Search

Background: Decades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them., Research Design and Methods: Working group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for hemophilia A and B into concrete research questions and scored their feasibility, impact, and risk., Results: WG1 defined 63 top priority research questions concerning arthropathy/pain/bone health, inhibitors, diagnostics, gene therapy, the pediatric to adult transition of care, disparities faced by the community, and cardiovascular disease. This research has the potential to empower PWH to thrive despite lifelong comorbidities and achieve new standards of wellbeing, including psychosocial., Conclusions: Collaborative research and care delivery will be key to capitalizing on current and horizon treatments and harnessing technical advances to improve diagnostics and testing, to advance health equity for all PWH.

With the current shortage of qualified staff at state and local public health departments, a flexible public health workforce could fill critical gaps in staffing. Disease intervention specialists (DISs) are public health outreach workers who are responsible for finding and counseling people with sexually transmitted diseases and their contacts. DIS skills and job duties parallel those that would be needed to respond quickly and efficiently to urgent public health problems, including bioterrorism. Including DISs in public health preparedness planning could be a practical way of providing surge capacity for departments of public health. In many states, DISs are already being used for functions that fall outside their traditional duties. However, planning and DIS training are essential for effective utilization of DIS skills in a public health emergency. North Carolina has included DISs in their bioterrorism response plans and currently deploys them on an as-needed basis for nonroutine activities.

Background and Objectives: Our objectives were to provide an update on the status of selection by medical students of family medicine as a specialty, to summarize what is known about influences on this specialty choice, and to propose a research agenda for the future., Methods: Data from the National Resident Matching Program and the American Academy of Family Physicians residency database were obtained. Past reviews of research on family medicine specialty selection were summarized, and recent research was reviewed. Gaps in the knowledge base and common research design weaknesses were listed., Results: As a result of our analysis, a set of 12 research questions are posed and a set of 11 study design recommendations made., Conclusions: Family medicine specialty choice research must be planned and conducted with the most robust methodology possible, building on past research, to produce results that can assist in formulating effective policy.

Hybrid courses are emerging as a viable option for content delivery across college campuses. In an attempt to maximize learning outcomes while leveraging resources, one institution used several sections of a Medical Terminology course as a pilot. Traditional and hybrid course delivery were compared utilizing a quantitative research method to evaluate the effectiveness of a hybrid course design in meeting and/or exceeding course objectives, as determined by student satisfaction and perceptions. Both hybrid and traditional class groups agreed that Medical Terminology has potential to be delivered in a hybrid format, but the hybrid group's agreement was significant stronger (+0.38 points on 5-point scale, P = 0.008).

Background: Little research has addressed the prevalence and predictors of complementary and alternative medicine (CAM) use among undergraduate students. Purpose: The purpose of this study was to: (1) measure the prevalence and type of CAM use among a sample of college undergraduates, and (2) test the significance of select social-cognitive constructs and demographics as predictors of CAM use among a college population. Methods: A random sample of undergraduate students within the Texas A&M University system was solicited via e-mail to complete a web-based survey. Results: Findings show high rates of CAM use. Gender, attitude toward CAM, outcome expectancies regarding the health care encounter, and social network use of CAM were shown to be significant predictors of CAM use. Discussion: CAM use is popular among college students. Results from this study can inform health care and health education professionals interested in improving health care processes and addressing positive and negative issues related to CAM use. Translation to Health Education Practice: Health educators should be prepared to present CAM as health care options and discuss benefits and risks associated with CAM therapies. Researchers should continue to explore the psychosocial determinants of CAM use as a guide for health education and intervention. (Contains 3 figures and 9 tables.)

Abstract Background In recent studies, receipt of chiropractic care has been associated with lower odds of receiving prescription opioids and, among those already prescribed, reduced doses of opioids among patients with non-cancer spine pain. These findings suggest that access to chiropractic services may reduce reliance on opioids for musculoskeletal pain. Objective To assess the impact of chiropractic care on initiation, or continued use, of prescription opioids among patients with non-cancer spine pain. Methods We will search for eligible randomized controlled trials (RCTs) and observational studies indexed in MEDLINE, Embase, AMED, CINAHL, Web of Science, and the Index to Chiropractic Literature from database inception to June 2024. Article screening, data extraction, and risk-of-bias assessment will be conducted independently by pairs of reviewers. We will conduct separate analyses for RCTs and observational studies and pool binary outcomes (e.g. prescribed opioid receipt, long-term opioid use, and higher versus lower opioid dose) as odds ratios (ORs) with associated 95% confidence intervals (CIs). When studies provide hazard ratios (HRs) or relative risks (RRs) for time-to-event data (e.g. time-to-first opioid prescription) or incidence rates (number of opioid prescriptions over time), we will first convert them to an OR before pooling. Continuous outcomes such as pain intensity, sleep quality, or morphine equivalent dose will be pooled as weighted mean differences with associated 95% CIs. We will conduct meta-analyses using random-effects models and explore sources of heterogeneity using subgroup analyses and meta-regression. We will evaluate the certainty of evidence of all outcomes using the GRADE approach and the credibility of all subgroup effects with ICEMAN criteria. Our systematic review will follow the PRISMA statement and MOOSE guidelines. Discussion Our review will establish the current evidence informing the impact of chiropractic care on new or continued prescription opioid use for non-cancer spine pain. We will disseminate our results through peer-reviewed publication and conference presentations. The findings of our review will be of interest to patients, health care providers, and policy-makers. Trial registration Systematic review registration: PROSPERO CRD42023432277.

Objective: Determine prevalence and types of complementary and alternative medicine (CAM) therapies used and test the significance of demographics and social cognitive constructs as predictors of CAM use in a college sample. Secondary purpose was to guide the integration of CAM therapies into college health services. Participants: Random, stratified sample of 2,553 undergraduates and graduate students enrolled at Columbia University. Methods: Web-based survey e-mailed to a random sample of 6,482 students. Regression analyses used to determine predictors of CAM use. Results: Nearly 82% of respondents reported using at least 1 form of CAM in the last 12 months, the most common being nonvitamin, nonmineral (NVNM) products, yoga, deep breathing exercises, massage therapy, and meditation. Sex, student home origin, outcome expectancies, observational learning, and attitude toward CAM were found as significant predictors of CAM use. Conclusions: Ongoing assessment of CAM use can assist administrators and providers to enhance college health services and programs.

Abstract Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as ‘FLASH’. This effect has been studied across several radiation modalities, including photons, protons and clinical energy electrons, however, very little data is available for the effect of FLASH with Very High Energy Electrons (VHEE). pBR322 plasmid DNA was used as a biological model to measure DNA damage in response to Very High Energy Electron (VHEE) irradiation at conventional (0.08 Gy/s), intermediate (96 Gy/s) and ultra-high dose rates (UHDR, (2 × 109 Gy/s) at the CERN Linear Electron Accelerator (CLEAR) user facility. UHDRs were used to determine if the biological FLASH effect could be measured in the plasmid model, within a hydroxyl scavenging environment. Two different concentrations of the hydroxyl radical scavenger Tris were used in the plasmid environment to alter the proportions of indirect damage, and to replicate a cellular scavenging capacity. Indirect damage refers to the interaction of ionising radiation with molecules and species to generate reactive species which can then attack DNA. UHDR irradiated plasmid was shown to have significantly reduced amounts of damage in comparison to conventionally irradiated, where single strand breaks (SSBs) was used as the biological endpoint. This was the case for both hydroxyl scavenging capacities. A reduced electron energy within the VHEE range was also determined to increase the DNA damage to pBR322 plasmid. Results indicate that the pBR322 plasmid model can be successfully used to explore and test the effect of UHDR regimes on DNA damage. This is the first study to report FLASH sparing with VHEE, with induced damage to pBR322 plasmid DNA as the biological endpoint. UHDR irradiated plasmid had reduced amounts of DNA single-strand breaks (SSBs) in comparison with conventional dose rates. The magnitude of the FLASH sparing was a 27% reduction in SSB frequency in a 10 mM Tris environment and a 16% reduction in a 100 mM Tris environment.

Abstract All-cause COVID-19 hospitalization ≤ 30 days of infection is a common outcome for severe illness in observational/surveillance studies. Milder COVID-19 disease and COVID-19-specific measurements calls for an evaluation of this endpoint. This was a descriptive, retrospective cohort study of adults ≥ 18 who were established in primary care at Veteran Health Administration (VHA) facilities. The outcome was hospitalization within 30 days of a laboratory-confirmed, symptomatic SARS-CoV-2 infection. Between December 15, 2021 and May 1, 2022, a simple random sample of all VA facilities, excluding Puerto Rico or Philippines, was drawn to identify these hospitalized cases and determine whether hospitalization was due to COVID-19-specific causes. A chart review was conducted to record the inpatient clinical team’s diagnosis and whether the inpatient team classified the diagnosis as COVID-19 related or not. These data were used to classify hospitalizations as either due to COVID-19-specific causes (direct manifestations of SARS-CoV-2 infection) or non-COVID-19-specific hospitalizations (incidental SARS-CoV-2 infection), A simple random sample of 9966 (12.3%) all-cause hospitalizations (95% CI: 12.1%, 12.5%) was used to select 300 representative patients. Of these, 226/300 (75.3%) were determined to be COVID-19-specific. COVID-19 pneumonia was most common (147/226, 65.0%). The highest proportion of COVID-19-specific hospitalizations occurred among unvaccinated (85.0%), followed by vaccinated but not boosted (73.7%) and boosted (59.4%) (p

Abstract Infrastructure is often a limiting factor in microplastics research impacting the production of scientific outputs and monitoring data. International projects are therefore required to promote collaboration and development of national and regional scientific hubs. The Commonwealth Litter Programme and the Ocean Country Partnership Programme were developed to support Global South countries to take actions on plastics entering the oceans. An international laboratory network was developed to provide the infrastructure and in country capacity to conduct the collection and processing of microplastics in environmental samples. The laboratory network was also extended to include a network developed by the University of East Anglia, UK. All the laboratories were provided with similar equipment for the collection, processing and analysis of microplastics in environmental samples. Harmonised protocols and training were also provided in country during laboratory setup to ensure comparability of quality-controlled outputs between laboratories. Such large networks are needed to produce comparable baseline and monitoring assessments.

Abstract Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R2 = 0.96–0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D0.5) and 10% (D0.1) cell survival. Using these values, VHEE RBE was measured as 0.93 (D0.5) and 0.99 (D0.1) for A549 and 0.74 (D0.5) and 0.93 (D0.1) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE.

Research shows that Americans are using increasing amounts of complementary and alternative medicine (CAM) and that education is a significant predictor of CAM use. The purpose of this systematic review is to summarize key research findings on CAM use rates among U.S. college students and recommend future actions for researchers and health educators. A systematic search sought out peer-reviewed studies that provide empirical data on rates of CAM use among the general college population in the U.S. Findings in 10 studies were reported and compared to 2007 NHIS data. Use of acupuncture, homeopathy, NVNM, massage therapy, healing therapy/Reiki and yoga is significantly higher among U.S. college samples than the general U.S. adult sample with NVNM and massage therapy showing small effect sizes (d greater than 0.20, r greater than 0.10). Future research must address the limitations of previous studies. Health education efforts are needed to prepare college students for making informed decisions regarding CAM use. Health educators can incorporate CAM topics into curricula, distribute CAM literature, organize campus-wide presentations, and include CAM providers in health fairs. Health educators should be prepared to discuss CAM safety and efficacy with students and provide referrals to reputable CAM providers. (Contains 4 tables

Highly pathogenic avian influenza (HPAI) viruses have potential to cross species barriers and cause pandemics. Since 2022, HPAI A(H5N1) belonging to the goose/Guangdong 2.3.4.4b hemagglutinin phylogenetic clade have infected poultry, wild birds, and mammals across North America. Continued circulation in birds and infection of multiple mammalian species with strains possessing adaptation mutations increase the risk for infection and subsequent reassortment with influenza A viruses endemic in swine. We assessed the susceptibility of swine to avian and mammalian HPAI H5N1 clade 2.3.4.4b strains using a pathogenesis and transmission model. All strains replicated in the lung of pigs and caused lesions consistent with influenza A infection. However, viral replication in the nasal cavity and transmission was only observed with mammalian isolates. Mammalian adaptation and reassortment may increase the risk for incursion and transmission of HPAI viruses in feral, backyard, or commercial swine.

Introduction: Pennsylvania opened its first medical marijuana (MMJ) dispensary in 2018. Qualifying conditions include six conditions determined to have no or insufficient evidence to support or refute MMJ effectiveness. We conducted a study to describe MMJ dispensary access in Pennsylvania and to determine whether dispensary proximity was associated with MMJ certifications and community demographics. Methods: Using data from the Pennsylvania Department of Health, we geocoded MMJ dispensary locations and linked them to US Census Bureau data. We created dispensary access measures from the population-weighted centroid of Zip Code Tabulation Areas (ZCTAs): distance to nearest dispensary and density of dispensaries within a 15-min drive. We evaluated associations between dispensary access and the proportion of adults who received MMJ certification and the proportion of certifications for low evidence conditions (amyotrophic lateral sclerosis, epilepsy, glaucoma, Huntington’s disease, opioid use disorder, and Parkinson’s disease) using negative binomial modeling, adjusting for community features. To evaluate associations racial and ethnic composition of communities and distance to nearest dispensary, we used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI), adjusting for median income. Results: Distance and density of MMJ dispensaries were associated with the proportion of the ZCTA population certified and the proportion of certifications for insufficient evidence conditions. Compared to ZCTAs with no dispensary within 15 min, the proportion of adults certified increased by up to 31% and the proportion of certifications for insufficient evidence decreased by up to 22% for ZCTAs with two dispensaries. From 2018 to 2021, the odds of being within five miles of a dispensary was up to 20 times higher in ZCTAs with the highest proportions of individuals who were not White (2019: OR: 20.14, CI: 10.7–37.8) and more than double in ZCTAs with the highest proportion of Hispanic individuals (2018: OR: 2.81, CI: 1.51–5.24), compared to ZCTAs with the lowest proportions. Conclusions: Greater dispensary access was associated with the proportions of certified residents and certifications for low evidence conditions. Whether these patterns are due to differences in accessibility or demand is unknown. Associations between community demographics and dispensary proximity may indicate MMJ access differences.

Purpose: To determine how beliefs about various disease outcomes caused by human papillomavirus (HPV) infection differ among young gay, bisexual, and other men who have sex with men (YGBMSM). Methods: From 2019 to 2021, we recruited cisgender YGBMSM ages 18–25 in the United States who were unvaccinated against HPV (n = 1,227). Survey items examined three disease outcomes (genital warts, anal cancer, and oropharyngeal cancer) for each of three different beliefs (perceived vulnerability, perceived severity, and worry) Results: Participants reported lower perceived vulnerability to and worry about anal cancer and oropharyngeal cancer compared to genital warts (all p

Functional interactions between the prefrontal cortex and hippocampus, as revealed by strong oscillatory synchronization in the theta (6–11 Hz) frequency range, correlate with memory-guided decision-making. However, the degree to which this form of long-range synchronization influences memory-guided choice remains unclear. We developed a brain-machine interface that initiated task trials based on the magnitude of prefrontal-hippocampal theta synchronization, then measured choice outcomes. Trials initiated based on strong prefrontal-hippocampal theta synchrony were more likely to be correct compared to control trials on both working memory-dependent and -independent tasks. Prefrontal-thalamic neural interactions increased with prefrontal-hippocampal synchrony and optogenetic activation of the ventral midline thalamus primarily entrained prefrontal theta rhythms, but dynamically modulated synchrony. Together, our results show that prefrontal-hippocampal theta synchronization leads to a higher probability of a correct choice and strengthens prefrontal-thalamic dialogue. Our findings reveal new insights into the neural circuit dynamics underlying memory-guided choices and highlight a promising technique to potentiate cognitive processes or behavior via brain-machine interfacing.

Objectives In the face of unprecedented demand, the Welsh Ambulance Services University NHS Trust developed ‘Blue Light Hub’: a new app to educate primary school-aged children about emergency services. Our overarching aim was to examine the effectiveness of the app.Design Primary school-aged children from three schools in South Wales, UK, played with the app for 2 hours over 2 weeks in class time. Children completed quizzes to assess their knowledge and awareness of, and confidence in engaging with, emergency services before and after using the app.Participants Our evaluation focused on N=393 children who completed both the pre-test and post-test quizzes. On average, children were 8–9 years old (median school year, Year 4); 47.8% were male and 50.9% were female.Results After using the app, there was a significant increase in the proportion of children who knew of appropriate actions to take in non-emergency scenarios, χ2(1) = 26.01, and could provide a question a call handler would ask them if they called 999, χ2(1) = 13.79. There was also an increase in the proportion of children who could identify an National Health Service (NHS) service that could help them if they were unwell, χ2(1) = 33.31, name different roles in the NHS, χ2(1) = 12.80 and knew how dialling 111 could help them χ2(1) = 90.05 (all p values

BackgroundThe shift toward online recruitment methods, accelerated by the COVID-19 pandemic, has brought to the forefront the growing concern of encountering fraudulent participants in health care research. The increasing prevalence of this issue poses a serious threat to the reliability and integrity of research data and subsequent findings. ObjectiveThis study aims to explore the experiences of health care researchers (HCRs) who have encountered fraudulent participants while using online recruitment methods and platforms. The primary objective was to gain insights into how researchers detect and mitigate fraudulent behavior in their work and provide prevention recommendations. MethodsA multimethod sequential design was used for this pilot study, comprising a quantitative arm involving a web-based survey followed by a qualitative arm featuring semistructured interviews. The qualitative description approach framed the qualitative arm of the study. Sample sizes for the quantitative and qualitative arms were based on pragmatic considerations that in part stemmed from encountering fraudulent participants in a concurrent study. Content analysis was used to analyze open-ended survey questions and interview data. ResultsA total of 37 HCRs participated, with 35% (13/37) of them engaging in qualitative interviews. Online platforms such as Facebook, email, Twitter (subsequently rebranded X), and newsletters were the most used methods for recruitment. A total of 84% (31/37) of participants indicated that fraudulent participation occurred in studies that mentioned incentives in their recruitment communications, with 71% (26/37) of HCRs offering physical or electronic gift cards as incentives. Researchers identified several indicators of suspicious behavior, including email surges, discrepancies in contact or personal information, geographical inconsistencies, and suspicious responses to survey questions. HCRs emphasized the need for a comprehensive screening protocol that extends beyond eligibility checks and is seamlessly integrated into the study protocol, grant applications, and research ethics board submissions. ConclusionsThis study sheds light on the intricate and pervasive problem of fraudulent participation in health care research using online recruitment methods. The findings underscore the importance of vigilance and proactivity among HCRs in identifying, preventing, and addressing fraudulent behavior. To effectively tackle this challenge, researchers are encouraged to develop a comprehensive prevention strategy and establish a community of practice, facilitating real-time access to solutions and support and the promotion of ethical research practices. This collaborative approach will enable researchers to effectively address the issue of fraudulent participation, ensuring the conduct of high-quality and ethically sound research in the digital age.

This paper reviews the substantial body of research on clinical judgment and decision making in medicine and psychology and urges the incorporation of clinical judgment into the speech-language pathology field. The accuracy of clinical judgment, methods of its study, and suggestions for incorporating it into professional training are considered. (Author/JDD)

Introduction Adolescents and young adults are susceptible population when it comes to healthy eating and dietary behaviours. The increasing use of social media by this age group presents a unique opportunity to promote healthy eating habits. Social media has become a popular platform for promoting health interventions, particularly among young people. However, there is a lack of consensus on the effectiveness of social media interventions in this population. This mixed-method systematic review aims to synthesise the available evidence on the impact of social media interventions on healthy eating behaviours among young people, their qualitative views and user experiences, and the intervention characteristics, behaviour change theories and techniques used to promote healthy eating.Methods and analysis We will conduct a comprehensive search of seven electronic databases, including ASSIA, Cochrane Library, Embase, MEDLINE, PsycINFO, Scopus and Web of Science. The search strategy will use a combination of Medical Subject Headings terms and keywords covering three domains: social media, eating behaviours and young people. The search will be limited to peer-reviewed published papers in any language, published from 2000. Three independent reviewers will screen studies based on predetermined eligibility criteria. Data will be extracted and analysed using a convergent segregated mixed-method approach. We will use random-effect meta-analysis or Synthesis Without Meta-analysis for quantitative data and thematic synthesis for qualitative data. Finally, narrative synthesis using concurrent triangulation will be used to bring together the results of the mixed-method data analysis to provide a comprehensive and integrated understanding of the impact and other features of social media interventions. This systematic review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.Ethics and dissemination Ethical approval is not required since this systematic review will not collect original data. The outcomes of this review will be shared through peer-reviewed publications and conference presentations and will contribute to the PhD thesis of the primary author.PROSPERO registration number CRD42023414476.

PurposeGlare is a known side effect of intraocular lens (IOL) implantation, affected principally by IOL material and optics, although it is reported subjectively to decrease in impact with time. However, little objective data have been published on changes over time, how these relate to subjective reports, and whether those who will report greater glare symptoms can be predicted prior to IOL implantation.MethodsA total of 32 patients (aged 72.4 ± 8.0 years) with healthy eyes were implanted bilaterally with hydrophilic 600s (Rayner, Worthing, UK) or hydrophobic Acrysof (Alcon, Texas, USA) acrylic IOLs (n = 16 each, randomly assigned). Each patient reported their dysphotopsia symptoms subjectively using the validated forced choice photographic questionnaire for photic phenomena, and halo size resulting from a bright light in a dark environment was quantified objectively in eight orientations using the Aston Halometer. Assessment was performed binocularly pre-operatively and at 1, 2, 3, and 4 weeks after IOL implantation.SettingThe study was carried out at the National Health Service Ophthalmology Department, Queen Elizabeth Hospital, Birmingham, UK.ResultsVisual acuity (average 0.37 ± 0.26 logMAR) did not correlate with subjective glare (r = 0.184, p = 0.494) or objective glare (r = 0.294, p = 0.270) pre-surgery. Objective halo size (F = 112.781, p < 0.001) decreased with cataract removal and IOL implantation and continued to decreased over the month after surgery. Subjective dysphotopsia complaints (p < 0.001) were also greater pre-surgery, but did not change thereafter (p = 0.228). In neither case was there a difference with IOL material (p > 0.05). It was not possible to predict post-surgery dysphotopsia from symptoms or a ratio of symptoms to halo size pre-surgery (p > 0.05).ConclusionsSubjective dysphotopsia and objective halos caused by cataracts are greatly reduced by implantation of IOL after cataract removal causing few perceivable symptoms. However, objective measures are able to quantify a further reduction in light scatter over the first month post-IOL implantation, suggesting that any subjective effects over this period are due to the healing process and not due to neuroadaptation.

Abstract Abundance of data on the role of inflammatory immune responses in the progression or inhibition of hepatocellular carcinoma (HCC) has failed to offer a curative immunotherapy for HCC. This is largely because of focusing on detailed specific cell types and missing the collective function of the hepatic immune system. To discover the collective immune function, we take systems immunology approach by performing high-throughput analysis of snRNAseq data collected from the liver of DIAMOND mice during the progression of nonalcoholic fatty liver disease (NAFLD) to HCC. We report that mutual signaling interactions of the hepatic immune cells in a dominant-subdominant manner, as well as their interaction with structural cells shape the immunological pattern manifesting a collective function beyond the function of the cellular constituents. Such pattern discovery approach recognized direct role of the innate immune cells in the progression of NASH and HCC. These data suggest that discovery of the immune pattern not only detects the immunological mechanism of HCC in spite of dynamic changes in immune cells during the course of disease but also offers immune modulatory interventions for the treatment of NAFLD and HCC.

Since SARS-CoV-2 emerged in late 2019, it spread from China to the rest of the world. An initial concern was the potential for vaccine- or antibody-dependent enhancement (ADE) of disease as had been reported with other coronaviruses. To evaluate this, we first developed a ferret model by exposing ferrets to SARS-CoV-2 by either mucosal inoculation (intranasal/oral/ocular) or inhalation using a small particle aerosol. Mucosal inoculation caused a mild fever and weight loss that resolved quickly; inoculation via either route resulted in virus shedding detected in the nares, throat, and rectum for 7-10 days post-infection. To evaluate the potential for ADE, we then inoculated groups of ferrets intravenously with 0.1, 0.5, or 1 mg/kg doses of a human polyclonal anti-SARS-CoV-2 IgG from hyper-immunized transchromosomic bovines (SAB-185). Twelve hours later, ferrets were challenged by mucosal inoculation with SARS-CoV-2. We found no significant differences in fever, weight loss, or viral shedding after infection between the three antibody groups or the controls. Signs of pathology in the lungs were noted in infected ferrets but no differences were found between control and antibody groups. The results of this study indicate that healthy, young adult ferrets of both sexes are a suitable model of mild COVID-19 and that low doses of specific IgG in SAB-185 are unlikely to enhance the disease caused by SARS-CoV-2.

Background: While the majority of reproductive-aged females will experience pelvic pain during their lives, biological mechanisms underlying pelvic pain are not well understood. We investigated associations between pelvic pain symptoms and oxidative stress among people with and without surgically-confirmed endometriosis. Methods: Using an enzyme-linked immunosorbent assay, we measured 8-Hydroxy-2’-deoxyguanosine (8-OHdG) in urine samples and corrected for creatinine levels in 434 surgically-confirmed endometriosis participants compared to 605 participants never diagnosed with endometriosis. At enrollment, participants reported details of their pelvic pain symptoms. Linear regression was used to compute geometric mean (GM) creatinine-corrected 8-OHdG levels with 95% confidence intervals (CI) among all participants and those with and without endometriosis separately, adjusting for potential confounders. Interactions by surgically-confirmed endometriosis status were tested by Wald statistics. Results: No trends in 8-OHdG were observed among those with or without endometriosis for severity or frequency of dysmenorrhea, acyclic pelvic pain, dyspareunia or pain with bowel movements. Among endometriosis participants, lower 8-OHdG levels were observed for participants with any white, blue/black, or brown lesions (GM=76.7 versus 82.9 ng/mg; p=0.10), which was primarily driven by lower levels of 8-OHdG for any blue/black lesions (GM=72.8 versus 81.6 ng/mg; p=0.05). Conclusion: While no associations were observed between 8-OHdG and pelvic pain symptoms, future research is needed to assess how other pathways of oxidative damage, e.g. through proteins or lipids, may affect endometriosis-associated symptoms. Additionally, further research is needed to understand differences in oxidative stress among endometriosis lesion sub-phenotypes.

Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien and Higham, 2019; Powell et al., 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date (e.g. Khaitovich et al., 2005; Khrameeva et al., 2020; Ma et al., 2022; Somel et al., 2009). To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-seq data from four brain regions in an unprecedented eighteen species. Here, we show a remarkable level of variation in gene expression among hominid species, including humans and chimpanzees, despite their relatively recent divergence time from other primates. We found that individual genes display a wide range of expression dynamics across evolutionary time reflective of the diverse selection pressures acting on genes within primate brain tissue. Using our samples that represent a 190-fold difference in primate brain size, we identified genes with variation in expression most correlated with brain size. Our study extensively broadens the phylogenetic context of what is known about the molecular evolution of the brain across primates and identifies novel candidate genes for the study of genetic regulation of brain evolution.

BackgroundPoor mental health is associated with obesity, but existing studies are either cross-sectional or have long time periods between measurements of mental health and weight. It is, therefore, unclear how small fluctuations in mental wellbeing within individuals predict bodyweight over short time periods, e.g. within the next month. Studying this could identify modifiable determinants of weight changes and highlight opportunities for early intervention.Methods2,133 UK adults from a population-based cohort completed monthly mental health and weight measurements using a mobile app over a period of 6-9 months. We used random intercept regression models to examine longitudinal associations of depressive symptoms, anxiety symptoms and stress with subsequent weight. In sub-group analyses, we included interaction terms of mental health variables with baseline characteristics. Mental health variables were split into "between-individual" measurements (= the participant's median score across all timepoints) and "within-individual" measurements (at each timepoint, the difference between the participant's current score and their median).ResultsWithin-individual variation in depressive symptoms predicted subsequent weight (0.045kg per unit of depressive symptom severity, 95% CI 0.021-0.069). We found evidence of a moderation effect of baseline BMI on the association between within-individual fluctuation in depressive symptoms and subsequent weight: The association was only apparent in those with overweight/obesity, and it was stronger in those with obesity than those with overweight (BMIConclusionIn this exploratory study, individuals with overweight or obesity were more vulnerable to weight gain following higher-than-usual (for that individual) depressive symptoms than individuals with a BMI

ABSTRACTObjective Through the lens of behavioral models such as the Theory of Planned Behavior (TPB) and the Health Belief Model, the present study (1) investigated U.S. university students’ willingness to receive the COVID-19 vaccine and (2) examined predictors (e.g. demographics, past vaccine experience, TPB constructs) of vaccine willingness.Method University students (n = 170) completed a survey assessing demographics, health behaviors, attitudes, perceived severity/susceptibility, norms, and vaccine intentions related to the COVID-19 pandemic. Data were collected from April 2020 through July 2020.Results Overall, 56.5% of participants indicated that they would be willing to receive the COVID-19 vaccine once it is available, 39.4% were unsure of whether they would receive the vaccine, and 4.1% indicated they would not receive the vaccine. Multinomial logistic regression indicated that greater adherence to CDC guidelines (p = .030) and greater perceived pro-vaccine norms (p

Objectives Opioid use disorder (OUD) is a major public health concern in the USA, resulting in high rates of overdose and other negative outcomes. Methadone, an OUD treatment, has been shown to be effective in reducing the risk of overdose and improving overall health and quality of life. This study analysed the distribution of methadone for the treatment of OUD across the USA over the past decade and through the COVID-19 pandemic.Design Retrospective observational study using secondary data analysis of the Drug Enforcement Administration and Medicaid Databases.Setting USA.Participants Patients who were dispensed methadone at US opioid treatment programmes (OTPs).Primary and secondary outcome measures The primary outcomes were the overall pattern in methadone distribution and the number of OTPs in the USA per year. The secondary outcome was Medicaid prescriptions for methadone.Results Methadone distribution for OUD has expanded significantly over the past decade, with an average state increase of +96.96% from 2010 to 2020. There was a significant increase in overall distribution of methadone to OTP from 2010 to 2020 (+61.00%, p

Abstract Tarsometatarsal joint arthrodesis is used to treat a variety of injuries and deformities in the midfoot. However, the surgical technique has not been optimized, in part due to limited knowledge of morphologic features and variation in the related joints. Previous research has relied primarily on dissection-based anatomical analysis, but quantitative imaging may allow for a more sophisticated description of this complex. Here, we used quantitative micro-CT imaging to examine dimensions, distance maps, and curvature of the four articular surfaces in the first and second tarsometatarsal joints. Image segmentation, articular surface identification, and anatomic coordinate systems were all done with semi or fully automatic methods, and distance and size measurements were all taken utilizing these anatomic planes. Surface curvature was studied using Gaussian curvature and a newly defined measure of curvature similarity on the whole joint and on four subregions of each surface. These data show larger articular surfaces on the cuneiforms, rather than metatarsals, and define the generally tall and narrow articular surfaces seen in these joints. Curvature analysis shows minimally curved opposing convex surfaces. Our results are valuable for furthering knowledge of surgical anatomy in this poorly understood region of the foot.

Abstract Background Ovarian cancer has a specific unmet clinical need, with a persistently poor 5-year survival rate observed in women with advanced stage disease warranting continued efforts to develop new treatment options. The amplification of BRD4 in a significant subset of high-grade serous ovarian carcinomas (HGSC) has led to the development of BET inhibitors (BETi) as promising antitumour agents that have subsequently been evaluated in phase I/II clinical trials. Here, we describe the molecular effects and ex vivo preclinical activities of i-BET858, a bivalent pan-BET inhibitor with proven in vivo BRD inhibitory activity. Results i-BET858 demonstrates enhanced cytotoxic activity compared with earlier generation BETis both in cell lines and primary cells derived from clinical samples of HGSC. At molecular level, i-BET858 triggered a bipartite transcriptional response, comprised of a ‘core’ network of genes commonly associated with BET inhibition in solid tumours, together with a unique i-BET858 gene signature. Mechanistically, i-BET858 elicited enhanced DNA damage, cell cycle arrest and apoptotic cell death compared to its predecessor i-BET151. Conclusions Overall, our ex vivo and in vitro studies indicate that i-BET858 represents an optimal candidate to pursue further clinical validation for the treatment of HGSC.

Abstract Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (

Abstract Background It is now understood that it is the quality rather than the absolute amount of adipose tissue that confers risk for obesity-associated disease. Adipose-derived stem cells give rise to adipocytes during the developmental establishment of adipose depots. In adult depots, a reservoir of progenitors serves to replace adipocytes that have reached their lifespan and for recruitment to increase lipid buffering capacity under conditions of positive energy balance. Main The adipose tissue expandability hypothesis posits that a failure in de novo differentiation of adipocytes limits lipid storage capacity and leads to spillover of lipids into the circulation, precipitating the onset of obesity-associated disease. Since adipose progenitors are specified to their fate during late fetal life, perturbations in the intrauterine environment may influence the rapid expansion of adipose depots that occurs in childhood or progenitor function in established adult depots. Neonates born to mothers with obesity or diabetes during pregnancy tend to have excessive adiposity at birth and are at increased risk for childhood adiposity and cardiometabolic disease. Conclusion In this narrative review, we synthesize current knowledge in the fields of obesity and developmental biology together with literature from the field of the developmental origins of health and disease (DOHaD) to put forth the hypothesis that the intrauterine milieu of pregnancies complicated by maternal metabolic disease disturbs adipogenesis in the fetus, thereby accelerating the trajectory of adipose expansion in early postnatal life and predisposing to impaired adipose plasticity.

Background: The Born in Bradford’s Better Start (BiBBS) interventional birth cohort study was designed as an innovative cohort platform for efficient evaluation of early life interventions delivered through the Better Start Bradford programme. There are a growing number of interventional cohorts being implemented internationally. This paper provides an interim analysis of BiBBS in order to share learning about the feasibility and value of this method. Methods: Recruitment began in January 2016 and will complete in December 2023 with a target sample of 5,000 pregnancies. An interim analysis was completed for all pregnancies recruited between January 2016 and November 2019 with an expected due date between 1st April 2016 and 8th March 2020. Descriptive statistics were completed on the data. Results: Of 4,823 eligible pregnancies, 2,626 (54%) pregnancies were recruited, resulting in 2,392 mothers and 2,501 children. The sample are representative of the pregnant population (61% Pakistani heritage; 12% White British; 8% other South Asian and 6% Central and Eastern European ethnicity). The majority of participants (84%) live in the lowest decile of the Index of Multiple Deprivation, and many live in vulnerable circumstances. A high proportion (85%) of BiBBS families have engaged in one or more of the Better Start Bradford interventions. Levels of participation varied by the characteristics of the interventions, such as the requirement for active participation and the length of commitment to a programme. Conclusions: We have demonstrated the feasibility of recruiting an interventional cohort that includes seldom heard families from ethnic minority and deprived backgrounds. The high level of uptake of interventions is encouraging for the goal of evaluating the process and outcomes of multiple early life interventions using the innovative interventional cohort approach. BiBBS covers a period before, during and after the coronavirus disease 2019 (COVID-19) pandemic which adds scientific value to the cohort.

Abstract Early life adversity (ELA) tends to accelerate neurobiological ageing, which, in turn, is thought to heighten vulnerability to both major depressive disorder (MDD) and Alzheimer’s disease (AD). The two conditions are putatively related, with MDD representing either a risk factor or early symptom of AD. Given the substantial environmental susceptibility of both disorders, timely identification of their neurocognitive markers could facilitate interventions to prevent clinical onset. To this end, we analysed multimodal data from the Adolescent Brain and Cognitive Development study (ages 9–10 years). To disentangle genetic from correlated genetic-environmental influences, while also probing gene-adversity interactions, we compared adoptees, a group generally exposed to substantial ELA, with children raised by their biological families via genetic risk scores (GRS) from genome-wide association studies. AD and MDD GRSs predicted overlapping and widespread neurodevelopmental alterations associated with superior fluid cognition. Specifically, among adoptees only, greater AD GRS were related to accelerated structural maturation (i.e., cortical thinning) and higher MDD GRS were linked to delayed functional neurodevelopment, as reflected in compensatory brain activation on an inhibitory control task. Our study identifies compensatory mechanisms linked to MDD risk and highlights the potential cognitive benefits of accelerated maturation linked to AD vulnerability in late childhood.

Abstract The goals of this study were to identify transcriptomic changes that arise in basal-like breast cancer cells during the development of resistance to epidermal growth factor receptor inhibitors (EGFRi) and to identify drugs that are cytotoxic once EGFRi resistance occurs. Human patient-derived xenografts (PDXs) were grown in immunodeficient mice and treated with a set of EGFRi; the EGFRi erlotinib was selected for more expansive in vivo studies. Single-cell RNA sequencing was performed on mammary tumors from the basal-like PDX WHIM2 that was treated with vehicle or erlotinib for 9 weeks. The PDX was then subjected to long-term erlotinib treatment in vivo. Through serial passaging, an erlotinib-resistant subline of WHIM2 was generated. Bulk RNA-sequencing was performed on parental and erlotinib-resistant tumors. In vitro high-throughput drug screening with > 500 clinically used compounds was performed on parental and erlotinib-resistant cells. Previously published bulk gene expression microarray data from MMTV-Wnt1 tumors were contrasted with the WHIM2 PDX data. Erlotinib effectively inhibited WHIM2 tumor growth for approximately 4 weeks. Compared to untreated cells, single-cell RNA sequencing revealed that a greater proportion of erlotinib-treated cells were in the G1 phase of the cell cycle. Comparison of WHIM2 and MMTV-Wnt1 gene expression data revealed a set of 38 overlapping genes that were differentially expressed in the erlotinib-resistant WHIM2 and MMTV-Wnt1 tumors. Comparison of all three data types revealed five genes that were upregulated across all erlotinib-resistant samples: IL19, KLK7, LCN2, SAA1, and SAA2. Of these five genes, LCN2 was most abundantly expressed in triple-negative breast cancers, and its knockdown restored erlotinib sensitivity in vitro. Despite transcriptomic differences, parental and erlotinib-resistant WHIM2 displayed similar responses to the majority of drugs assessed for cytotoxicity in vitro. This study identified transcriptomic changes arising in erlotinib-resistant basal-like breast cancer. These data could be used to identify a biomarker or develop a gene signature predictive of patient response to EGFRi. Future studies should explore the predictive capacity of these gene signatures as well as how LCN2 contributes to the development of EGFRi resistance.

Since the COVID-19 pandemic began, different SARS-CoV-2 variants have been identified and associated with higher transmissibility than the ancestral nonvariant strain. During January 1, 2021–January 15, 2022, we assessed differences in clinical and viral parameters in a convenience sample of COVID-19 outpatients and inpatients 0–21 years of age in Columbus, Ohio, USA, according to the infecting variant, identified using a mutation-specific reverse transcription PCR assay. Of the 676 patients in the study, 17.75% were infected with nonvariant strains, 18.49% with the Alpha variant, 41.72% with Delta, and 16.42% with Omicron. Rates of SARS-COV-2/viral co-infections were 15.66%–29.41% and were comparable across infecting variants. Inpatients with acute Delta and Omicron infections had lower SARS-CoV-2 cycle threshold values and more frequent fever and respiratory symptoms than those with nonvariant strain infections. In addition, SARS-COV-2/viral co-infections and the presence of underlying conditions were independently associated with worse clinical outcomes, irrespective of the infecting variant.

Abstract Elevated prostate-specific antigen (PSA) levels often lead to unnecessary and possibly harmful transrectal ultrasound guided biopsy, e.g. when the biopsy is negative or contains only low-grade insignificant cancer, unlikely to become symptomatic in the man’s normal lifespan. A model based on four-kallikrein markers in blood (commercialized as 4Kscore) predicts risk of Grade group 2 or higher prostate cancer at biopsy, reducing unnecessary biopsies. We assessed whether these results extend to a single institution prostate biopsy cohort of Danish men and are enhanced by three microRNAs from urine (referred to as uCaP). The 4Kscore measured in cryopreserved blood from 234 men referred for 10+ core biopsy to Aarhus University Hospital, 29 with PSA > 25 ng/ml. We explored uCaP in urine from 157 of these men. Combined with age and DRE findings, both 4Kscore and uCaP could accurately predict Grade group 2 or higher prostate cancer (all patients: AUC = 0.802 and 0.797; PSA ≤ 25: AUC = 0.763 and 0.759). There was no additive effect when combining the 4Kscore and uCaP. Limitations include a study cohort with higher risk than commonly reported for biopsy cohorts. Our findings further support the clinical use of the 4Kscore to predict Grade group 2 or higher cancers in men being considered for biopsy.

Background: Positive maternal mental health during the perinatal period contributes to general well-being and positive emotional bonds with the child, encouraging an optimal developmental trajectory. Online interventions to enhance maternal well-being and develop coping skills, such as meditation-based interventions, can be a low-cost way to improve mother and child outcomes. However, this depends on end-user engagement. To date, there is limited evidence about women’s willingness to engage and preferences for online programmes. Objectives: This study explored pregnant women’s attitudes towards and likelihood to undertake minimal online well-being training programmes (mindfulness, self-compassion, or general relaxation), engagement barriers and enablers, and programme structure preferences. Design: A mixed methods triangulation design was undertaken using a validating quantitative model. Quantile regressions were applied to the quantitative data. Content analysis was undertaken for the qualitative data. Methods: Consenting pregnant women ( n = 151) were randomized equally to read about three online programme types. Participants were sent an information leaflet, tested by a consumer panel prior to distribution. Results: Participants generally held positive attitudes about all three types of interventions, with no statistically significant differences in preferences between programme types. Participants appreciated the importance of mental health and were receptive to fostering skills to support their emotional well-being and stress management. The most frequent perceived barriers were lack of time, tiredness, and forgetfulness. Programme structure preferences indicated one to two modules per week, less than 15 min in duration, and over 4 weeks. Programme functionality, such as regular reminders and easy accessibility, is important to end users. Conclusion: Our findings reinforce the importance of determining participant preferences in designing and communicating engaging interventions for perinatal women. This research contributes to the understanding of population-based interventions that can be provided as simple, scalable, cost-effective, and home-based activities in pregnancy for the benefit of individuals, their families, and society more broadly.

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.

Introduction The global antiretroviral therapy era has led to a decline in the number of children newly acquiring HIV and an increase in the number of children who are HIV-exposed and uninfected (HEU). This shift has prompted extensive research focussing on health and survival outcomes of children who are HEU. Study findings, particularly in relation to adverse birth outcomes, have been disparate, inconclusive and have not always been generalisable. Thus, the objectives of this scoping review are (1) to identify and extract definitions used for the adverse birth outcome terms ‘low birth weight’, ‘small for gestational age’, ‘stillbirth’ and ‘preterm birth’; (2) to compare the characteristics of studies from which birth outcome definitions were extracted by (a) temporal periods and (b) study country setting (high-income vs low-income and middle-income countries); (3) to use content analysis to map and describe the temporal and geographic distribution of the definitions used and construct a logical model of their evolution.Methods and analysis The online databases of PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library and CINHAL/EBSCOhost will be used to identify published and grey literature from 2011 to 2022 to identify definitions for the adverse birth outcome terms ‘low birth weight’, ‘small for gestational age’, ‘stillbirth’ and ‘preterm birth’. A three-step process of (1) duplicate removal, (2) title and abstract screening and (3) full text screening will be used to select included studies. The extracted data will be used to conduct a comparative analysis, content analysis and construct a logic model.Ethics and dissemination This review will be used to inform a consensus process around the development of harmonised definitions for the specified adverse birth outcomes. Our dissemination plan includes presentations, publications as well as the development infographics and a resource hub. The study is approved by the Human Research Ethics Committee of Stellenbosch University.

Abstract When faced with difficult choices, the possible outcomes are considered through a process known as deliberation. In rats, deliberation is thought to be reflected by pause-and-reorienting behaviors, better known as vicarious trial and errors (VTEs). While VTEs are thought to require medial prefrontal cortex (mPFC) and dorsal hippocampal (dHPC) interactions, no empirical evidence has yet demonstrated such a dual requirement. The nucleus reuniens (Re) of the ventral midline thalamus is anatomically connected with both the mPFC and dHPC, is required for HPC-dependent spatial memory tasks, and is critical for mPFC-dHPC neural synchronization. Currently, it is unclear if, or how, the Re is involved in deliberation. Therefore, by examining the role of the Re on VTE behaviors, we can better understand the anatomical and physiological mechanisms supporting deliberation. Here, we examined the impact of Re suppression on VTE behaviors and mPFC-dHPC theta synchrony during asymptotic performance of a HPC-dependent delayed alternation (DA) task. Pharmacological suppression of the Re increased VTE behaviors that occurred with repetitive choice errors. These errors were best characterized as perseverative behaviors, in which some rats repeatedly selected a goal arm that previously yielded no reward. We then examined the impact of Re suppression on mPFC-dHPC theta synchrony during VTEs. We found that during VTEs, Re inactivation was associated with a reduction in mPFC-dHPC theta coherence and mPFC-to-dHPC theta directionality. Our findings suggest that the Re contributes to deliberation by coordinating mPFC-dHPC neural interactions.

Abstract The significance of serotonin (5HT) in mental health is underscored by the serotonergic action of many classes of psychiatric medication. 5HT is known to have a significant role in neurodevelopment, thus 5HT disruption during development may have a long term impact on brain structure and circuits. We previously generated a model of 5HT alteration throughout neurodevelopment by maternal administration of the selective serotonin reuptake inhibitor fluoxetine. We found resulting social behavior alterations in the offspring during both postnatal and adult ages. Previous work by others has indicated that early 5HT disruption influences neuronal morphology. Therefore, in the current study we sought to determine if dendritic morphological changes occur in areas involved in the social behavior deficits we previously observed, specifically the primary motor (M1) and medial prefrontal (mPFC) cortices. We quantified dendritic morphology of projection neurons in M1 and mPFC at postnatal day (P)10 and P79 in mice exposed to fluoxetine. Basilar dendritic complexity and spine density were persistently decreased in M1 fluoxetine-exposed neurons while in the mPFC, similar reductions were observed at P79 but were not present at P10. Our findings underscore that the developing brain, specifically the projection cortex, is vulnerable to 5HT system perturbation, which may be related to later behavioral disruptions.

Abstract Background Recent studies have reignited the tinderbox of debate surrounding the use of race and ancestry in medicine. These controversial studies have argued for a strong correlation between genetic ancestry and race, justifying continued use of genetic ancestry measures in studies of disease. These studies contend that increased use of continental ancestry estimates can inform clinical risk assessments and management. Further, recent studies of racial corrections used in clinical algorithms, such as those used to estimate 'normal' lung function, also advocate for use of genetic ancestry in place of race for refining risk algorithms. Main body These positions are misleading, harmful, and reflect superficial interpretations of population genetics. In this Perspective, we argue that continental genetic ancestry, often proxied by race, serves as a poor indicator of disease risk, and reinforces racialized inequities. Conclusion Instead, we endorse that racial disparities in disease should be investigated by rigorous measures of structural racism alongside careful measures of genetic factors in relevant disease pathways, rather than relying on genetic ancestry or race as a crude proxy for disease-causing alleles.

Abstract Objective Person-to-person transmission can occur during outbreaks of verotoxigenic Escherichia coli (VTEC), however the impact of this transmission route is not well understood. This study aimed to examine the role of person-to-person transmission during a VTEC outbreak, and how targeting this route may reduce outbreak size. A deterministic compartmental model describing a VTEC outbreak was constructed and fit to data from a 2008 outbreak in Ontario, Canada. Using the best-fit model, simulations were run to calculate the: reduction in transmission rate after implementing interventions, proportion of cases infected through both transmission routes, and number of cases prevented by interventions. Latin hypercube sensitivity analysis was conducted to examine the sensitivity of the outbreak size to the model parameters. Results Based on the best-fit model, ~ 14.25% of the cases likely arose due to person-to-person transmission. Interventions reduced this transmission rate by ~ 73%, causing a reduction in outbreak size of ~ 17% (47 cases). Sensitivity analysis showed that the model was highly sensitive to changes in all parameters of the model. The model demonstrates that person-to-person could be an important transmission route during VTEC outbreaks. Targeting this route of transmission through hand hygiene and work exclusions could reduce the final outbreak size.

Female cancer survivors are significantly more likely to experience infertility than the general population. It is well established that chemotherapy and radiotherapy can damage the ovary and compromise fertility, yet the ability of cancer treatments to induce uterine damage, and the underlying mechanisms, have been understudied. Here, we show that in mice total-body γ-irradiation (TBI) induced extensive DNA damage and apoptosis in uterine cells. We then transferred healthy donor embryos into ovariectomized adolescent female mice that were previously exposed to TBI to study the impacts of radiotherapy on the uterus independent from effects to ovarian endocrine function. Following TBI, embryo attachment and implantation were unaffected, but fetal resorption was evident at midgestation in 100% of dams, suggesting failed placental development. Consistent with this hypothesis, TBI impaired the decidual response in mice and primary human endometrial stromal cells. TBI also caused uterine artery endothelial dysfunction, likely preventing adequate blood vessel remodeling in early pregnancy. Notably, when pro-apoptotic protein Puma-deficient (Puma–/–) mice were exposed to TBI, apoptosis within the uterus was prevented, and decidualization, vascular function, and pregnancy were restored, identifying PUMA-mediated apoptosis as a key mechanism. Collectively, these data show that TBI damages the uterus and compromises pregnancy success, suggesting that optimal fertility preservation during radiotherapy may require protection of both the ovaries and uterus. In this regard, inhibition of PUMA may represent a potential fertility preservation strategy.

Introduction: After discharge from the emergency department (ED), pain management challenges parents, who have been shown to undertreat their children’s pain. Our goal was to evaluate the effectiveness of a five-minute instructional video for parents on pain treatment in the home setting to address common misconceptions about home pediatric pain management. Methods: We conducted a randomized, single-blinded clinical trial of parents of children ages 1–18 years who presented with a painful condition, were evaluated, and were discharged home from a large, tertiary care pediatric ED. Parents were randomized to a pain management intervention video or an injury prevention control video. The primary outcome was the proportion of parents that gave their child pain medication at home after discharge. These data were recorded in a home pain diary and analyzed using the chi square test to determine significant difference. Parents’ knowledge about components of at-home pain treatment were tested before, immediately following, and two days after intervention. We used McNemar’s test statistic to compare incorrect pretest/correct post-test answers between intervention and control groups. Results: A total of 100 parents were enrolled: 59 parents watched the pain education video, and 41 the control video. Overall, 75% of parents completed follow-up, providing information about home medication use. Significantly more parents provided pain medication to their children after watching the educational video: 96% vs 80% (difference 16%; 95% CI 7.8–31.3%). Significantly more parents had correct pain treatment knowledge immediately following the educational video about pain scores (P = 0.04); the positive effects of analgesics (P

Abstract Exposure to heat stress during a cow’s dry period disrupts mammary gland remodeling, impairing mammary function and milk production during the subsequent lactation. Yet, proteomic changes in the mammary gland underlying these effects are not yet known. We investigated alterations in the mammary proteome and phosphoproteome during lactation as a result of dry period heat stress using an isobaric tag for relative and absolute quantitation (iTRAQ)-based approach. Cows were cooled (CL; n = 12) with fans and water soakers in a free stall setting or were heat stressed through lack of access to cooling devices (HT; n = 12) during the entire dry period (approximately 46 days). All cows were cooled postpartum. Mammary biopsies were harvested from a subset of cows (n = 4 per treatment) at 14, 42, and 84 days in milk. Overall, 251 proteins and 224 phosphorylated proteins were differentially abundant in the lactating mammary gland of HT compared to CL cows. Top functions of differentially abundant proteins and phosphoproteins affected were related to immune function and inflammation, amino acid metabolism, reactive oxygen species production and metabolism, tissue remodeling, and cell stress response. Patterns of protein expression and phosphorylation are indicative of increased oxidative stress, mammary gland restructuring, and immune dysregulation due to prior exposure to dry period heat stress. This study provides insights into the molecular underpinnings of disrupted mammary function and health during lactation arising from prior exposure to dry period heat stress, which might have led to lower milk yields.

Abstract Preclinical radiation research lacks standardized dosimetry procedures that provide traceability to a primary standard. Consequently, ensuring accuracy and reproducibility between studies is challenging. Using 3D printed murine phantoms we undertook a dosimetry audit of Xstrahl Small Animal Radiation Research Platforms (SARRPs) installed at 7 UK centres. The geometrically realistic phantom accommodated alanine pellets and Gafchromic EBT3 film for simultaneous measurement of the dose delivered and the dose distribution within a 2D plane, respectively. Two irradiation scenarios were developed: (1) a 10 × 10 mm2 static field targeting the pelvis, and (2) a 5 × 5 mm2 90° arc targeting the brain. For static fields, the absolute difference between the planned dose and alanine measurement across all centres was 4.1 ± 4.3% (mean ± standard deviation), with an overall range of − 2.3 to 10.5%. For arc fields, the difference was − 1.2% ± 6.1%, with a range of − 13.1 to 7.7%. EBT3 dose measurements were greater than alanine by 2.0 ± 2.5% and 3.5 ± 6.0% (mean ± standard deviation) for the static and arc fields, respectively. 2D dose distributions showed discrepancies to the planned dose at the field edges. The audit demonstrates that further work on preclinical radiotherapy quality assurance processes is merited.