Search

Background:. Large-scale retrospective studies have identified implicit gender bias in citation behaviors across multiple medical fields. There are minimal resources to directly assess one’s own citation behavior before publication at a laboratory level. In this study, we performed an internal audit of our own citation practices and behavior, looking at the representation of authors by gender in our own bibliographies. Methods:. Bibliographies were collated from our laboratory’s publications between 2015 and 2022 with a single senior author, who was excluded from participating in this study. Bibliographies were run through a simulation originally constructed and used by authors from the University of Pennsylvania that categorized authors of each article by gender: man or woman, according to external database records. Results:. Of the 1697 citations, the first and last authorship sequences displayed to be 60.8% male/male, 10.1% male/female, 16.3% female/male and 12.8% female/female. Men-led articles within our laboratory cited 67.4% male/male articles in their bibliographies compared with women-led articles citing 53.9%. All laboratory bibliographies consisted of 77.1% male senior authors compared with 22.9% female senior authors. Conclusions:. Our data confirm that a gender bias in citation practices exists at the laboratory level. Promisingly, these data also indicate that diversity within an individual laboratory group leads to diversity in representation; therefore, diversifying a team of researchers is prone to improve the overall work and success of the laboratory. We encourage laboratory groups to challenge their own biases by replicating their own results and discovering how these biases might be impacting their publications.

Objective Health literacy is an important social determinant of health, with limited health literacy associated with worse health outcomes. This study examined the associations between limited health literacy with patient‐reported outcomes and disease activity/damage among 267 Black women with active systemic lupus erythematosus (SLE) enrolled in the Peer Approaches to Lupus Self‐Management (PALS) program. Methods The three‐item Chew Health Literacy Screening was used to dichotomize those reporting in the “limited” range on any item with outcomes compared via generalized linear models. Baseline surveys and assessments obtained at study entry as part of the PALS study were used. Primary outcomes included disease activity and lupus damage; other secondary outcomes included patient activation, self‐efficacy, physician/patient communication, and quality of life. Results The study included 267 Black women with SLE. In covariate‐adjusted analyses, participants with limited health literacy (88 [33%]) were more likely to have lower patient activation (Patient Activation Measure P

Abstract Background Hazardous alcohol use and alcohol use disorder (AUD) are highly prevalent among clients in mental health services, yet significant gaps remain in the adequate assessment of alcohol use and provision of appropriate alcohol interventions. The aim of this study was to conduct an exploration of (i) alcohol intervention elements used in mental health services and (ii) professionals’ reported barriers and facilitators in identifying and intervening with hazardous alcohol use and AUD. Methods Qualitative data were obtained by conducting semi-structured interviews among a purposive sample of 18 professionals from 13 different Dutch mental health services organizations (i.e., five integrated mental health organizations with addiction services, five mental health organizations without addiction services, and three addiction services organizations without mental health services). Transcripts were qualitatively analyzed using inductive thematic analysis. Results Identified alcohol intervention elements included conducting assessments, brief interventions, treatment, referrals of clients, collaborations with other parties, and providing information to professionals. Professionals mentioned nine barriers and facilitators in the identification and intervention with hazardous alcohol use and AUD, including three aspects of professionals’ behavior (i.e., professionals’ agenda setting, knowledge and skills, and attitudes), actions related to identification and intervening, client contact, collaboration with other parties, and three factors in a wider context (i.e., organizational characteristics, organizational resources, and governmental aspects). Conclusions Although diverse alcohol intervention elements are available in Dutch mental health services, it remains unclear to what extent these are routinely implemented. To better address hazardous alcohol use and AUD in mental health services, efforts should focus on enhancing alcohol training, improving collaboration with addiction services, providing appropriate tools, and facilitating support through organizational and governmental measures.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n = 120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n = 80), and 2) sham: deactivated negative ion generator (n = 40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in 85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Mucopolysaccharidosis type I (MPS I) is a rare metabolic disorder caused by deficiency of α-L-iduronidase (IDUA), resulting in glycosaminoglycan (GAG) accumulation and multisystemic disease. Current treatments include hematopoietic stem cell transplantation and enzyme replacement therapy, but these do not address all manifestations of the disease. We infused MPS I mice with an adeno-associated virus 9 (AAV9)-IDUA vector (RGX-111) at doses from 107 to 1010 vector genomes (vg) via intrathecal (IT), intravenous (IV), and intrathecal+intravenous (IT+IV) routes of administration. In mice administered doses ≤109 vg IT or ≤108 vg IV, there was no therapeutic benefit, while in mice administered 109 vg IV, there was a variable increase in IDUA activity with inconclusive neurocognitive and cardiac assessments. However, at the 1010 vg dose, we observed substantial metabolic correction, with restored IDUA levels and normalized tissue GAGs for all treatment groups. Aortic insufficiency was mostly normalized, neurologic deficit was prevented, and microcomputed tomography (micro-CT) analysis showed normalization of skeletal parameters. Histologic analysis showed minimal GAG storage and lysosomal pathology. We thus report a minimal effective dose of 1010 vg (5 × 1011 per kg) RGX-111 for IV and IT routes of administration in MPS I mice, which prevented neurocognitive deficit, cardiac insufficiency, and skeletal manifestations, as a model for genetic therapy of human MPS I.

Anhedonia, a reduced ability to experience positive affect and seek rewards, is present across many psychiatric disorders, notably among individuals who experienced trauma. Within the social domain, anhedonia manifests as an altered sense of belonging and social isolation and is associated with poorer clinical outcomes. Yet, mechanistic operationalizations of social anhedonia are lacking, limiting our understanding of the relationship between these mechanisms and affective symptoms. To address these questions, we developed a social reward exploration task which was administered to a transdiagnostic sample of trauma-exposed Veterans (N = 33) while they underwent functional magnetic resonance imaging. The goal was to maximize compliments from two unknown partners, as participants were told these partners selected compliments based on seeing their picture. A Bayesian reinforcement learning modeling approach was used to extract cognitive and neural markers of compliment (reward) exploration. To address these questions, we developed a social reward exploration task which was administered to a transdiagnostic sample of trauma-exposed Veterans (N = 33) while they underwent functional magnetic resonance imaging. The goal was to maximize compliments from two unknown partners, as participants were told these partners selected compliments based on seeing their picture. A Bayesian reinforcement learning modeling approach was used to extract cognitive and neural markers of compliment (reward) exploration. Higher social connectedness (β = 0.51; 95 % CI=[0.11,0.94]) and anxiety (β = 0.57; 95 % CI=[0.13,1.00]) were independently associated with more model-based choices of the partner they anticipated to be most complimenting. In the dorsal anterior cingulate cortex (ACC; z = 3.89, p .001) and left inferior parietal lobule (z = 3.96, p .001), neural responses to reward prediction errors (RPE) were more positive in response to compliment relative to non-compliment outcomes. Greater positive RPE ACC activation was associated with lower anxiety (β = −0.51; 95 % CI=[−0.99,−0.10]. Computational approaches to social reinforcement learning can help identify important neurocognitive differences in social reward sensitivity among individuals with complex affective profiles, such as trauma-exposed individuals. Understanding these differences may help develop new prediction and treatment tools for social anhedonia.

Abstract Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery. To do so, we characterized the effect of tactile rehabilitation combined with VNS across a range of stimulation intensities on recovery of somatosensory function in a rat model of chronic sensory loss in the forelimb. Consistent with previous studies in other applications, we find that moderate intensity VNS yields the most effective restoration of somatosensation, and both lower and higher VNS intensities fail to enhance recovery compared to rehabilitation without VNS. We next used the optimized, moderate intensity to evaluate the mechanisms that underlie recovery. We find that moderate intensity VNS enhances transcription of Arc, a canonical mediator of synaptic plasticity, in the cortex, and that transcript levels were correlated with the degree of somatosensory recovery. Moreover, we observe that blocking plasticity by depleting acetylcholine in the cortex prevents the VNS-dependent enhancement of somatosensory recovery. Collectively, these findings identify neural mechanisms that subserve VNS-dependent somatosensation recovery and provide a basis for selecting optimal stimulation parameters in order to facilitate translation of this potential intervention.

Abstract Background Research on cannabis use motives has focused on youth. Little is known about motives among working adults, including how work may play a role. This study aimed to describe cannabis use motives and their connection to work, and identify the personal and work correlates of work-related motives among a sample of workers. Methods A national, cross-sectional sample of Canadian workers were queried about their cannabis use. Workers reporting past-year cannabis use (n = 589) were asked their motives for using cannabis and whether each motive was related to work or helped them manage at work (i.e., work-related). Multinomial logistic regression analyses were conducted to estimate the associations of personal and work characteristics with work-related cannabis use motives (no work-related motives,

Community-based prevention strategies (e.g. bystander programs) have the potential to reduce sexual violence against women, but have mainly been implemented in high-income countries and geared towards specific contexts, such as university campuses. Based on local priorities for sexual violence prevention, a community-informed bystander intervention training program, “El que ve y ayuda” (“Who Sees and Helps;” WSH), was developed in Ayacucho, Peru: a post-conflict community. This study reports on the pilot evaluation of the WSH program, conducted with a sample of 155 participants, using a pre- and post-intervention survey. After the program, participants reported a significant increase in their willingness to intervene in potential situations of sexual violence (t [133]=−7.10, p < .000) and a significant reduction in their acceptance of rape myths or victim-blaming beliefs (t [116]=4.72, p < .001). This community-engaged approach, reflective of the local priorities on sexual violence prevention, fostered research and capacity-building benefits despite some limitations. This study contributes to the ongoing efforts in crafting culturally accessible tools that enhance community involvement in prevention measures which may potentially lead to long-term reductions in the occurrence of sexual violence. Key implications for practice • Community engagement in the development of sexual violence prevention programs is possible and can support attitudinal changes. • Following community priorities and customs is necessary for culturally safe and responsive bystander approaches in the prevention of sexual violence. • Enlisting community members representing key populations interested in prevention is crucial for evaluating the future outcomes and challenges of pilot programs.

Abstract Liquid biopsy can detect circulating cancer cells or tumor cell-derived DNA at various stages of cancer. The fluid from these biopsies contains extracellular vesicles (EVs), such as apoptotic bodies, microvesicles, exomeres, and exosomes. Exosomes contain proteins and nucleic acids (DNA/RNA) that can modify the microenvironment and promote cancer progression, playing significant roles in cancer pathology. Clinically, the proteins and nucleic acids within the exosomes from liquid biopsies can be biomarkers for the detection and prognosis of cancer. We review EVs protein and miRNA biomarkers identified for select cancers, specifically melanoma, glioma, breast, pancreatic, hepatic, cervical, prostate colon, and some hematological malignancies. Overall, this review demonstrates that EV biomolecules have great potential to expand the diagnostic and prognostic biomarkers used in Oncology; ultimately, EVs could lead to earlier detection and novel therapeutic targets. Clinical implications EVs represent a new paradigm in cancer diagnostics and therapeutics. The potential use of exosomal contents as biomarkers for diagnostic and prognostic indicators may facilitate cancer management. Non-invasive liquid biopsy is helpful, especially when the tumor is difficult to reach, such as in pancreatic adenocarcinoma. Moreover, another advantage of using minimally invasive liquid biopsy is that monitoring becomes more manageable. Identifying tumor-derived exosomal proteins and microRNAs would allow a more personalized approach to detecting cancer and improving treatment.

Background/Objectives: Rotavirus (RV) is the primary cause of gastroenteritis in children worldwide, contributing significantly to morbidity and mortality, particularly among children under five years of age. The introduction of Rotavirus vaccines (RVV) has markedly reduced RV-related childhood deaths, especially in Europe, where substantial reductions in hospitalizations and disease prevalence have been observed. Despite these advances, RVV uptake in Italy remains below the desired targets, with notable regional disparities. In Sicily, vaccination rates have fluctuated, with current coverage failing to meet national goals. Safety concerns and insufficient parental awareness are major barriers to RVV acceptance. Methods: This case-control study was conducted in Southern Italy to identify factors influencing parental acceptance of RVV. Data were collected from parents using a structured questionnaire that assessed socio-demographic factors, vaccine knowledge, and attitudes based on the Health Belief Model (HBM). Results: Overall, 226 parents were enrolled. Higher perceived benefit of RVV was significantly associated with increased vaccine adherence (Odds Ratio = 13.65; 95% Confidence Interval = 6.88–27.09; p < 0.001). Conclusions: These results highlight the need for targeted interventions to improve vaccine coverage and address regional and socio-economic barriers to RVV acceptance. Furthermore, tailored educational campaigns and univocal information from healthcare providers could play pivotal roles in achieving higher vaccine uptake.

Background: Human immunodeficiency virus (HIV) establishes latent infections in cellular reservoirs, including microglia. HC69 cells, a microglial model of HIV latency, contain an HIV promoter long terminal repeat (LTR)-GFP reporter and were used for testing the efficacy of a two-step magnetoelectric nanoparticle (MENP) and extracellular vesicle (xEV) latency-targeting (MELT) nanotherapeutic. GFP expression in HC69 at rest is low (GFPLo), and upon exposure to LTR, transcription-activating agents (i.e., TNF-α) are induced to be high expressing (GFPHi). Methods: The first step of MELT utilized ZL0580, an HIV Tat inhibitor loaded into EVs (80%) via incubation. ZL0580-EVs were taken up by GFPLo and blocked LTR transcriptional reactivation by 50% and were 90% less toxic than ZL0580 alone. The second step in MELT involved conjugation of monomethyl auristatin E (MMAE) to MENPs. HPLC measurements showed 80% MMAE attachment to MENPs. Flow cytometry-based measurements of the membrane potential indicated that the membranes of GFPHi HC69 were 60% more polarized than GFPLo HC69 cells. More MMAE–MENPs were internalized by GFPLo HC69. Results: Using a mixed-cell blood–brain barrier (BBB) Transwell model, we demonstrated that 20% of MELT crossed the BBB, was taken up by HC69 cells, and reduced LTR reactivation by 10%. Conclusions: Overall, this study demonstrated that MELT can potentially be utilized as a nanotherapeutic to target HIV latency in microglia.

Abstract Background Complex diseases are multifactorial traits caused by both genetic and environmental factors. They represent the major part of human diseases and include those with largest prevalence and mortality (cancer, heart disease, obesity, etc.). Despite a large amount of information that has been collected about both genetic and environmental risk factors, there are few examples of studies on their interactions in epidemiological literature. One reason can be the incomplete knowledge of the power of statistical methods designed to search for risk factors and their interactions in these data sets. An improvement in this direction would lead to a better understanding and description of gene-environment interactions. To this aim, a possible strategy is to challenge the different statistical methods against data sets where the underlying phenomenon is completely known and fully controllable, for example simulated ones. Results We present a mathematical approach that models gene-environment interactions. By this method it is possible to generate simulated populations having gene-environment interactions of any form, involving any number of genetic and environmental factors and also allowing non-linear interactions as epistasis. In particular, we implemented a simple version of this model in a Gene-Environment iNteraction Simulator (GENS), a tool designed to simulate case-control data sets where a one gene-one environment interaction influences the disease risk. The main aim has been to allow the input of population characteristics by using standard epidemiological measures and to implement constraints to make the simulator behaviour biologically meaningful. Conclusions By the multi-logistic model implemented in GENS it is possible to simulate case-control samples of complex disease where gene-environment interactions influence the disease risk. The user has full control of the main characteristics of the simulated population and a Monte Carlo process allows random variability. A knowledge-based approach reduces the complexity of the mathematical model by using reasonable biological constraints and makes the simulation more understandable in biological terms. Simulated data sets can be used for the assessment of novel statistical methods or for the evaluation of the statistical power when designing a study.

Human Papillomavirus (HPV), a prevalent sexually transmitted infection, comprises high-risk (HR-HPV) and low-risk (LR-HPV) viruses, the former posing a high risk for developing malignancies whereas the latter mainly for benign warts. Despite increasing awareness of HPV’s impact on men’s health, the influence of HR-HPV and LR-HPV urogenital infections on male fertility potential remains uncertain. This study aimed to investigate whether male urogenital infection with HR- or LR-HPV associates with impaired sperm quality, oxidative stress, and inflammation. A total of 205 male patients attending an urology clinic were enrolled. Semen samples were analyzed for HPV using PCR and genotyped by RFLP. Semen quality was evaluated following WHO guidelines. Semen leukocytes, reactive oxygen species (ROS), and sperm viability were analyzed using flow cytometry. HPV was detected in 19% (39/205) of semen samples. HR-HPV infections were more prevalent, with HPV-16 being the most frequent genotype. Neither HR-HPV nor LR-HPV were associated with significant alterations in routine sperm quality parameters. However, HR-HPV+ individuals showed significantly higher levels of sperm necrosis and exhibited increased proportions of ROS+ spermatozoa compared to LR-HPV+ or control individuals. Furthermore, no significant semen inflammation was detected in patients infected with either HR-HPV or LR-HPV, and unexpectedly reduced semen leukocytes and inflammatory cytokines (IL-6 and IL-1β) were observed in HR-HPV+ patients compared to controls. These observations underscore the importance of comprehensive HPV screening, including genotyping, in urology and fertility clinics to understand the progression of the infection, potential adverse effects on reproductive health, and the oncogenic risks involved.

Background & Aims: Breast regression protein 39 (BRP39) (Chi3L1) and its human homolog YKL-40, is an established biomarker of liver fibrosis in nonalcoholic steatohepatitis (NASH) patients, but its role in NASH pathogenesis remains unclear. We recently identified Chi3L1 as one of the top up-regulated genes in mice with inducible gain-of-function NOD-like receptor protein 3 (NLRP3) activation that mimics several liver features of NASH. This study aimed to investigate the effects of BRP39 deficiency on NLRP3-induced liver inflammation using tamoxifen-inducible Nlrp3 knockin mice sufficient (Nlrp3A350V CRT) and deficient for BRP39 (Nlrp3A350V/BRP-/- CRT). Methods: Using Nlrp3A350V CRT mice and Nlrp3A350V BRP-/- CRT, we investigated the consequences of BRP39 deficiency influencing NLRP3-induced liver inflammation. Results: Our results showed that BRP39 deficiency in NLRP3-induced inflammation improved body weight and liver weight. Moreover, liver inflammation, fibrosis, and hepatic stellate cell activation were reduced significantly, corresponding to significantly decreased Ly6C+ infiltrating macrophages, CD68+ osteopontin-positive hepatic lipid-associated macrophages, and activated Lymphocyte antigen 6 complex locus G6D positive (Ly6G+) and citrullinated histone H3 postivie (H3Cit+) neutrophil accumulation in the liver. Further investigation showed that circulatory neutrophils from NLRP3-induced BRP39-deficient mice have impaired chemotaxis and migration ability, and this was confirmed by RNA bulk sequencing showing reduced immune activation, migration, and signaling responses in neutrophils. Conclusions: These data showcase the importance of BRP39 in regulating the NLRP3 inflammasome during liver inflammation and fibrotic NASH by altering cellular activation, recruitment, and infiltration during disease progression, and revealing BRP39 to be a potential therapeutic target for future treatment of inflammatory NASH and its associated diseases.

Traditionally, pollen presentation is thought to be a function of pollinator type and visitation frequency. However, despite the repeated observation that pollen presentation is influenced by flower morphology and abiotic factors, these aspects have been little studied in the wild. Here, we evaluated the effect of climate, anther morphology, and pollination syndrome on anther dehiscence time (the length of time an anther takes to fully dehisce after a flower opens). We recorded anther dehiscence time in twelve species of Penstemon including the four major anther types and the two most common pollination syndromes. We also conducted an experiment to measure the effect of humidity and temperature on anther dehiscence. We found that anther morphology was correlated with anther dehiscence time. Anthers with wide openings take the longest time to dehiscence. These results provide some support for the hypothesis that anther dehiscence time has evolved to decrease pollen wastage. Contrary to the assumption that bird-pollinated species have simultaneous pollen presentation, hummingbird-pollinated species had longer anther dehiscence time than most bee-pollinated species. The experiment revealed that high humidity and low temperature increase anther dehiscence time. Our results suggest that pollen presentation is influenced by anther morphology, pollination syndrome, and the physical environment. Optimal pollen presentation presumably maximizes conspecific pollen transfer and reduces pollen thieving.

The rise in opioid prescriptions with a parallel increase in opioid use disorders remains a significant challenge in some developed countries (opioid epidemic). However, little is known about opioid consumption in low- and middle-income countries (LMICs). In this short report, we aim to discuss the increase in opioid consumption in LMICs by providing an update on the opioid perspective in Brazil.

Abstract Several studies have reported associations between appetitive traits and weight gain during infancy or childhood, but none have directly compared these associations across both age periods. Here, we tested the associations between appetitive traits and growth velocities from birth to childhood. Appetitive trait data were collected using the Children’s Eating Behaviour Questionnaire (CEBQ) in 149 children from the Cambridge Baby Growth Study at age 9–17 years. These participants also provided anthropometric measurements during infancy (birth, 3, 12, 18, and 24 months) and childhood (5 to 11 years). Standardized growth velocities (in weight, length/height, BMI, and body fat percentage) for 0–3 months, 3–24 months, and 24 months to childhood were estimated using individual linear-spline models. Associations between each of the eight CEBQ traits and each growth velocity were tested in separate multilevel linear regression models, adjusted for sex, age at CEBQ completion, and the corresponding birth measurement (weight, length, BMI, or body fat percentage). The three food-approach traits (food responsiveness, enjoyment of food and emotional overeating) were positively associated with infancy and childhood growth velocities in weight, BMI, and body fat percentage. By contrast, only one of the food-avoidant traits, satiety responsiveness, was negatively associated with all growth velocities. Significant associations were mostly of similar magnitude across all age periods. These findings reveal a broadly consistent relationship between appetitive traits with gains in weight and adiposity throughout infancy and childhood. Future interventions and strategies to prevent obesity may benefit from measuring appetitive traits in infants and children and targeting these as part of their programs.

Objective: The study aims to investigate the patient perspective on the pathway from healthcare practitioners’ presentations of their cases at a Project ECHO (Extension for Community Healthcare Outcomes) tele-clinic to the management of those patients’ chronic pain. Introduction: Managing patients with chronic and complex pain constitutes a prevalent, stressful challenge in the primary care setting. Primary care physicians typically have received little training in treating such patients and, until recently, have relied heavily on opioid and other pharmaceutical therapies as part of their regimen. Project ECHO Ontario Chronic Pain and Opioid Stewardship is an interprofessional telementoring program connecting pain specialists to primary care practitioners with the aim of supporting them in managing their patients with chronic pain, although the patients concerned do not generally participate in the telementoring sessions. While a number of papers have described the benefits accruing to healthcare professionals through participating in Project ECHO, there has been little exploration concerning patients’ perceptions of their care subsequent to case presentation. Methods: Using data from in-depth interviews with 20 patients along with their associated case presentation forms and the recommendations following the presentation, we look at the alignment of patient and practitioner views and inquire about the patient’s perceptions of how Project ECHO affects them. Results: Results suggest that the impact on patients is indirect but positive: most respondents express pleasure in contributing to research around chronic pain management, though only two of them identified a direct impact on their own treatment. They also appreciated their practitioner’s efforts to bring expert attention to the patient’s situation. Conclusions: Patients whose cases are presented to Project ECHO sessions experience positive emotions at being part of the process of research and quality improvement, regardless of changes in their own conditions. This study highlights the importance to patients of their practitioners’ commitment to managing their chronic pain.

Background Intracerebral hemorrhage (ICH) is a major cause of maternal morbidity, but its pathophysiology is poorly characterized. We investigated characteristics of pregnancy‐associated ICH (P‐ICH), compared with ICH in similar aged nonpregnant adults of both sexes. Methods and Results We performed a retrospective analysis of 134 adults aged 18 to 44 years admitted to our center with nontraumatic ICH from January 1, 2012, to December 31, 2021. We compared ICH characteristics among 3 groups: those with P‐ICH (pregnant or within 12 months of end of pregnancy); nonpregnant women; and men. We categorized ICH pathogenesis according to a modified scheme, SMASH‐UP (structural, medications, amyloid angiopathy, systemic, hypertension, undetermined, posterior reversible encephalopathy syndrome/reversible cerebral vasoconstriction syndrome), and calculated odds ratios and 95% CIs for primary (spontaneous small‐vessel) ICH versus secondary ICH (structural lesions or coagulopathy related), using nonpregnant women as the reference. We also compared specific ICH pathogenesis by SMASH‐UP criteria and functional outcomes between groups. Of 134 young adults with nontraumatic ICH, 25 (19%) had P‐ICH, of which 60% occurred postpartum. Those with P‐ICH had higher odds of primary ICH compared with nonpregnant women (adjusted odds ratio, 4.5 [95% CI, 1.4–14.7]). The odds of primary ICH did not differ between men and nonpregnant women. SMASH‐UP pathogenesis for ICH differed significantly between groups (P

Managerial coaching remains a widespread and popular organizational development intervention applied across numerous industries to enhance critical workplace outcomes and employee attitudes, yet no studies to date have evaluated the temporal precedence within these relationships. This study sought to assess the predictive validity of the widely used Employee Perceptions of Supervisor/Line Manager Coaching Behavior Measure managerial coaching scale (CBI), employing a longitudinal design and following the testing of the causal hypothesized relationship framework. Three hypotheses were evaluated using three commonly associated variables with managerial coaching (role clarity, job satisfaction, and organization commitment), using longitudinal data collected over two waves from full-time US employees (n = 313). The study followed a two-wave design, collecting data over two time points to test for longitudinal measurement invariance and three reciprocal cross-lagged models. Results detected statistically significant cross-lagged and reciprocal cross-lagged effects in the role clarity and organization commitment models, highlighting a reciprocal relationship between managerial coaching behaviors and the two variables. However, only the reciprocal cross-lagged effect was statistically significant in the job satisfaction model. Findings suggest the predictive validity of the CBI scale for role clarity and organization commitment. Moreover, results indicate employee attitudes influenced managerial coaching behaviors over time across all three models, emphasizing the potential impact of employee attitudes on leadership effectiveness. This study highlights the complex relationships between managerial coaching and workplace outcomes, offering nuanced insights for improved understanding.

Objectives This study set out to understand how (which elements), in what context and why (which mechanisms) interventions are successful in reducing (problematic) alcohol use among older adults, from the perspective of professionals providing these interventions.Design Guided by a realist evaluation approach, an existing initial programme theory (IPT) on working elements in alcohol interventions was evaluated by conducting semistructured interviews with professionals.Setting and participants These professionals (N=20) provide interventions across several contexts: with or without practitioner involvement; in-person or not and in an individual or group setting. Data were coded and links between contexts, elements, mechanisms and outcomes were sought for to confirm, refute or refine the IPT.Results From the perspective of professionals, there are several general working elements in interventions for older adults: (1) pointing out risks and consequences of drinking behaviour; (2) paying attention to abstinence; (3) promoting contact with peers; (4) providing personalised content and (5) providing support. We also found context-specific working elements: (1) providing personalised conversations and motivational interviewing with practitioners; (2) ensuring safety, trust and a sense of connection and a location nearby home or a location that people are familiar with in person and (3) sharing experiences and tips in group interventions. Furthermore, the mechanisms awareness and accessible and low threshold participation were important contributors to positive intervention outcomes.Conclusion In addition to the IPT, our findings emphasise the need for social contact and support, personalised content, and strong relationships (both between client and practitioner, and client and peers) in interventions for older adults.

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.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disease caused by iduronate-2-sulfatase (IDS) deficiency, leading to accumulation of glycosaminoglycans (GAGs) and the emergence of progressive disease. Enzyme replacement therapy is the only currently approved treatment, but it leaves neurological disease unaddressed. Cerebrospinal fluid (CSF)-directed administration of AAV9.CB7.hIDS (RGX-121) is an alternative treatment strategy, but it is unknown if this approach will affect both neurologic and systemic manifestations. We compared the effectiveness of intrathecal (i.t.) and intravenous (i.v.) routes of administration (ROAs) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1 × 109 gc resulted in appreciable IDS activity levels in plasma but not tissues. Total doses of 1 × 1010 and 1 × 1011 gc by either ROA resulted in supraphysiological plasma IDS activity, substantial IDS activity levels and GAG reduction in nearly all tissues, and normalized zygomatic arch diameter. In the brain, a dose of 1 × 1011 gc i.t. achieved the highest IDS activity levels and the greatest reduction in GAG content, and it prevented neurocognitive deficiency. We conclude that a dose of 1 × 1010 gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1 × 1011 gc, thereby suggesting the prospect of a similar direct benefit in humans.

Here we offer perspectives on phenotypic screening based on a wide-ranging discussion entitled “Phenotypic screening, target ID, and multi-omics: enabling more disease relevance in early discovery?” at the Screen Design and Assay Technology Special Interest Group Meeting at the 2023 SLAS Conference. During the session, the authors shared their own experience from within their respective organizations, followed by an open discussion with the audience. It was recognized that while substantial progress has been made towards translating disease-relevant phenotypic early discovery into clinical success, there remain significant operational and scientific challenges to implementing phenotypic screening efforts, and improving translation of screening hits comes with substantial resource demands and organizational commitment. This Perspective assesses progress, highlights pitfalls, and offers possible solutions to help unlock the therapeutic potential of phenotypic drug discovery. Areas explored comprise screening and hit validation strategy, choice of cellular model, moving beyond 2D cell culture into three dimensions, and leveraging high-dimensional data sets downstream of phenotypic screens.

Abstract Objective: To explore on-package formula messaging with reference to legislation and government-issued guidance in Great Britain (GB). Design: Formula products were identified, pictures of all sides of packs collated and on-package text and images were coded. Compliance with both GB legislation and guidance issued by the Department of Health and Social Care (DHSC) was assessed. Setting: All formula packs that were available for sale over the counter in GB between April and October 2020. Participants: Formula packs (n 71) including infant formula, follow-on formula, growing-up formula and specialist formula were identified, coded and analysed. Results: In total, 41 % of formula packs included nutrition claims, and 18 % included health claims that may be considered non-permitted, according to DHSC guidance. Additionally, 72 % of products showed images considered ‘non-permitted’. Breast Milk Substitute (BMS) legislation states infant and follow-on formula packs should be clearly distinguishable but does not provide criteria to assess similarity. Based on DHSC guidance, 72 % of infant and follow-on formula packs were categorised as showing a high degree of similarity. Marketing practices not covered by current legislation were widespread, such as 94 % of infant formula packs including advertisements for follow-on or growing-up formula. Conclusions: Text and images considered non-permitted according to DHSC guidance for implementing BMS legislation were widespread on formula products available in GB. As terms such as ‘similarity’ are not defined in BMS legislation, it was unclear if breaches had occurred. Findings support the WHO call for loopholes in domestic legislation to be closed as a matter of urgency.

OBJECTIVES: In a cohort of workers disabled by a work-related injury or illness, this study aimed to: (i) compare pre-injury prevalence estimates for common chronic conditions to chronic condition prevalence in a representative sample of working adults; (ii) calculate the incidence of chronic conditions post-injury; and (iii) estimate the association between persistent pain symptoms and the incidence of common chronic conditions.METHODS: Eighteen months post-injury, 1832 workers disabled by a work-related injury or illness in Ontario, Canada, completed an interviewer-administered survey. Participants reported pre- and post-injury prevalence of seven physician-diagnosed chronic conditions, and demographic, employment, and health characteristics. Pre-injury prevalence estimates were compared to estimates from a representative sample of workers. Multivariable logistic regression was used to examine the association of persistent pain with post-injury chronic condition incidence.RESULTS: Age-standardized pre-injury prevalence rates for diabetes, hypertension, arthritis, and back problems were similar to prevalence rates observed among working adults in Ontario, while prevalence rates for mood disorder, asthma and migraine were moderately elevated. Post-injury prevalence rates of mood disorder, migraine, hypertension, arthritis, and back problems were elevated substantially in this cohort. High persistent pain symptoms were strongly associated with the 18-month incidence of these conditions.CONCLUSIONS: The incidence of five chronic conditions over an 18-month follow-up period post injury was substantial. Persistent pain at 18 months was associated with this elevated incidence, with population attributable fraction estimates suggesting that 37–39% of incident conditions may be attributed to exposure to high levels of persistent pain.

Abstract Objective The Diabetes Prevention Program (DPP) is the gold standard lifestyle modification program that reduces incident type 2 diabetes mellitus. Patients with prediabetes and patients with non‐alcoholic fatty liver disease (NAFLD) often share metabolic features; we hypothesized that the DPP could be adapted and used to improve outcomes in patients with NAFLD. Methods NAFLD patients were recruited into a 1 year modified DPP. Demographics, medical comorbidities, and clinical laboratory values were collected at baseline, 6 and 12 months. The primary endpoint was change in weight at 12 months. Secondary endpoints were changes in hepatic steatosis, metabolic comorbidities, and liver enzymes (per‐protocol basis) and retention at 6 and 12 months. Results Fourteen NAFLD patients enrolled; three dropped out before 6 months. From baseline to 12 months, hepatic steatosis (p = 0.03), alanine aminotransferase (p = 0.02), aspartate aminotransferase (p = 0.02), high‐density lipoprotein (p = 0.01) and NAFLD fibrosis score (p

Abstract Background The reliability of culture-independent pathogen detection in foods using metagenomics is contingent on the quality and composition of the reference database. The inclusion of microbial sequences from a diverse representation of taxonomies in universal reference databases is recommended to maximize classification precision for pathogen detection. However, these sizable databases have high memory requirements that may be out of reach for some users. In this study, we aimed to assess the performance of a foodborne pathogen (FBP)-specific reference database (taxon-specific) relative to a universal reference database (taxon-agnostic). We tested our FBP-specific reference database's performance for detecting Listeria monocytogenes in two complex food matrices—ready-to-eat (RTE) turkey deli meat and prepackaged spinach—using three popular read-based DNA-to-DNA metagenomic classifiers: Centrifuge, Kraken 2 and KrakenUniq. Results In silico host sequence removal led to substantially fewer false positive (FP) classifications and higher classification precision in RTE turkey deli meat datasets using the FBP-specific reference database. No considerable improvement in classification precision was observed following host filtering for prepackaged spinach datasets and was likely a consequence of a higher microbe-to-host sequence ratio. All datasets classified with Centrifuge using the FBP-specific reference database had the lowest classification precision compared to Kraken 2 or KrakenUniq. When a confidence-scoring threshold was applied, a nearly equivalent precision to the universal reference database was achieved for Kraken 2 and KrakenUniq. Recall was high for both reference databases across all datasets and classifiers. Substantially fewer computational resources were required for metagenomics-based detection of L. monocytogenes using the FBP-specific reference database, especially when combined with Kraken 2. Conclusions A universal (taxon-agnostic) reference database is not essential for accurate and reliable metagenomics-based pathogen detection of L. monocytogenes in complex food matrices. Equivalent classification performance can be achieved using a taxon-specific reference database when the appropriate quality control measures, classification software, and analysis parameters are applied. This approach is less computationally demanding and more attainable for the broader scientific and food safety communities.

Objective: Patients who survive critical illness endure complex physical and mental health conditions, referred to as post-intensive care syndrome (PICS). The University of Michigan's post-intensive cardiac care outpatient long-term outreach (PICCOLO) clinic is designed for patients recently admitted to the coronary care unit (CCU). The long-term goal of this clinic is to understand post-CCU patients' needs and design targeted interventions to reduce their morbidity and mortality post-discharge. As a first step toward this goal, we aimed to define the post-discharge needs of CCU survivors. Design, setting, particpants: We retrospectively reviewed case-mix data (including rates of depression, PTSD, disability, and cognitive abnormalities) and health outcomes for patients referred to the PICCOLO clinic from July 1, 2018, through June 30, 2021 at Michigan Medicine. Results: Of the 134 referred patients meeting inclusion criteria, 74 (55 %) patients were seen in the PICCOLO clinic within 30 days of discharge. Patients seen in the clinic frequently screened positive for depression (PHQ-2 score ≥3, 21.4 %) and cognitive impairment (MOCA

Abstract Background Black patients have higher hepatocellular carcinoma (HCC)‐related mortality than White patients and more often develop HCC in non‐cirrhotic liver. HCC surveillance is primarily directed toward cirrhotic patients. We aimed to characterize HCC in non‐cirrhotic patients and to identify factors associated with HCC beyond Milan criteria. Methods Demographic, imaging, laboratory, and pathology data of HCC patients at our institution, 2003–2018, were reviewed, retrospectively. Race/ethnicity were self‐reported. Cirrhosis was defined as a Fibrosis‐4 score ≥3.25. Results Compared to 1146 cirrhotic patients, 411 non‐cirrhotic patients had larger tumors (median 4.7 cm vs. 3.1 cm, p

The use of exclusion fencing as part of wildlife conservation programs has been increasing in recent years, particularly in Australia. Soil corrosion damage sustained on fences is a significant management concern as the weakened fence netting can provide opportunities for feral animal incursions into fenced safe havens. Soil corrosivity risk mapping can assist with the design of fenced nature reserves to reduce the frequency of fence repair and replacement. However, very little research has focused on developing methods for accurately predicting fence corrosion rates in different surface soil environments. This paper assesses the use of different soil attributes as corrosivity indicators for identifying areas of low, moderate and high fence corrosion risk in different soil environments present in South Australia (20 field sites). Zinc corrosion rates measured on zinc-aluminium fence samples (buried at sites for 9 months) ranged by a factor of nearly 50, with low rates of fence corrosion (0.1–0.7 µm/year) observed at five sites, medium rates (0.7–2.1 µm/year) observed at 10 sites, and extreme rates (>8.4 µm/year) observed at four sites. Fence corrosion risk was predicted using soil pH, soil salinity and texture data, and a soil corrosivity risk index developed for use in arid soils in South Australia. Predicted zinc corrosion rates matched field observations at 45 % of field sites. The highest rates of zinc corrosion (>4.2 µm/year) were observed at field sites with highly alkaline (pH > 8.5) and highly saline (ECe ≥ 5 dS/m) soils. An improved fence corrosion risk classification method, referred as the Fence Corrosion Risk Decision Tree was developed using these soil pH and salinity thresholds, which correctly predicted fence corrosion risk at 67 % of field sites at Olympic Dam and Farina and 50 % of field sites on the Yorke Peninsula. Further research is needed to assess the ability of this method to predict long-term fence damage (>2 years exposed to soil conditions).

IntroductionManagerial coaching is considered a powerful developmental intervention in the workplace that has gained tremendous popularity in recent years. A growing base of scholarship examining the efficacy of this form of coaching has identified numerous benefits, primarily for employees receiving this form of coaching, and some limited attention has focused on benefits for managers who coach. However, an important topic related to managerial coaching that has gone under-explored is the beliefs that managers have about coaching. Since beliefs often guide behaviors, obtaining a more robust understanding of the beliefs that guide managers who serve as coaches is warranted and several scholars have called for more research on this aspect of managerial coaching. Therefore, the study reported here presents a subset of findings that relate to the coaching behaviors that managers enact along with a comprehensive understanding of their guiding beliefs.MethodsThese specific findings are drawn from a larger qualitative multi-case study employing an adaptation of the critical incident technique that was designed to examine the beliefs, behaviors, and learning and development outcomes for both managers who coach and their respective coachees. This larger study obtained perspectives about these aspects of managerial coaching from both the coaches and coachees which also reflects an approach seldom taken when researching managerial coaching.Results and DiscussionFour research questions are addressed here: 1) What are the behaviors enacted by managers who coach (facilitate the learning of) their employees from the perspective of managers; 2), what are the behaviors enacted by managers who coach (facilitate the learning of) their employees from the perspective of employees; 3) What are the beliefs held by managers who coach (facilitate the learning of) their employees from the perspective of managers; and, 4) What are the beliefs held by managers who coach (facilitate the learning of) their employees from the perspective of their employees (coachees)? In addition to thick rich descriptions that illustrate these findings, implications for theory, research, and practice are also discussed.

AbstractEnvironmental DNA (eDNA) methods complement traditional aquatic monitoring surveys and are especially advantageous for rare and listed species to detect spatial and temporal distribution patterns. However, improvements in ease of use and portability could increase the utility of eDNA methods, leading to more widespread application, including expanding its role in management decision‐making processes. We describe the development of an eDNA detection assay for delta smelt (Hypomesus transpacificus), an endangered fish in the San Francisco Estuary, using SHERLOCK (Specific High‐Sensitivity Enzymatic Reporter Unlocking). SHERLOCK is a clustered regularly interspaced short palindromic repeats (CRISPR)‐based diagnostic tool with the ability to detect species‐specific genetic variants, making it ideal for genetic‐based taxonomic identification of any organism. Because of its high sensitivity and specificity, SHERLOCK is adaptable to eDNA detection in water samples. Here, we describe adaptation of a delta smelt SHERLOCK assay for use with estuarine water eDNA samples. This version of the assay exhibits increased sensitivity compared to the original delta smelt SHERLOCK protocol (new limit of detection approximately three copies per reaction compared to ~300 in original assay) and successfully detected delta smelt eDNA in both experimental and natural contexts. Overall, our results demonstrate that SHERLOCK eDNA detection offers managers an alternative, isothermal methodology, and highlights some challenges for detection of rare, endangered species at low abundance.

Many people with chronic stroke (PwCS) exhibit deficits in step width modulation, an important strategy for walking balance. A single exposure to swing leg perturbations can temporarily strengthen this modulation. The objective of this parallel, double-blinded, randomized controlled trial was to investigate whether repeated perturbations cause sustained increases in step modulation (NCT02964039; funded by the VA). 54 PwCS at the Medical University of South Carolina were randomly assigned to one of three intervention groups: Control (n = 18), with minimal forces; Assistive (n = 18), pushing the swing leg toward a mechanically appropriate location; Perturbing (n = 18), pushing the swing leg away from a mechanically appropriate location. All intervention groups included 24 training sessions over 12-weeks with up to 30-minutes of treadmill walking while interfaced with a novel force-field and a 12-week follow-up period, with five interspersed assessment sessions. Our primary outcome measure was paretic step width modulation, the partial correlation between step width and pelvis displacement (ρSW). Secondarily, we quantified swing and stance leg contributions to step modulation, clinical assessments of walking balance and confidence, and real-world falls. Outcomes were analyzed for participants who completed all assessment sessions (n = 44). Only the Perturbing group exhibited significant increases in paretic ρSW, which were present after 4-weeks of training and sustained through follow-up (t = 2.42-3.17). These changes were due to improved control of paretic swing leg positioning. However, perturbation-induced changes in step modulation were not always significantly greater than those in the Control group, and clinical assessments were similar across intervention groups. Participants in the Perturbing group experienced a lower fall rate than those in the Control group (incidence rate ratio = 0.53), although our small sample size warrants caution. The present results indicate that perturbations can cause sustained modifications of targeted biomechanical characteristics of post-stroke gait, although such changes alone may be insufficient to change more complex clinical assessments.

BackgroundHealthcare workers (HCWs) experienced high levels of stress and mental health consequences associated with the COVID-19 pandemic, which may have contributed to unhealthy coping behaviors, such as substance use coping (SUC). This study aimed to understand the extent of and predictors of SUC.MethodsThe sample consisted of 263 HCWs in North Central Florida. Univariable and multivariable logistic regression analyses investigated whether moral injury and other work risk factors, protective factors, and clinically relevant symptoms (i.e., work exhaustion, interpersonal disengagement, depression, anxiety, and/or PTSD) were associated with likelihood of SUC.ResultsClinically relevant levels of interpersonal disengagement and anxiety increased the likelihood of SUC. Mediational analyses found that interpersonal disengagement and anxiety explained 54.3% of the relationship between Self Moral Injury and SUC and explained 80.4% of the relationship between professional fulfillment and SUC.ConclusionHealthcare supervisors should be aware that providers who are experiencing moral injury and less professional fulfillment may be experiencing significant interpersonal disengagement and anxiety, which could lead to SUC. Future studies should examine the effects of implementing targeted prevention and treatment interventions, along with longitudinal outcomes related to SUC behaviors.

Objective:. Using health records from the Department of Veterans Affairs (VA), the largest healthcare training platform in the United States, we estimated independent associations between the intensity of attending supervision of surgical residents and 30-day postoperation patient outcomes. Background:. Academic leaders do not agree on the level of autonomy from supervision to grant surgery residents to best prepare them to enter independent practice without risking patient outcomes. Methods:. Secondary data came from a national, systematic 1:8 sample of n = 862,425 teaching encounters where residents were listed as primary surgeon at 122 VA medical centers from July 1, 2004, through September 30, 2019. Independent associations between whether attendings had scrubbed or not scrubbed on patient 30-day all-cause mortality, complications, and 30-day readmission were estimated using generalized linear-mixed models. Estimates were tested for any residual confounding biases, robustness to different regression models, stability over time, and validated using moderator and secondary factors analyses. Results:. After accounting for potential confounding factors, residents supervised by scrubbed attendings in 733,997 nonemergency surgery encounters had fewer deaths within 30 days of the operation by 14.2% [0.3%, 29.9%], fewer case complications by 7.9% [2.0%, 14.0%], and fewer readmissions by 17.5% [11.2%, 24.2%] than had attendings not scrubbed. Over the 15 study years, scrubbed surgery attendings may have averted an estimated 13,700 deaths, 43,600 cases with complications, and 73,800 readmissions. Conclusions:. VA policies on attending surgeon supervision have protected patient safety while allowing residents in selected teaching encounters to have limited autonomy from supervision.

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (C2–C5a). Our lead direct-acting antiviral (DAA), C5a, is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro. The compounds C2–C5a exhibit broad-spectrum activity against Omicron subvariants (BA.5, BQ.1.1, and XBB.1.5) and seasonal human coronavirus-229E infection in human cells. Notably, C5a has median effective concentrations of 30–50 nM against BQ.1.1 and XBB.1.5 in two different human cell lines. X-ray crystallography has confirmed the unique binding modes of C2–C5a to the 3CLpro, which can limit virus cross-resistance to emerging Paxlovid-resistant variants. We tested the effect of C5a with two of our newly discovered host-directed antivirals (HDAs): N-0385, a TMPRSS2 inhibitor, and bafilomycin D (BafD), a human vacuolar H+-ATPase [V-ATPase] inhibitor. We demonstrated a synergistic action of C5a in combination with N-0385 and BafD against Omicron BA.5 infection in human Calu-3 lung cells. Our findings underscore that a SARS-CoV-2 multi-targeted treatment for circulating Omicron subvariants based on DAAs (C5a) and HDAs (N-0385 or BafD) can lead to therapeutic benefits by enhancing treatment efficacy. Furthermore, the high-resolution structures of SARS-CoV-2 3CLpro in complex with C2–C5a will facilitate future rational optimization of our novel broad-spectrum active-site-directed 3C-like protease inhibitors.

Abstract Background Successful treatment of hepatitis C reduces liver inflammation and fibrosis; however, patients remain at risk of developing hepatocellular carcinoma (HCC). Aims To identify risk factors for new‐onset HCC in patients cured of hepatitis C. Methods Imaging, histological, and clinical data on patients whose first HCC was diagnosed >12 months of post‐SVR were analyzed. Histology of 20 nontumor tissues was analyzed in a blinded manner using the Knodel/Ishak/HAI system for necroinflammation and fibrosis/cirrhosis stage and the Brunt system for steatosis/steatohepatitis. Factors associated with post‐SVR HCC were identified by comparison with HALT‐C participants who did not develop post‐SVR HCC. Results Hepatocellular carcinoma was diagnosed in 54 patients (45 M/9F), a median of 6 years of post‐SVR [interquartile range (IQR) =1.4‐10y] at a median age of 61 years (IQR, 59–67). Approximately one‐third lacked cirrhosis, and only 11% had steatosis on imaging. The majority (60%) had no steatosis/steatohepatitis in histopathology. The median HAI score was 3 (1.25–4), indicating mild necroinflammation. In a multivariable logistic regression model, post‐SVR HCC was positively associated with non‐Caucasian race (p = 0.03), smoking (p = 0.03), age > 60 years at HCC diagnosis (p = 0.03), albumin1 (p = 0.05), and platelets

Abstract Introduction An estimated 39,010 Indiana residents were diagnosed with cancer in 2021. To address the cancer burden, Project ECHO (Extension Community Healthcare Outcomes) was launched in 2019 in Indiana to build specialty healthcare capacity among non‐specialists. Due to positive outcomes from the pilot year, the Cancer Prevention, Screening, and Survivorship ECHO was implemented for a second year. The purpose of this study was to measure the participation and regional impact of this ECHO. Methods ECHO sessions occurred twice monthly from October 2020 to October 2021. Changes were implemented in response to feedback from the pilot year, including making the curriculum more practical for learners and adding accreditation opportunities. Participant information and feedback was extracted from electronic surveys for review. Results There were 24 ECHO sessions with 213 unique participants, increased from 140 unique participants in the pilot year. An average of 23.5 individuals attended each session, increased from 15.5 individuals per session. Enrolled participants served in a diverse set of roles and represented 247 zip codes, 30 Indiana counties, and 32 states across the United States, each of which increased from the pilot year. Discussion In this second year, this ECHO expanded to reach more participants with increased attendance and a more diverse distribution of roles within healthcare, which may be attributed to feedback‐driven curriculum design. Cancer care is multi‐disciplinary, with health educators, nurses, and administrators, each acting within the cancer care continuum. As a result, this ECHO has been adapted to serve an increasingly broad distribution of professionals. Conclusion The second year of the Cancer Prevention, Screening, and Survivorship ECHO displayed increased overall enrollment and participation, greater diversity among participant roles, and a wider reach across Indiana and the United States.

Abstract The Berry curvature (BC)—a quantity encoding the geometric properties of the electronic wavefunctions in a solid—is at the heart of different Hall-like transport phenomena, including the anomalous Hall and the non-linear Hall and Nernst effects. In non-magnetic quantum materials with acentric crystalline arrangements, local concentrations of BC are generally linked to single-particle wavefunctions that are a quantum superposition of electron and hole excitations. BC-mediated effects are consequently observed in two-dimensional systems with pairs of massive Dirac cones and three-dimensional bulk crystals with quartets of Weyl cones. Here, we demonstrate that in materials equipped with orbital degrees of freedom local BC concentrations can arise even in the complete absence of hole excitations. In these solids, the crystals fields appearing in very low-symmetric structures trigger BCs characterized by hot-spots and singular pinch points. These characteristics naturally yield giant BC dipoles and large non-linear transport responses in time-reversal symmetric conditions.

Measurement(s) Protein expression Technology Type(s) Mass Spectrometry Factor Type(s) genetically distinct human cell lines Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location United States

Abstract Insight impairment contributes significantly to morbidity in psychiatric disorders. The neurologic concept of anosognosia, reflecting deficits in metacognitive awareness of illness, is increasingly understood as relevant to psychopathology, but has been little explored in psychiatric disorders other than schizophrenia. We explored anosognosia as an aspect of insight impairment in n = 71 individuals with DSM-5 hoarding disorder. We used a standardized clutter severity measure to assess whether individuals with hoarding disorder underreport home clutter levels relative to independent examiners. We then explored whether underreporting, as a proxy for anosognosia, is predicted by clinical or neurocognitive behavioral measures. We found that individuals with hoarding disorder underreport their clutter, and that underreporting is predicted by objective severity of clutter. In an n = 53 subset of participants, we found that underreporting is predicted by altered performance on tests of cognitive control and inhibition, specifically Go/No-Go and Stroop tests. The relation of underreporting to objective clutter, the cardinal symptom of hoarding disorder, suggests that anosognosia may reflect core pathophysiology of the disorder. The neurocognitive predictors of clutter underreporting suggest that anosognosia in hoarding disorder shares a neural basis with metacognitive awareness deficits in other neuropsychiatric disorders and that executive anosognosia may be a transdiagnostic manifestation of psychopathology.

Abstract Background Over 250 million children under 5 years, globally, are at risk of developmental delay. Interventions during the first 2 years of life have enduring positive effects if children at risk are identified, using standardized assessments, within this window. However, identifying developmental delay during infancy is challenging and there are limited infant development assessments suitable for use in low- and middle-income (LMIC) settings. Here, we describe a new tool, the Oxford Neurodevelopment Assessment (OX-NDA), measuring cognition, language, motor, and behaviour, outcomes in 1-year-old children. We present the results of its evaluation against the Bayley Scales of Infant Development IIIrd edition (BSID-III) and its psychometric properties. Methods Sixteen international tools measuring infant development were analysed to inform the OX-NDA’s construction. Its agreement with the BSID-III, for cognitive, motor and language domains, was evaluated using intra-class correlations (ICCs, for absolute agreement), Bland-Altman analyses (for bias and limits of agreement), and sensitivity and specificity analyses (for accuracy) in 104 Brazilian children, aged 12 months (SD 8.4 days), recruited from the 2015 Pelotas Birth Cohort Study. Behaviour was not evaluated, as the BSID-III’s adaptive behaviour scale was not included in the cohort’s protocol. Cohen’s kappas and Cronbach’s alphas were calculated to determine the OX-NDA’s reliability and internal consistency respectively. Results Agreement was moderate for cognition and motor outcomes (ICCs 0.63 and 0.68, p