In addition, the observed visible spectrum from charged-current scattering on ^{127}I has been measured between 10 and 55 MeV, and the exclusive zero-neutron and one-or-more-neutron emission cross sections are measured to be 5.2_{-3.1}^{+3.4}×10^{-40} and 2.2_{-0.5}^{+0.4}×10^{-40} cm^{2}, respectively.

Interventions Targeting Depression and Posttraumatic Stress Disorder in United States Black Women Experiencing Intimate Partner Violence: A Systematic Review.

There is a dearth of evidence indicating the effectiveness of psychological interventions targeting depression and/or posttraumatic stress disorder (PTSD) for Black women in the United States (US) exposed to intimate partner violence (IPV). We searched PubMed, MEDLINE, PsycINFO, EBSCOhost, Social Sciences, Social Sciences Full Text, Social Work Abstracts, and Cochrane databases between September 2021 and October 2022, for original studies of randomized control trials (RCTs) reporting depression and/or PTSD interventions delivered to US Black women with histories of IPV. Of the 1,276 articles, 46 were eligible and 8 RCTs were ultimately included in the review; interventions for depression (four interventions, n = 1,518) and PTSD (four interventions, n = 477). Among Depression and PTSD interventions (one intervention, n = 208), Beck's Depression Inventory II indicated M = 35.2, SD = 12.6 versus M = 29.5, SD = 13.1, <.01, and Davidson Trauma Scale indicated M = 79.4, SD = 31.5 versus M = 72.1, SD = 33.5, <.01, at pre- and post-intervention respectively. Also, some interventions reported severity of depression M = 13.9 (SD = 5.4) versus M = 7.9 (SD = 5.7) < 0.01, and PTSD (M = 8.08 vs. M = 14.13, F(1,117) = 9.93, p < .01) at pre- and post-intervention respectively. Publication bias was moderate and varied between 12 and 17 via the Downs and Black Checklist for Methodological Rigor for RCTs. Psychological interventions targeting depression and/or PTSD for Black women with histories of IPV reflect moderate improvement. Interventions that account for cultural nuances specific to Black women are fundamental for improving outcomes for survivors presenting with depression and/or PTSD.

Dataset on risk factors for seroconversion against Mycobacterium avium subspecies paratuberculosis in dairy cows.

Johne's disease (JD) is a chronic wasting disease caused by Mycobacterium avium subspecies paratuberculosis (MAP). MAP is responsible for large economic losses for the dairy sector and has been linked to human disease. Susceptibly to MAP is mainly limited to young animals and diagnostic tests are poor at detecting MAP in early stages of infection. Therefore, ascertaining the contribution of the dam to the risk of calf infection and the relative role of the different infection routes is important to inform disease control measures. This data article presents MAP exposures at time of calving on a cohort of 439 calves born between 2012 and 2013 from 6 UK dairy herds. Each calf participated in routine quarterly MAP milk ELISA testing using the IDEXX Porquire ELISA. Each animal was followed until testing MAP positive, being culled or end of follow up (January 2023). The dataset includes risk factors associated with transmission via colostrum route (MAP status of cow giving colostrum); transmission via the dam (MAP status of the dam) and transmission via fecal oral route (whether at birth the calf spent a long time in a dirty yard). Ascertainment of exposure to risk factors involved video recording and self-capture data forms from time of calving in the maternity area of the farms until calf left the area. The dataset provides a unique opportunity to examine MAP infection and its relationship with different exposures at time of birth, where cows were followed up during their entire lives.

Constraints on the Decay of

^{180m}Ta is a rare nuclear isomer whose decay has never been observed. Its remarkably long lifetime surpasses the half-lives of all other known ß and electron capture decays due to the large K-spin differences and small energy differences between the isomeric and lower-energy states. Detecting its decay presents a significant experimental challenge but could shed light on neutrino-induced nucleosynthesis mechanisms, the nature of dark matter, and K-spin violation. For this study, we repurposed the Majorana Demonstrator, an experimental search for the neutrinoless double-beta decay of ^{76}Ge using an array of high-purity germanium detectors, to search for the decay of ^{180m}Ta. More than 17 kg, the largest amount of tantalum metal ever used for such a search, was installed within the ultralow-background detector array. In this Letter, we present results from the first year of Ta data taking and provide an updated limit for the ^{180m}Ta half-life on the different decay channels. With new limits up to 1.5×10^{19} yr, we improved existing limits by 1-2 orders of magnitude which are the most sensitive searches for a single ß and electron capture decay ever achieved. Over all channels, the decay can be excluded for T_{1/2}<0.29×10^{18} yr.

Nanoscale LiZnN - Luminescent Half-Heusler Quantum Dots.

Colloidal semiconductor quantum dots are a well-established technology, with numerous materials available either commercially or through the vast body of literature. The prevalent materials are cadmium-based and are unlikely to find general acceptance in most applications. While the III-V family of materials is a likely substitute, issues remain about its long-term suitability, and other earth-abundant materials are being explored. In this report, we highlight a nanoscale half-Heusler semiconductor, LiZnN, composed of readily available elements as a potential alternative system to luminescent II-VI and III-V nanoparticle quantum dots.

Communicating without words: Measuring nonverbal communication between veterinarians and farmers during routine herd health consultations.

Uptake of advice and the ability to facilitate change on-farm are key elements for successful veterinary practice. However, having the necessary clinical skills and knowledge is not enough to achieve this: effective communication skills are essential for veterinarians to realize their advisory role by exploring and understanding the farmer's worldview. Research of verbal aspects of veterinarian communication supports the use of a relationship-centered communication style; we next need to study how veterinarian-farmer nonverbal communication (NVC) can influence interactions and their outcomes, which has been examined in medical and companion animal practice. In this study, we considered which aspects of NVC should be measured, and how, to provide an essential first step toward understanding the significance of NVC for veterinarians working in dairy practice, which should be of interest to researchers, veterinary educators, and practitioners. Eleven video recordings of routine consultations in the UK were analyzed for farmer and veterinarian NVC. The NVC attributes with established links to positive patient and client outcomes from medical and social science studies were chosen, and a methodology developed for their measurement, by adapting measures typically used in NVC research. Each consultation was segmented into intervals defined by the main activity and location on farm: introduction, fertility examination, discussion, and closing. This approach allowed us to analyze the content more consistently, establish which aspects of NVC featured within each interval, and whether the activity and location influenced the observed NVC. We measured 12 NVC attributes, including body orientation, interpersonal distance, head position, and body lean, which have been shown to influence empathy, rapport, and trust: key components of relationship-centered communication. Future research should seek to establish the significance of NVC in effective communication between veterinarian and farmer, building on our findings that show it is possible to measure nonverbal attributes. Veterinarians may benefit from becoming skilled nonverbal communicators and have more effective conversations during routine consultations, motivating farmers to make changes and improve herd health.

Erratum: Search for Spontaneous Radiation from Wave Function Collapse in the Majorana Demonstrator [Phys. Rev. Lett. 129, 080401 (2022)].

This corrects the article DOI: 10.1103/PhysRevLett.129.080401.

Co-creation of a training for community health workers to enhance skills in serving LGBTQIA+ communities.

This paper describes creating and implementing a 30-h LGBTQIA+ specialty training for community health workers (CHWs). The training was co-developed by CHW training facilitators (themselves CHWs), researchers with expertise in LGBTQIA+ populations and health information, and a cohort of 11 LGBTQIA+ CHWs who theater tested and piloted the course. The research and training team collected cohort feedback through focus groups and an evaluative survey. Findings stress the importance of a curriculum designed to elicit lived experiences and informed by a pedagogical framework centered on achieving LGBTQIA+ visibilities. This training is a vital tool for CHWs to foster cultural humility for LGBTQIA+ populations and identify opportunities to support their health promotion, especially considering their limited and sometimes absent access to affirming and preventative healthcare. Future directions include revising the training content based on cohort feedback and adapting it to other contexts, such as cultural humility training for medical and nursing professionals and staff.

Robotic colorectal resection in combination with a multimodal enhanced recovery program - results of the first 100 cases.

PURPOSE: In Germany, colorectal robot-assisted surgery (RAS) has found its way and is currently used as primary technique in colorectal resections at our clinic. We investigated whether RAS can be extensively combined with enhanced recovery after surgery (ERAS®) in a large prospective patient group. METHODS: Using the DaVinci Xi surgical robot, all colorectal RAS from 09/2020 to 01/2022 were incorporated into our ERAS® program. Perioperative data were prospectively recorded using a data documentation system. The extent of resection, duration of the operation, intraoperative blood loss, conversion rate, and postoperative short-term results were analyzed. We documented the postoperative duration of Intermediate Care Unit (IMC) stay and major and minor complications according to the Clavien-Dindo classification, anastomotic leak rate, reoperation rate, hospital-stay length, and ERAS® guideline adherence. RESULTS: One hundred patients (65 colon and 35 rectal resections) were included (median age: 69 years). The median durations of surgery were 167 min (colon resection) and 246 min (rectal resection). Postoperatively, four patients were IMC-treated (median stay: 1 day). In 92.5% of the colon and 88.6% of the rectum resections, no or minor complications occurred postoperatively. The anastomotic leak rate was 3.1% in colon and 5.7% in rectal resection. The reoperation rate was 7.7% (colon resection) and 11.4% (rectal resection). The hospital stay length was 5 days (colon resection) and 6.5 days (rectal resection). The ERAS® guideline adherence rate was 88% (colon resection) and 82.6% (rectal resection). CONCLUSION: Patient perioperative therapy per the multimodal ERAS® concept is possible without any problems in colorectal RAS, leading to low morbidity and short hospital stays.

'Nesting networks': Women's experiences of social network support in high-risk pregnancy.

OBJECTIVE: Social support, an individual's social relationships (both online and offline), may provide protection against adverse mental health outcomes, such as anxiety and depression, which are high in women who have been hospitalised with high-risk pregnancy. This study explored the social support available to women at higher risk of preeclampsia during pregnancy by examining personal social networks. DESIGN: Semi-structured interviews were accompanied by social network mapping using the web-based social networking tool GENIE. SETTING: England. PARTICIPANTS: Twenty-one women were recruited, of whom 18 were interviewed both during pregnancy and postnatally between April 2019 and April 2020. Nineteen women completed maps pre-natally, 17 women completed maps pre-natally and post-natally. Women were taking part in the BUMP study, a randomised clinical trial that included 2441 pregnant individuals at higher risk of preeclampsia and recruited at a mean of 20 weeks' gestation from 15 hospital maternity units in England between November 2018 and October 2019. RESULTS: Women's social networks tightened during pregnancy. The inner network changed most dramatically postnatally with women reporting fewer network members. Interviews revealed networks were primarily 'real-life' rather than online social networks, with members providing emotional, informational, and practical support. Women with a high-risk pregnancy valued the relationships they developed with health professionals during pregnancy, and would like their midwife to have a more central role in their networks by providing informational and, where needed, emotional support. The social network mapping data supported the qualitative accounts of changing networks across high-risk pregnancy. CONCLUSION: Women with a high-risk pregnancy seek to build "nesting networks" to support them through pregnancy into motherhood. Different types of support are sought from trusted sources. Midwives can play a key role. PRACTICE IMPLICATIONS: As well as highlighting other potential needs during pregnancy and the ways in which they can be met, support from midwives has a key role. Through talking to women early in their pregnancy, signposting information and explaining ways to contact health professionals regarding informational or emotional support would fill a gap that currently is met by other aspects of their network.

Enhancing diabetes care for the most vulnerable in the 21st century: Interim findings of the National Advisory Panel on Care Home Diabetes (NAPCHD).

Older adults with diabetes may carry a substantial health burden in Western ageing societies, occupy more than one in four beds in care homes, and are a highly vulnerable group who often require complex nursing and medical care. The global pandemic (COVID-19) had its epicentre in care homes and revealed many shortfalls in diabetes care resulting in hospital admissions and considerable mortality and comorbid illness. The purpose of this work was to develop a national Strategic Document of Diabetes Care for Care Homes which would bring about worthwhile, sustainable and effective quality diabetes care improvements, and address the shortfalls in care provided. A large diverse and multidisciplinary group of stakeholders (NAPCHD) defined 11 areas of interest where recommendations were needed and using a subgroup allocation approach were set tasks to produce a set of primary recommendations. Each subgroup was given 5 starter questions to begin their work and a format to provide responses. During the initial phase, 16 key findings were identified. Overall, after a period of 18 months, 49 primary recommendations were made, and 7 major conclusions were drawn from these. A model of community and integrated diabetes care for care home residents with diabetes was proposed, and a series of 5 'quick-wins' were created to begin implementation of some of the recommendations that would not require significant funding. The work of the NAPCHD is ongoing but we hope that this current resource will help leaders to make these required changes happen.

Final Result of the Majorana Demonstrator's Search for Neutrinoless Double-ß Decay in

The Majorana Demonstrator searched for neutrinoless double-ß decay (0νßß) of ^{76}Ge using modular arrays of high-purity Ge detectors operated in vacuum cryostats in a low-background shield. The arrays operated with up to 40.4 kg of detectors (27.2 kg enriched to ∼88% in ^{76}Ge). From these measurements, the Demonstrator has accumulated 64.5 kg yr of enriched active exposure. With a world-leading energy resolution of 2.52 keV FWHM at the 2039 keV Q_{ßß} (0.12%), we set a half-life limit of 0νßß in ^{76}Ge at T_{1/2}>8.3×10^{25} yr (90% C.L.). This provides a range of upper limits on m_{ßß} of (113-269) meV (90% C.L.), depending on the choice of nuclear matrix elements.