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Abstract Background Chronic pelvic pain is a common yet undertreated condition that significantly impacts quality of life for women worldwide. Digital exercise therapy designed to target pelvic pain can improve symptomology while reducing time and cost-related barriers to in-person clinical care. Methods This longitudinal, observational study of a digital women’s pelvic health program examined pelvic pain, anxiety, and depression at 4 and 12 weeks in female adults experiencing chronic pelvic pain. Intervention participants received a digital pelvic health program including personalized exercise therapy sessions, health education articles, and health coaching. A comparison group of nonparticipants received a series of education articles related to pelvic health. Data were collected at baseline, 4 and 12 weeks. Unadjusted and adjusted linear mixed effects models were conducted to model changes in clinical outcomes over time. Results A total of 797 participants (intervention: 495, nonparticipants: 302) were included in the sample. Baseline mean (SD) age was 41.5 (11.7) years and mean pain was 45.7 (18.5) out of 100. Compared to baseline, the intervention group showed significantly more pain improvement at 4 and 12 weeks versus nonparticipants after adjusting for baseline factors. The intervention group’s pain scores decreased by 44.5% at 4 weeks and 53.6% at 12 weeks. The intervention group’s adjusted pain scores decreased from 42.0 (95% CI: [39.4, 44.7]) at baseline to 23.3 (95% CI: [20.5, 26.2]) at 4 weeks to 19.5 (95% CI: [16.7, 22.4]) at 12 weeks. In contrast, nonparticipants’ pain scores decreased by 21.6% at 4 weeks and 32.7% at 12 weeks. Nonparticipants’ adjusted pain scores decreased from 42.1 (95% CI: [38.4, 45.9]) at baseline to 33.0 (95% CI: [29.2, 36.8]) at 4 weeks to 28.3 (95% CI: [24.5, 32.2]) at 12 weeks. After adjustments, the probability of the intervention group screening for moderate or severe depression was significantly lower by 11.0% at 12 weeks versus nonparticipants. There were no significant differences in anxiety outcomes between groups at baseline, week 4, or week 12. Conclusions A digital women’s pelvic health program may help reduce short-term pelvic pain and depression symptoms. Trial registration The WIRB-Copernicus Group Institutional Review Board (registration number IRB20234932) approved this study on November 6, 2023.

Abstract Background This study aims to develop Z-Score models to normalize measurements of three coronary arteries and enhance the diagnosis of Kawasaki disease (KD) in children from newborns to 10 years old. Developing a reliable Z-Score model is challenging, as some existing models fail the normality test. Overcoming these challenges is crucial for improving KD diagnosis. Method Detailed measurements of the left main coronary artery (LCA), left anterior descending coronary artery (LAD), and right coronary artery (RCA) were collected, along with patient demographics such as age, height, weight, and body surface area (BSA). Several Z-Score models, named the Kuo Z-Score models, were proposed, with separate designs for different coronary arteries and different age groups, resulting in multiple Z-Score models. The Z-Score model for the RCA employs the Box-Cox method for data transformation. Finally, we tested various age group combinations, selecting models that passed the Anderson–Darling normality test and had higher R-square values for robustness and best data fit. Results The study included 1180 participants free from coronary or heart diseases. The Kuo Z-Score models were optimized for LCA, LAD, and RCA across the five age groups 0–6 years, 6–7 years, 7–8 years, 8–9 years, and 9–10 years. Only the normality test for the RCA in the 7–8 year age group failed. The proposed model fitted to the normality assumption outperforming the other models. Conclusion The Kuo Z-Score models, applicable across a broad age range, provides robust identification of coronary artery dilatation and aneurysm in KD. The models’ capability to normalize diverse data sets marks a significant advancement in KD diagnostic sensitivity, aiding in better clinical decision-making and potentially improving patient outcomes.

Abstract Neuroinflammation in the central nervous system (CNS), driven largely by resident phagocytes, has been proposed as a significant contributor to disability accumulation in multiple sclerosis (MS) but has not been addressed therapeutically. Bruton’s tyrosine kinase (BTK) is expressed in both B-lymphocytes and innate immune cells, including microglia, where its role is poorly understood. BTK inhibition may provide therapeutic benefit within the CNS by targeting adaptive and innate immunity-mediated disease progression in MS. Using a CNS-penetrant BTK inhibitor (BTKi), we demonstrate robust in vivo effects in mouse models of MS. We further identify a BTK-dependent transcriptional signature in vitro, using the BTKi tolebrutinib, in mouse microglia, human induced pluripotent stem cell (hiPSC)-derived microglia, and a complex hiPSC-derived tri-culture system composed of neurons, astrocytes, and microglia, revealing modulation of neuroinflammatory pathways relevant to MS. Finally, we demonstrate that in MS tissue BTK is expressed in B-cells and microglia, with increased levels in lesions. Our data provide rationale for targeting BTK in the CNS to diminish neuroinflammation and disability accumulation.

Abstract Background Cerebral palsy (CP) is considered the most prevalent developmental motor disorder in children. There is a need for training programs that enhance motor abilities and normalize function from an early age. Previous studies report improved motor outcomes in dance interventions for CP. Investigating the neurophysiological mechanisms underlying such improvements is necessary for efficient and safe intervention design. This study reports changes in stretch reflex responses as the primary neurophysiological motor outcome of a targeted ballet class intervention. Results A case series of participants with mixed spastic and dyskinetic CP (n = 4, mean age = 12.5 years, SD = 6.9S years, three female, one male) who learned ballet technique in a course of one-hour classes twice per week for six weeks is presented. Changes in stretch reflex responses and in clinical motor tests as secondary outcomes were observed after the course and at one-month follow-up. Quantitative measures of elbow or ankle stretch reflex were obtained using electromyography and electrogoniometry. The joint angle of the stretch reflex onset varied across velocities of stretch, and its variability decreased after the intervention. Within-subject tests of the central tendency of stretch reflex angle coefficients of variation and frequency distribution demonstrated significant changes (p-values

In the United States in 2021, an outbreak of 4 cases of Burkholderia pseudomallei, the etiologic agent of melioidosis and a Tier One Select Agent (potential for deliberate misuse and subsequent harm), resulted in 2 deaths. The causative strain, B. pseudomallei ATS2021, was unintentionally imported into the United States in an aromatherapy spray manufactured in India. We established that ATS2021 represents a virulent strain of B. pseudomallei capable of robust formation of biofilm at physiologic temperatures that may contribute to virulence. By using mouse melioidosis models, we determined median lethal dose estimates and analyzed the bacteriologic and histopathologic characteristics of the organism, particularly the potential neurologic pathogenesis that is probably associated with the bimABm allele identified in B. pseudomallei strain ATS2021. Our data, combined with previous case reports and the identification of endemic B. pseudomallei strains in Mississippi, support the concept that melioidosis is emerging in the United States.

Abstract Background Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research. Methods This prospective observational cohort study was conducted at nine pilot sites between February 2020 and August 2022. Patients with JIA-associated CAU (JIA-U) were treated according to either the MTX or TNFi CTP. Uveitis activity and medication use were recorded at 0, 3, and 6 months. We assessed patient enrollment rates, CTP arm selection, uveitis control, and quality of data collection. We also evaluated CTP arm selection in a retrospective cohort of similar JIA-U patients enrolled in the CARRA Registry during the same study period. Results Seventeen patients were included in the pilot cohort. Eight were treated with the MTX CTP (4 oral MTX, 4 subcutaneous MTX), and 9 with the TNFi CTP (9 received standard-dose adalimumab, none selected high-dose adalimumab or infliximab). Uveitis was controlled in 13 of 17 patients by 6 months. Query of the CARRA-wide Registry identified 42 patients with JIA-U who were treated according to the MTX or TNFi CTPs. Among these, 26 were treated with MTX (8 oral, 18 subcutaneous) and 16 with TNFi (12 standard dose adalimumab, 2 high dose adalimumab, and 2 infliximab). Conclusion Both the MTX and TNFi uveitis CTPs can practically be implemented in clinical settings and are currently being utilized across Registry sites. However, in patients starting TNFi therapy, all pilot study participants and most patients across the CARRA Registry were treated with a standard dose of adalimumab. This consensus on the treatment approach underscores its broad acceptance but also limits the applicability of the uveitis TNFi CTP for comparative effectiveness research.

Abstract Background Interprofessional simulation-based team training (ISBTT) is commonly used to optimize interprofessional teamwork in healthcare. The literature documents the benefits of ISBTT, yet effective interprofessional collaboration continues to be challenged by complex hierarchies and power dynamics. Explicitly addressing these issues during ISBTT may help participants acquire skills to navigate such challenges, but guidelines on how to do this are limited. Methods We applied an educational design research approach to develop and pilot structured facilitator guidelines that explicitly address power and hierarchy with interprofessional teams. We conducted this work in a previously established ISBTT program at our institution, between September 2020 and December 2021. We first reviewed the literature to identify relevant educational theories and developed design principles. We subsequently designed, revised, and tested guidelines. We used qualitative thematic and content analysis of facilitator interviews and video-recording of IBSTT sessions to evaluate the effects of the guidelines on the pre- and debriefs. Results Qualitative content analysis showed that structured guidelines shifted debriefing participation and content. Debriefings changed from physician-led discussions with a strong focus on medical content to conversations with more equal participation by nurses and physicians and more emphasis on teamwork and communication. The thematic analysis further showed how the conversation during debriefing changed and how interprofessional learning improved after the implementation of the guidelines. While power and hierarchy were more frequently discussed, for many facilitators these topics remained challenging to address. Conclusion We successfully created and implemented guidelines for ISBTT facilitators to explicitly address hierarchy and power. Future work will explore how this approach to ISBTT impacts interprofessional collaboration in clinical practice.

Abstract Background Calcified coronary arteries encountered during percutaneous intervention increase the probability of unsuccessful procedures. Heavy calcification of coronary arteries may lead to suboptimal stent expansion. Intravascular lithotripsy (IVL) is a novel method of transmitting sonic waves in pulses, which fractures the calcific plaque in the vessel with minimal soft tissue injury. This study systematically reviews and summarizes the reported clinical scenarios in which IVL was successfully used in coronary lesions. Main text Articles were obtained by searching PubMed and Embase databases for IVL use in coronary arteries. We restricted the search to case reports. Our study included 84 patients from 70 case reports/case series. The mean age was 70.3 years (SD 10) and ranged from 27 to 96 years, and 67% were males. The indications for the angiogram that led to the use of IVL include chest pain (37.7%), non-ST elevated myocardial infarction (27.9%), ST elevated myocardial infarction (13.1%), and previous under-expanded stent (8.2%). The IVL was used in the left anterior descending artery (60.7%), right coronary artery (35.7%), left main disease (23.8%), and left circumflex (9.5%). Coronary IVL was safely and successfully used in different clinical scenarios for heavily calcified coronary lesions, including in-stent restenosis of native coronary arteries, saphenous vein grafts, and under-expanded stents. In addition, IVL was successfully used synergistically with orbital and rotational atherectomy and drug-coated balloon angioplasty in select patients. Conclusion IVL has successfully been used in an expanding array of clinical scenarios.

Abstract A sense of belonging to a community is a dimension of subjective well-being that is of growing population health interest. We evaluated sex-stratified associations between community belonging and risk of avoidable hospitalization. Adult men and women from the Canadian Community Health Survey (2000–2014) were asked to rate their sense of community belonging (N = 456,415) and were also linked to acute inpatient hospitalizations to 31 March 2018. We used Cox proportional hazards models to assess the association between community belonging and time to hospitalization related to ambulatory care sensitive conditions (ACSCs) and adjusted for a range of sociodemographic, health, and behavioural confounders. Compared to those who reported intermediate levels of belonging, both very weak and very strong sense of belonging were associated with greater risk of avoidable hospitalization for women (HR 1.29, 95% CI 1.12, 1.47, very weak; HR 1.15, 95% CI 1.03, 1.27, very strong), but not for men (HR 1.12, 95% CI 0.97, 1.29, very weak; HR 1.08, 95% CI 0.98, 1.19, very strong). This study suggests that community belonging is associated with risk of ACSC hospitalization for women and provides a foundation for further research on community belonging and population health.

Abstract Type 2 diabetes (T2D) is a common metabolic disorder in which only 25% of patients meet management targets. While the primary care setting is positioned to provide lifestyle management education, studies are lacking which integrate behavior interventions in this setting utilizing clinic staff. Thus, we evaluated a 90‐day lifestyle intervention for management of glycemia at a family practice clinic administered by clinic medical assistants. Twenty patients with non‐insulin‐dependent T2D completed a 90‐day intervention driven by patient choices of nutrition and physical activity. Medical assistants were trained by members of the study team and administered the intervention under nurse practitioner supervision. HbA1c trended toward significant reduction 8.59 ± 0.9% to 8.15 ± 1.2% (p = 0.051, 95% CI: −0.88 to 0.003). Modest reductions were observed for waist circumference (115.5 ± 12.6 vs. 112.5 ± 15.2 cm; p = 0.014, 95% CI: −5.66 to −0.26), body weight (97.7 ± 21.9 vs. 95.6 ± 23.9 kg; p = 0.016. 95% CI: −3.84 to −0.31), and BMI (33.7 ± 7.2 vs. 32.8 ± 7.5 kg/m2; p = 0.028, 95% CI: −1.29 to −0.12). This 90‐day, patient choice‐intervention was successful at lowering HbA1c in patients with T2D. Our study is limited by a lack of control group, and results should be interpreted as such. These data have implications for team‐based care models in clinic settings to improve health outcomes in patients with T2D.

ABSTRACT Purpose Caregivers in pediatric oncology need accurate and understandable information about their child's condition, treatment, and side effects. This study assesses the performance of publicly accessible large language model (LLM)‐supported tools in providing valuable and reliable information to caregivers of children with cancer. Methods In this cross‐sectional study, we evaluated the performance of the four LLM‐supported tools—ChatGPT (GPT‐4), Google Bard (Gemini Pro), Microsoft Bing Chat, and Google SGE—against a set of frequently asked questions (FAQs) derived from the Children's Oncology Group Family Handbook and expert input (In total, 26 FAQs and 104 generated responses). Five pediatric oncology experts assessed the generated LLM responses using measures including accuracy, clarity, inclusivity, completeness, clinical utility, and overall rating. Additionally, the content quality was evaluated including readability, AI disclosure, source credibility, resource matching, and content originality. We used descriptive analysis and statistical tests including Shapiro–Wilk, Levene's, Kruskal–Wallis H‐tests, and Dunn's post hoc tests for pairwise comparisons. Results ChatGPT shows high overall performance when evaluated by the experts. Bard also performed well, especially in accuracy and clarity of the responses, whereas Bing Chat and Google SGE had lower overall scores. Regarding the disclosure of responses being generated by AI, it was observed less frequently in ChatGPT responses, which may have affected the clarity of responses, whereas Bard maintained a balance between AI disclosure and response clarity. Google SGE generated the most readable responses whereas ChatGPT answered with the most complexity. LLM tools varied significantly (p

Objective: The impetus for this project is to begin to understand open science practices and obstacles at the XXX. This project uses open-ended questions to understand the ways in which university-affiliated individuals learn about, think about, and interact with open science. The goal of this study is to showcase the complexity and diversity of activity and challenges in this domain to help determine how best to move open science forward. Methods: From March to October 2022, 45 semi-structured interviews were conducted with faculty, graduate students, librarians and administrative staff. Interviews were conducted and recorded using Zoom and the audio was transcribed using otter.ai. As part of a commitment to open science practices, a data management plan was created and with participant consent, 26 transcripts were uploaded to Dataverse. Data analysis used structured coding and thematic development to investigate responses. Results: The core finding of this study is that there is no singular status of open science at XXX. The qualitative findings reflect a diversity of opinions, practices and relationships to open science. Conclusion: For open science practices and scholarship to have longevity, there must be systemic changes to adopt more open activities. XXX is well positioned to guide the transition and harness open principles to move into the future.

This cluster focuses on the cross-confessional nature of European queenship, particularly the role which different confessional identities play in the education, marriage, childbirth, patronage, expressions of agency, legal context, and posthumous legacy of queens, both regnant and consort. Ranging from the education of Isabella I’s daughters to Catholic consorts in the Stuart realms to posthumous understandings of Anne Boleyn, this cluster features the work of both emerging and established scholars, all of whom seek to contribute to the field of royal studies’ engagement with queens’ religion across confessional lines, including intra-Christian relations and the interplay between the Christian, Jewish, and Muslim faiths. After a brief introduction to the conceptual framework of the cluster, eight discrete short-form articles examine different aspects of European queenship and their cross-confessional identities.

AbstractThe Global Burden of Disease (GBD) study aims to characterize the worldwide prevalence and morbidity of major diseases, while PatientsLikeMe (PLM) is an online community providing patient-generated insights into lived experiences; for dermatologic conditions, quantitative comparisons of GBD and PLM data revealed expected demographic differences but also notable correlations, highlighting their potential as complementary data sources elucidating unmet patient needs and priorities.

Purpose Cross-sector collaboration can improve community health because decisions made across sectors influence health. Health Impact Assessments (HIAs) and other health-focused, cross-sector collaborations encounter challenges. This case study uses a completed HIA to explore factors impeding and supporting health-related cross-sectoral collaboration. Methods Semi-structured key informant interviews with 10 of 12 HIA working group participants were conducted and analysed using a content analysis approach. Results Analysis generated 48 codes across seven themes in three primary groups: HIA as a collaborative tool; logistical and systemic barriers; and benefits and logistical, interpersonal, and sectoral facilitators. Recognizing the importance of knowledge, analysis, and principles outside of one’s field (n = 62) was the most common facilitator. Limited time was the most common barrier (n = 21). Participants discussed more facilitators (n = 303) than barriers (n = 144); perceived multiple benefits (n = 92), including networking and connecting land use and health; and described facilitators like communication, continuity, engagement, project management, compensation, varying perspectives, and diverse skills. They identified coordination challenges, needs to engage more with stakeholders and the community, limited time, and changes among partners as primary barriers. Conclusions Findings can help prepare cross-sector partners about what to expect, aid in mitigating challenges, and further knowledge about what supports and hinders Health in All Policies collaborations.

Objective: This study created personas using quantitative segmentation and knowledge user enhancement to inform intervention and service design for rural patients to encourage preventive care uptake. Methods: This study comprised a cross-sectional survey of rural unattached patients and a co-design workshop for persona development. Cross-sectional survey data were analyzed for meaningful subgroups based on quartiles of preventive care completion. These quartiles informed “relevant user segments” grouped according to demographics (age, sex), length of unattachment, percentage of up-to-date preventive activities, health care visit frequency, preventive priorities, communication confidence with providers, and chronic health conditions, which were then used in the workshop to build the final personas. Results: 207 responses informed persona user segments, and five health care providers and 13 patients attended the workshop. The resulting four personas, included John (not up-to-date on preventive care activities), Terrance (few up-to-date preventive care activities), George (moderately up-to-date preventive care activities), and Anne (mostly up-to-date preventive care activities). Conclusion: Quantitative persona development with integrated knowledge user co-design/enhancement elevated and enriched final personas that achieved robust profiles for intervention design. Innovation: This project's use of a progressive methodology to build robust personas coupled with participant feedback on the co-design process offers a replicable approach for health researchers.

Permafrost-agroecosystems include all cultivation and pastoral activities in areas underlain by permafrost. These systems support local livelihoods and food production and are rarely considered in global agricultural studies but may become more relevant as climate change is increasing opportunities for food production in high latitude and mountainous areas. The exact locations and amount of agricultural production in areas containing permafrost are currently unknown, therefore we provide an overview of countries where both permafrost and agricultural activities are present. We highlight the socioecological diversity and complexities of permafrost-agroecosystems through seven case studies: (1) crop cultivation in Alaska, USA; (2) Indigenous food systems and crop cultivation in the Northwest Territories, Canada; (3) horse and cattle husbandry and Indigenous hay production in the Sakha Republic, Russia; (4) mobile pastoralism and husbandry in Mongolia; (5) yak pastoralism in the Central Himalaya, Nepal; (6) berry picking and reindeer herding in northern Fennoscandia; and (7) reindeer herding in northwest Russia. We discuss regional knowledge gaps associated with permafrost and make recommendations to policy makers and land users for adapting to changing permafrost environments. A better understanding of permafrost-agroecosystems is needed to help sustainably manage and develop these systems considering rapidly changing climate, environments, economies, and industries.

Abstract While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8 jck ), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction.

Abstract How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.

Abstract Background Hepatitis C is a blood-borne infection with the hepatitis C virus (HCV) that can progress to cirrhosis and liver cancer. About 70% (50–80%) of infections become chronic and exhibit anti-HCV and HCV nucleic acid (NAT) positivity. Direct acting oral pan genotypic antiviral treatment became available in 2014 and was free for most Canadians in 2018. Clinical screening for HCV infection is risk-based. About 1% of Canadians have been infected with HCV, with 0.5% chronically infected (about 25% unaware) disproportionately impacting marginalized groups. Blood donors are in good health, are deferred for risks such as injection drug use and can provide insight into the low-risk undiagnosed population. Here we describe HCV epidemiology in first-time blood donors over 28 years of monitoring. Methods All first-time blood donors in all Canadian provinces except Quebec (1993 to 2021) were analyzed. All blood donations were tested for HCV antibodies (anti-HCV) and since late 1999 also HCV NAT. A case-control study was also included. All HCV positive donors (cases) since 2005 and HCV negative donors (1:4 ratio controls) matched for age, sex and location were invited to complete a risk factor interview. Separate logistic regression models for anti-HCV positivity and chronic HCV assessed the association between age cohort, sex, region and neighbourhood material deprivation and ethnocultural concentration. Case: control data were analysed by logistic regression. Results There were 2,334,238 donors from 1993 to 2021 included. Prevalence for anti-HCV was 0.33% (0.30,0.37) in 1993 and 0.07% (0.05,0.09) in 2021 (p

Abstract Damoctocog alfa pegol (BAY 94-9027, Jivi®), is a site-specifically PEGylated, extended half-life recombinant factor VIII (FVIII) that is approved in several European and non-European countries for on-demand treatment and prophylaxis of bleeding in previously treated patients aged ≥ 12 years with hemophilia A. Reliable measurements can be obtained using most one-stage and chromogenic FVIII assays over a wide concentration range. The efficacy, safety and pharmacokinetics (PK) of damoctocog alfa pegol have been studied extensively in the PROTECT VIII clinical trials, and its long-term safety and effectiveness profile is continuing to build through observational and interventional real-world studies. The PK of damoctocog alfa pegol was shown to be improved as compared with that of sucrose-formulated rFVIII (rFVIII-FS, Kogenate®), and was also demonstrated to be non-inferior to and, for some variables, more favorable than rFVIII-Fc fusion protein, efmoroctocog alfa (Elocta®; NCT03364998), rurioctocog alfa pegol (BAX 855, Adynovate®/Adynovi®; NCT04015492), and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, Advate®; NCT02483208). Damoctocog alfa pegol was generally well tolerated and none of the patients in any of the clinical trials, including the PROTECT VIII clinical program, HEM-POWR, or ongoing single-center studies, developed FVIII inhibitors. Efficacy for perioperative hemostasis has been demonstrated. Low bleeding rates were achieved across the studies, with twice weekly, every 5-day and every 7-day prophylaxis offering patients ≥ 12 years and their clinicians the chance to tailor treatment to individual needs and lifestyles, while maintaining long-term protection from bleeds and their consequences. Graphical Abstract

Abstract Background Electronic health records (EHRs) can accelerate documentation and may enhance details of notes, or complicate documentation and introduce errors. Comprehensive assessment of documentation quality requires comparing documentation to what transpires during the clinical encounter itself. We assessed outpatient primary care notes and corresponding recorded encounters to determine accuracy, thoroughness, and several additional key measures of documentation quality. Methods Patients and primary care clinicians across five midwestern primary care clinics of the US Department of Veterans Affairs were recruited into a prospective observational study. Clinical encounters were video-recorded and transcribed verbatim. Using the Physician Documentation Quality Instrument (PDQI-9) added to other measures, reviewers scored quality of the documentation by comparing transcripts to corresponding encounter notes. PDQI-9 items were scored from 1 to 5, with higher scores indicating higher quality. Results Encounters (N = 49) among 11 clinicians were analyzed. Most issues that patients initiated in discussion were omitted from notes, and nearly half of notes referred to information or observations that could not be verified. Four notes lacked concluding assessments and plans; nine lacked information about when patients should return. Except for thoroughness, PDQI-9 items that were assessed achieved quality scores exceeding 4 of 5 points. Conclusions Among outpatient primary care electronic records examined, most issues that patients initiated in discussion were absent from notes, and nearly half of notes referred to information or observations absent from transcripts. EHRs may contribute to certain kinds of errors. Approaches to improving documentation should consider the roles of the EHR, patient, and clinician together.

Objective: The study objective was to determine if intraoperative peritoneal catheter placement is associated with improved outcomes in neonates undergoing high-risk cardiac surgery with cardiopulmonary bypass. Methods: This propensity score–matched retrospective study used data from 22 academic pediatric cardiac intensive care units. Consecutive neonates undergoing Society of Thoracic Surgeons–European Association for Cardio-Thoracic Surgery category 3 to 5 cardiac surgery with cardiopulmonary bypass at centers participating in the NEonatal and Pediatric Heart Renal Outcomes Network collaborative were studied to determine the association of the use of an intraoperative placed peritoneal catheter for dialysis or passive drainage with clinical outcomes, including the duration of mechanical ventilation. Results: Among 1490 eligible neonates in the NEonatal and Pediatric Heart Renal Outcomes Network dataset, a propensity-matched analysis was used to compare 395 patients with peritoneal catheter placement with 628 patients without peritoneal catheter placement. Time to extubation and most clinical outcomes were similar. Postoperative length of stay was 5 days longer in the peritoneal catheter placement cohort (17 vs 22 days, P = .001). There was a 50% higher incidence of moderate to severe acute kidney injury in the no-peritoneal catheter cohort (12% vs 18%, P = .02). Subgroup analyses between specific treatments and in highest risk patients yielded similar associations. Conclusions: This study does not demonstrate improved outcomes among neonates with placement of a peritoneal catheter during cardiac surgery. Outcomes were similar apart from longer hospital stay in the peritoneal catheter cohort. The no-peritoneal catheter cohort had a 50% higher incidence of moderate to severe acute kidney injury (12% vs 18%). This analysis does not support indiscriminate peritoneal catheter use, although it may support the utility for postoperative fluid removal among neonates at risk for acute kidney injury. A multicenter controlled trial may better elucidate peritoneal catheter effects.

We evaluate the cytotoxicity, intracellular redox conditions, apoptosis, and methylation of DNMTs/TETs upon exposure to LiTFSI, a novel Per and Polyfluoroalkyl Substances (PFAS) commonly found in lithium-ion batteries, on human renal carcinoma cells (A498) and hepatoma cells (HepG2). The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay showed both Perfluorooctane sulfonate (PFOS) and Lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) had a dose-dependent effect on A498 and HepG2, with LiTFSI being less toxic. Intracellular redox conditions were assessed with a microplate reader and confocal, which showed a significant decrease in Reactive Oxygen Species (ROS) levels and an increase in Superoxide dismutase (SOD) content in both cells. Exposure to LiTFSI enhanced cell apoptosis, with HepG2 being more susceptible than A498. Quantitative analysis of mRNA expression levels of 19 genes associated with kidney injury, methylation, lipid metabolism and transportation was performed. LiTFSI exposure impacted kidney function by downregulating smooth muscle alpha-actin (Acta2) and upregulating transforming growth factor beta 1 (Tgfb1), B-cell lymphoma 2-like 1) Bcl2l1, hepatitis A virus cellular receptor 1 (Harvcr1), nuclear factor erythroid 2-like 2 (Nfe2l2), and hairy and enhancer of split 1 (Hes1) expression. LiTFSI exposure also affected the abundance of transcripts associated with DNA methylation by the expression of ten-eleven translocation (TET) and DNA methyltransferase (DNMT) genes. Furthermore, LiTFSI exposure induced an increase in lipid anabolism and alterations in lipid catabolism in HepG2. Our results provide new insight on the potential role of a new contaminant, LiTFSI in the regulation of oxidative stress, apoptosis and methylation in human renal carcinoma and hepatoma cells.

Abstract Background Although a growing body of literature documents the importance of neighborhood effects on late-life cognition, little is known about the relative strength of objective and subjective neighborhood measures on late-life cognitive changes. This study examined effects of objective and subjective neighborhood measures in three neighborhood domains (neighborhood safety, physical disorder, food environments) on longitudinal changes in processing speed, an early marker of cognitive aging and impairment. Methods The analysis sample included 306 community-dwelling older adults enrolled in the Einstein Aging Study (mean age = 77, age range = 70 to 91; female = 67.7%; non-Hispanic White: 45.1%, non-Hispanic Black: 40.9%). Objective and subjective measures of neighborhood included three neighborhood domains (i.e., neighborhood safety, physical disorder, food environments). Processing speed was assessed using a brief Symbol Match task (unit: second), administered on a smartphone device six times a day for 16 days and repeated annually for up to five years. Years from baseline was used as the within-person time index. Results Results from mixed effects models showed that subjective neighborhood safety (β= -0.028) and subjective availability of healthy foods (β= -0.028) were significantly associated with less cognitive slowing over time. When objective and subjective neighborhood measures were simultaneously examined, subjective availability of healthy foods remained significant (β= -0.028) after controlling for objective availability of healthy foods. Associations of objective neighborhood crime and physical disorder with processing speed seemed to be confounded by individual-level race and socioeconomic status; after controlling for these confounders, none of objective neighborhood measures showed significant associations with processing speed. Conclusion Subjective neighborhood safety and subjective availability of healthy foods, rather than objective measures, were associated with less cognitive slowing over time over a five-year period. Perception of one’s neighborhood may be a more proximal predictor of cognitive health outcomes as it may reflect one’s experiences in the environment. It would be important to improve our understanding of both objective and subjective neighborhood factors to improve cognitive health among older adults.

Background: Morton neuroma (MN) is a common pathology with many reported subjective features and physical examination tests. The objective of this systematic review was to examine the diagnostic accuracy of subjective features and physical examination tests for MN. Methods: CINAHL, CENTRAL, EMBASE, MEDLINE, PubMed, Opengrey, PEDro, PsycINFO, Scopus and Trials register were searched in January 2021. Two reviewers independently screened studies for inclusion using the following criteria: (1) prospective or retrospective cohort studies, (2) participants aged ≥18 years with suspected MN, (3) primary data allowing construction of 2 × 2 diagnostic table or reported sensitivity and specificity figures, (4) diagnosis of MN using magnetic resonance imaging, ultrasonography, surgery, positive response to steroid and/or anesthetic injection, and (5) in English or translatable. Quality of included studies was assessed using the Quality Assessment for Diagnostic Accuracy Studies version-2 (QUADAS-2) tool. Results: The search yielded 1170 results, of which 9 were included in this systematic review. Narrative synthesis revealed that subjective clicking reported by a patient was highly specific (0.96) and had a high positive likelihood ratio (13.14). The modified webspace tenderness test (thumb index finger squeeze test) was highly sensitive (0.96) with a low negative likelihood ratio (0.04). The commonly reported feeling of “walking on a pebble” and “burning pain” had sensitivities of 43% to 53% and 54% to 57% and associated specificities of 52% and 48%, respectively. Only 1 study had low risk of bias. The review was limited by the number of studies that included few or no patients without MN, and the impact this had on the ability to calculate diagnostic accuracy. Conclusion: There is strong evidence that clicking reported by a patient rules in MN and that the modified webspace tenderness test rules out MN when negative.

ABSTRACT Candida glabrata exhibits innate resistance to azole antifungal drugs but also has the propensity to rapidly develop clinical drug resistance. Azole drugs, which target Erg11, is one of the major classes of antifungals used to treat Candida infections. Despite their widespread use, the mechanism controlling azole-induced ERG gene expression and drug resistance in C. glabrata has primarily revolved around Upc2 and/or Pdr1. Phylogenetic and syntenic analyses revealed that C. glabrata, following a whole genome duplication event, maintained HAP1A and HAP1B, whereas Saccharomyces cerevisiae only retained the HAP1A ortholog, HAP1. In this study, we determined the function of two zinc cluster transcription factors, Hap1A and Hap1B, as direct regulators of ERG genes. In S. cerevisiae, Hap1, an ortholog of Hap1A, is a known transcription factor controlling ERG gene expression under aerobic and hypoxic conditions. Interestingly, deleting HAP1 or HAP1B in either S. cerevisiae or C. glabrata, respectively, showed altered susceptibility to azoles. In contrast, the strain deleted for HAP1A did not exhibit azole susceptibility. We also determined that the increased azole susceptibility in a hap1BΔ strain is attributed to decreased azole-induced expression of ERG genes, resulting in decreased levels of total ergosterol. Surprisingly, Hap1A protein expression is barely detected under aerobic conditions but is specifically induced under hypoxic conditions, where Hap1A is required for the repression of ERG genes. However, in the absence of Hap1A, Hap1B can compensate as a transcriptional repressor. Our study shows that Hap1A and Hap1B is utilized by C. glabrata to adapt to specific host and environmental conditions.IMPORTANCEInvasive and drug-resistant fungal infections pose a significant public health concern. Candida glabrata, a human fungal pathogen, is often difficult to treat due to its intrinsic resistance to azole antifungal drugs and its capacity to develop clinical drug resistance. Therefore, understanding the pathways that facilitate fungal growth and environmental adaptation may lead to novel drug targets and/or more efficacious antifungal therapies. While the mechanisms of azole resistance in Candida species have been extensively studied, the roles of zinc cluster transcription factors, such as Hap1A and Hap1B, in C. glabrata have remained largely unexplored until now. Our research shows that these factors play distinct yet crucial roles in regulating ergosterol homeostasis under azole drug treatment and oxygen-limiting growth conditions. These findings offer new insights into how this pathogen adapts to different environmental conditions and enhances our understanding of factors that alter drug susceptibility and/or resistance.

Coral reefs are being degraded at alarming rates and decisive intervention actions are urgently needed. One such intervention is coral cryopreservation. Although the cryopreservation of coral sperm and larvae has been achieved, preservation of coral fragments including both its tissue and skeleton, has not. The overarching aim of this study was to understand and assess the physiological stressors that might underlie coral fragment cryopreservation, understand the long-term consequences of these exposures to continued growth, and develop a health metrics scale for future research. Therefore, we assessed small fragments (~1 cm2) from the Hawaiian coral, Porites compressa, examining: (1) chill sensitivity; (2) chemical sensitivity to complex cryoprotectants; (3) methods to safely remove algal symbionts of coral for cryopreservation; (4) continued growth over time of coral fragments exposed to chilling and cryoprotectants; and (5) assessment of health and viability of coral fragments post the applied treatments. Corals were able to withstand chilling to 0 °C for 1 min and after 2 weeks were not significantly different from the live controls, whereas, corals exposed to complex cryoprotectants needed 3 weeks of recovery. Most importantly, it appears that once the coral fragments had surpassed this initial recovery, there was no difference in subsequent growth. Technological advances in cryo-technology promise to support successful coral fragment cryopreservation soon, and its success could help secure much of the genetic and biodiversity of reefs in the next decade.

Market hog lymph nodes (LNs) can contaminate carcasses with Salmonella, as well as ground and comminuted pork products. The objective of this study was to perform a qualitative and quantitative analysis of LNs from several regions and seasons in the United States to establish a Salmonella prevalence and concentration baseline. Six types of LNs (axillary, mesenteric, subiliac, tracheobronchial, superficial inguinal, prescapular), and tonsils were sampled from market hog carcasses from different regions (east, central, and west) and seasons (winter, spring, and summer/fall). Salmonella was detected and enumerated using BAX®-System-SalQuant® methods and the BAX®-System Real-Time Salmonella Assay. Salmonella prevalence (N = 4,132) was 36% for tonsils, 35% for mesenteric LN, and less than 10% for the other LN types. Of the 601 carcasses tested, 62% were positive for Salmonella, with the highest prevalence occurring during spring in the east (90.9%), and the lowest prevalence occurring during spring in the central region (26.0%). Tonsil prevalence was greatest in the eastern region during spring. Mesenteric LN prevalence was high (>20%) regardless of season or region. Salmonella prevalence in tracheobronchial, subiliac, axillary, and superficial inguinal LNs was generally greatest during the spring or fall and in the eastern region. The median SalQuant® Salmonella concentration was 2.18 log10 Salmonella cells/sample. Median SalQuant® concentration for all other sample types fell below the limit of quantification (1 log10 Salmonella cells/sample). This longitudinal study can be used by the pork industry for risk assessments and risk-based decision-making.

Current literature states the importance of mental and physical health in combating the effects of metabolic syndrome; however, there is limited information on whether providing education on the syndrome along with mental and individualized physical exercises improves perceived confidence in the older adult population. A solution to this problem would be to provide a course to this population with a primary goal of education and exercise prescription. A community case study was implemented in the spring of 2024 with the purpose of measuring perceived confidence in metabolic syndrome, management of stress and anxiety, and how to move safely with exercise. Twenty-nine older adults with an average age of 76.1 years were recruited from a local senior citizen center. A course was given to the participants that included education and prescription of exercises tailored to the needs of the individual. Before and after the course, participants completed a confidence survey investigating their confidence in lowering the risk for metabolic syndrome, managing stress/anxiety, and understanding how to move safely with exercise. Regarding the post surveys, knowing how to lower the risk of metabolic syndrome increased by 46%, learning how to manage stress and anxiety increased by 50%, and understanding how to exercise safely increased by 41%. The data from this study suggests that providing education along with specific exercise prescription improved the participant’s confidence in lowering their risk for metabolic syndrome, management of stress and anxiety, and how to move safely with exercise.

AbstractAnalyses of women dermatology literature authorship from 2018 to 2022 reveal a slight increase in total female authors, female first authors, and female senior authors with no substantial immediate impact of COVID-19 on current trends, encouraging future examination of long-term effects and ongoing promotion of systemic initiatives to support gender equity.

BackgroundPassive sensing through smartphone keyboard data can be used to identify and monitor symptoms of mood disorders with low participant burden. Behavioral phenotyping based on mobile keystroke data can aid in clinical decision-making and provide insights into the individual symptoms of mood disorders. ObjectiveThis study aims to derive digital phenotypes based on smartphone keyboard backspace use among 128 community adults across 2948 observations using a Bayesian mixture model. MethodsEligible study participants completed a virtual screening visit where all eligible participants were instructed to download the custom-built BiAffect smartphone keyboard (University of Illinois). The BiAffect keyboard unobtrusively captures keystroke dynamics. All eligible and consenting participants were instructed to use this keyboard exclusively for up to 4 weeks of the study in real life, and participants’ compliance was checked at the 2 follow-up visits at week 2 and week 4. As part of the research protocol, every study participant underwent evaluations by a study psychiatrist during each visit. ResultsWe found that derived phenotypes were associated with not only the diagnoses and severity of depression and mania but also specific individual symptoms. Using a linear mixed-effects model with random intercepts accounting for the nested data structure from daily data, the backspace rates on the continuous scale did not differ between participants in the healthy control and in the mood disorders groups (P=.11). The 3-class model had mean backspace rates of 0.112, 0.180, and 0.268, respectively, with a SD of 0.048. In total, 3 classes, respectively, were estimated to comprise 37.5% (n=47), 54.4% (n=72), and 8.1% (n=9) of the sample. We grouped individuals into Low, Medium, and High backspace rate groups. Individuals with unipolar mood disorder were predominantly in the Medium group (n=54), with some in the Low group (n=27) and a few in the High group (n=6). The Medium group, compared with the Low group, had significantly higher ratings of depression (b=2.32, P=.008). The High group was not associated with ratings of depression with (P=.88) or without (P=.27) adjustment for medication and diagnoses. The High group, compared with the Low group, was associated with both nonzero ratings (b=1.91, P=.02) and higher ratings of mania (b=1.46, P

AbstractTikTok is a social media platform that can educate users about dermatology, but this longitudinal analysis of skin of color–related TikTok hashtags from 2021 to 2022 suggests that nondermatologist influencers continue to dominate content creation, highlighting the need for more participation from board-certified dermatologists to actively counter misinformation and address potential disparities in skin-of-color health care.

Background A consensus definition for active sacroiliitis by MRI, mentioned in the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), was published in 2009 and included a qualitative and quantitative MRI cut-off component. In 2021, updates to the quantitative component were preliminarily proposed. This post hoc analysis of part A of the phase 3 open-label C-OPTIMISE study (NCT02505542) explores the differences by applying the 2009 and preliminary 2021 inflammatory cut-offs on clinical outcomes of axSpA patients treated with certolizumab pegol.Methods Baseline MRI scans were used to classify 657 patients as MRI+ or MRI– according to the quantitative components of the 2009 and preliminary 2021 MRI cut-offs for inflammatory lesions. Clinical outcomes, including ASAS ≥40% improvement (ASAS40), Ankylosing Spondylitis Disease Activity Score and Bath Ankylosing Spondylitis Disease Activity Index, were reported to week 48.Results Across all analysed outcomes, 2009 MRI+ and preliminary 2021 MRI+ subgroups showed similar results. Notably, clinical outcomes for the discordant group (2009 MRI+but preliminary 2021 MRI– group; 53/657 [8.1%]) were close to those seen in MRI– patients according to either 2009 or preliminary 2021 inflammatory cut-offs, and notably different from the totality of MRI+ subgroups.Conclusion This analysis suggests that the preliminary 2021 cut-offs for MRI inflammatory lesions may slightly increase the specificity of the quantitative part of the 2009 MRI inflammatory lesion definition. The effects of the updated MRI cut-offs need to be assessed on the basis of efficacy outcomes and with the inclusion of aspects of structural changes.Trial registration number NCT02505542.

Abstract Introduction Rural cancer caregivers experience obstacles in accessing services, obtaining respite, and ensuring their care recipients receive quality care. These challenges warrant opportunities to participate in evidence‐based behavioral intervention trials to fill support gaps. Adaptation to rural settings can facilitate appropriate fit, given higher caregiver service needs and unique challenges. We present findings from the adaptation process of a psychoeducational intervention designed to support cancer caregivers in rural settings. Methods We adapted Reblin's CARING intervention, designed for neuro‐oncology, to target caregivers of rural cancer patients across cancer sites. First, we conducted formative work to determine the unmet social and supportive care needs rural cancer caregivers faced. We used the Framework for Reporting Adaptations and Modifications to Evidence‐based Implementation Strategies (FRAME‐IS) to guide the modifications. To conduct the adaptation, we elicited feedback through qualitative interviews of seven caregivers and three cancer hospital staff and thematic analysis to inform intervention modifications. Our qualitative study was guided by the Consolidated Criteria for Reporting Qualitative Research (COREQ). Results Interviews revealed that service access was a pressing need, along with financial (e.g., treatment costs, employment challenges) and geographic barriers (e.g., distance to treatment, road conditions). We modified content, training, and context using the FRAME‐IS steps. Changes enhanced fit through the following adaptations: changes to social support domains, session content, interventionist training, resource offerings, screening and recruitment processes, and virtual delivery. Discussion Challenges to establishing successful psychosocial oncology interventions may be improved through participant‐centered approaches and implementation science. Additional systemic challenges, including lack of systematic documentation of caregivers, persist and may especially disadvantage under‐represented and underserved groups, such as rural dwellers. The enCompass intervention is undergoing ongoing single‐arm pilot of rural cancer patient/caregiver dyads targeting caregiver coping self‐efficacy and patient/caregiver distress (Clinical Trials #NCT05828927).

Abstract Background COVID-19 survivors may develop long-term symptoms of fatigue, dyspnea, mental health issues, and functional limitations: a condition termed post-acute sequelae of COVID-19 (PASC). Pulmonary rehabilitation (PR) is a recommended treatment for PASC; however, there is a lack of data regarding PR’s effect on multiple health indices and the factors that influence patient outcomes. The aim of our study is to evaluate the impact of pulmonary rehabilitation on functional and psychological parameters in patients diagnosed with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), thereby offering insights into the efficacy of such interventions in improving the quality of life and clinical outcomes for these individuals. Methods We extracted patient demographic, comorbidity, and outcome data from Allegheny Health Network’s electronic medical records. Functionality test results were compared before and after PR, including 6-minute walk test (6MWT), chair rise repetitions (CR reps), timed up and go test (TUG), gait speed (Rehab gait), modified medical research council scale (MMRC), shortness of breath questionnaire (SOBQ), hospital anxiety and depression scale (HADS) and chronic obstructive pulmonary disease assessment test (CAT) scores. Multiple regression analysis was done to evaluate the effect of comorbidities and patient factors on patient responses to PR. Results The 55 patients included in this study had a mean time of 4 months between the initial COVID-19 diagnosis and the subsequent PASC diagnosis. Following pulmonary rehabilitation (PR), significant improvements were observed across various metrics. The distance covered in the 6-minute walk test (6MWT) increased markedly from a pre-rehabilitation average of 895 feet (SD 290) to 1,300 feet (SD 335) post-rehabilitation, with a mean change of 405 feet (95% CI [333, 477]). Chair rise repetitions (CR reps) saw an increase from 9 (SD 3) reps to 13 (SD 3) reps, with a change of 4 reps (95% CI [3.7, 4.9]). The timed up and go test (TUG) time decreased significantly from 13 s (SD 5) to 10 s (SD 2), reflecting a mean reduction of 3 s (95% CI [-4.5, -2.5]). Rehabilitation gait speed improved from 1.0 m/s to 1.3 m/s, changing by 0.3 m/s (95% CI [0.2, 0.3]). The Modified Medical Research Council (MMRC) dyspnea scale showed a notable decrease from a mean of 2 (SD 1) to 1 (SD 1), a change of -1 (95% CI [-1.5, -1]). The Shortness of Breath Questionnaire (SOBQ) scores reduced significantly from 51 (SD 21) to 22 (SD 18), with a change of -29 (95% CI [-34, -23]). The Hospital Anxiety and Depression Scale (HADS) scores decreased from 11 (SD 7) to 8 (SD 7), a reduction of -4 (95% CI [-5, -2]). Lastly, the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) scores significantly dropped from 18 (SD 7) to 9 (SD 7), changing by -10 (95% CI [-11, -8]). However, the presence of hypertension, diabetes, chronic lung diseases, outpatient status, and receipt of specific pharmacologic treatments (decadron, decadron + remdesivir, and decadron + remdesivir + tocilizumab) were identified as factors associated with a poor response to PR. Conclusion Our study supports PR as an integrated model of care for PASC patients to improve several physical and mental health indices. The long-term effects of PR on patients’ functional status should be investigated in the future.

Abstract Background Plasmodium vivax represents the most geographically widespread human malaria parasite affecting civilian and military populations in endemic areas. Targeting the pre-erythrocytic (PE) stage of the parasite life cycle is especially appealing for developing P. vivax vaccines as it would prevent disease and transmission. Here, naturally acquired immunity to a panel of P. vivax PE antigens was explored, which may facilitate vaccine development and lead to a better understanding of naturally acquired PE immunity. Methods Twelve P. vivax PE antigens orthologous to a panel of P. falciparum antigens previously identified as highly immunogenic in protected subjects after immunization with radiation attenuated sporozoites (RAS) were used for evaluation of humoral and cellular immunity by ELISA and IFN-γ ELISpot. Samples from P. vivax infected individuals (n = 76) from a low endemic malaria region in the Peruvian Amazon Basin were used. Results In those clinical samples, all PE antigens evaluated showed positive IgG antibody reactivity with a variable prevalence of 58–99% in recently P. vivax diagnosed patients. The magnitude of the IgG antibody response against PE antigens was lower compared with blood stage antigens MSP1 and DBP-II, although antibody levels persisted better for PE antigens (average decrease of 6% for PE antigens and 43% for MSP1, p

Abstract Introduction Bepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis. Methods Population PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration–time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations. Results Bepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure. Conclusions This analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.

Abstract Human cytomegalovirus (CMV) is the most common infectious cause of complications post-transplantation, while a CMV vaccine for transplant recipients has yet to be licensed. Triplex, a multiantigen Modified Vaccinia Ankara (MVA)-vectored CMV vaccine candidate based on the immunodominant antigens phosphoprotein 65 (pp65) and immediate-early 1 and 2 (IE1/2), is in an advanced stage of clinical development. However, its limited genetic and expression stability restricts its potential for large-scale production. Using a recently developed fully synthetic MVA (sMVA) platform, we developed a new generation Triplex vaccine candidate, T10-F10, with different sequence modifications for enhanced vaccine stability. T10-F10 demonstrated genetic and expression stability during extensive virus passaging. In addition, we show that T10-F10 confers comparable immunogenicity to the original Triplex vaccine to elicit antigen-specific T cell responses in HLA-transgenic mice. These results demonstrate improvements in translational vaccine properties of an sMVA-based CMV vaccine candidate designed as a therapeutic treatment for transplant recipients.

This article analyzes the consequences of the United States implementing unilateral policies to reduce greenhouse gas (GHG) emissions from agriculture. The policy representation is based loosely on current and past policy initiatives that have subsidized GHG reductions and considered special treatment for sectors heavily involved in trade. To do so, our first step is to generate new estimates of key parameters, elasticities of demand and supply, that are critical to understanding interactions among agricultural commodities, such as between livestock and crop products, in this area of research and more broadly. We apply these parameters in a widely used economic model that estimates the effects of a unilateral U.S. agricultural GHG policy on both domestic and foreign markets as well as global GHG emissions. Livestock effects dominate, driving most U.S. livestock product consumer prices higher and causing mixed crop and crop product price effects. A unilateral policy increases food costs in the implementing country and, if applied to all supplies, domestic and imported, tends to raise prices elsewhere as well. Alternative implementation strategies, such as not imposing the costs on exports or not imposing the costs on imports, can lead to lower food prices and greater consumption in other countries, as well as have important implications for the overall GHG reductions achieved by the unilateral effort.

This paper investigates how changes to work (caused by the COVID-19 pandemic) and job insecurity relate to identification and subsequent compliance to public health mitigation guidelines. Specifically, we argue that job insecurity and certain changes to social contacts, workload and autonomy can be related to a lowered identification with the working population. Three-country survey data from Belgium, the UK and the US collected at the height of the pandemic supports that people who reported changes that were in line with what most people experienced (e.g., a decrease in social contacts at work) and changes that symbolised more importance (e.g., an increase in workload due to the pandemic) identified more strongly with the working population. Higher job insecurity was associated with less identification with the working population. Changes to autonomy did not play a role. Identification with the working population was related to higher compliance with national COVID-19 health guidelines. A 2SLS instrumental variable estimation controlled for endogeneity issues and confirmed the relationship between identification and health compliance. The study brings important general lessons for the societal impact of work-related changes and discusses applications beyond the pandemic context.

The U.S. population has suffered worse health consequences owing to COVID-19 than comparable wealthy nations. COVID-19 had caused more than 1.1 million deaths in the U.S. as of May 2023 and contributed to a 3-year decline in life expectancy. A coalition of public health workers and community activists launched an external review of the Centers for Disease Control and Prevention's pandemic management from January 2021 to May 2023. The authors used a modified Delphi process to identify core pandemic management areas, which formed the basis for a survey and literature review. Their analysis yields 3 overarching shortcomings of the Centers for Disease Control and Prevention's pandemic management: (1) Centers for Disease Control and Prevention leadership downplays the serious impacts and aerosol transmission risks of COVID-19, (2) Centers for Disease Control and Prevention leadership has aligned public guidance with commercial and political interests over scientific evidence, and (3) Centers for Disease Control and Prevention guidance focuses on individual choice rather than emphasizing prevention and equity. Instead, the agency must partner with communities most impacted by the pandemic and encourage people to protect one another using layered protections to decrease COVID-19 transmission. Because emerging variants can already evade existing vaccines and treatments and Long COVID can be disabling and lacks definitive treatment, multifaceted, sustainable approaches to the COVID-19 pandemic are essential to protect people, the economy, and future generations.

Visceral white adipose tissues (WAT) regulate systemic lipid metabolism and inflammation. Dysfunctional WAT drive chronic inflammation and facilitate atherosclerosis. Adipose tissue-associated macrophages (ATM) are the predominant immune cells in WAT, but their heterogeneity and phenotypes are poorly defined during atherogenesis. The scavenger receptor CD36 mediates ATM crosstalk with other adipose tissue cells, driving chronic inflammation. Here, we combined the single-cell RNA sequencing technique with cell metabolic and functional assays on major WAT ATM subpopulations using a diet-induced atherosclerosis mouse model (Apoe-null). We also examined the role of CD36 using Apoe/Cd36 double-null mice. Based on transcriptomics data and differential gene expression analysis, we identified a previously undefined group of ATM displaying low viability and high lipid metabolism and labeled them as “unhealthy macrophages”. Their phenotypes suggest a subpopulation of ATM under lipid stress. We also identified lipid-associated macrophages (LAM), which were previously described in obesity. Interestingly, LAM increased 8.4-fold in Apoe/Cd36 double-null mice on an atherogenic diet, but not in Apoe-null mice. The increase in LAM was accompanied by more ATM lipid uptake, reduced adipocyte hypertrophy, and less inflammation. In conclusion, CD36 mediates a delicate balance between lipid metabolism and inflammation in visceral adipose tissues. Under atherogenic conditions, CD36 deficiency reduces inflammation and increases lipid metabolism in WAT by promoting LAM accumulation.

Abstract Fostemsavir is an approved gp120‐directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment‐experienced adults with multi‐drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug–drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co‐administered with fostemsavir.

Environment and lifestyle can affect the epigenome passed down from generation to generation. A mother’s nutrition can impact the methylation levels of her offspring’s epigenome, but it’s unclear which genes may be affected by malnutrition during gestation or early development. In this study, we examined the levels of methylated GC in the promoter region of HLA-C in mothers and infants from the Kichwa community in Ecuador. To do this, we analyzed saliva samples using bisulfite DNA sequencing. While we did not observe any significant differences in the mean methylation percentages in exon 1 of HLA-C between mothers and their infants after the first two years of lactation and life, respectively, we did find that infants tended to increase their methylation level during the first two years of life, while mothers tended to decrease it after the first two years of breastfeeding. When we compared methylation levels between mothers and infants using an ANOVA/posthoc Tukey test, we found that the average methylation for the entire population was less than 3% at T1 and T2. Although there was a tendency for infants to have higher methylation levels during their first two years of life and for mothers to have lower methylation levels after the first two years of breastfeeding, the mean values were not significantly different. However, we found a significant difference when we contrasted the data using a Kruskal-Wallis test at 0.05 for T1 AND T2 (p-value: 0.0148). Specifically, mothers had an average of X̅ = 2.06% and sons had X̅ = 1.57% at T2 (p-value: 0.7227), while the average for mothers was X̅ = 1.83% and for sons X̅ =1.77%. Finally, we identified three CpG motif nucleotide positions (32–33, 43–44, and 96–97) along the 122 bp analysis of HLA-C exon one, which was found to retain methylation patterns over time and is inherited from mother to offspring. Finally, our small pilot study did not reveal significant correlations between maternal and offspring nutritional status and DNA methylation levels of HLA-C exon one.