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Objective: To explore the mental health experiences of adolescents and young adults (AYA) with inflammatory bowel disease (IBD) enrolled in a randomized controlled trial evaluating the impact of a multimodal transition intervention., Study Design: Virtual semistructured interviews were held with 21 AYA aged 16 through 18 years with IBD. Guided by qualitative description, interviews were digitally recorded, transcribed verbatim, and analyzed using an inductive approach to reflexive thematic analysis., Results: Three themes were generated from the data: (1) a continuum of integration between IBD and personal identity in adolescence and young adulthood; (2) manifestations of the mind-gut connection among AYA with IBD; and (3) hopes and priorities for addressing mental health in IBD care., Conclusions: AYA with IBD endorsed the criticality of incorporating mental health discussions into routine care during the transition to adult care, given the co-occurrence of psychosocial stressors throughout this period. A series of factors promoting and hindering the integration of IBD into one's identity were identified and could be explored in clinical encounters., Competing Interests: Declaration of Competing Interest This study was supported by a grant from the Leona M. and Harry B. Helmsley Charitable Trust and Crohn's and Colitis Canada. This study was also supported by The Canadian Children IBD Network (with funding provided by the CH.I.L.D. Foundation). The funding sources did not support the study design, collection, data analysis and interpretation, manuscript preparation, or the decision to submit the article for publication. David R. Mack is supported in part through a Distinguished Clinical Chair in Pediatric IBD through the Faculty of Medicine, University of Ottawa. Eric I. Benchimol holds the Northbridge Financial Corporation Chair in Inflammatory Bowel Disease, a joint Hospital-University Chair between the University of Toronto, The Hospital for Sick Children, and the SickKids Foundation. L.K. is an equity owner and scientific advisor to Trellus Health, and a consultant to Pfizer and Coprata Health. E.B. has acted as a consultant for McKesson Canada and the Dairy Farmers of Ontario for matters unrelated to medications used to treat inflammatory bowel disease. He has also acted as a consultant for the Canadian Agency for Drugs and Technology in Health (CADTH). The other authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Our objectives were to quantify the relationships among fatigue, pain interference, and physical disability in children with juvenile idiopathic arthritis (JIA) and to test whether fatigue mediates the relationship between pain interference and physical disability in JIA., Methods: Patients enrolled within three months of JIA diagnosis in the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry between February 2017 and May 2023 were included. Their parents completed the Patient-Reported Outcomes Measurement Information System fatigue and pain interference short proxy questionnaires and the Childhood Health Assessment Questionnaire disability index at registry enrollment. Associations were assessed using Pearson correlations and multiple linear regression. Structural equation modeling (SEM) was used to test if fatigue mediates the relationship between pain interference and physical disability., Results: Among 855 patients (61.4% female, 44.1% with oligoarthritis), most reported fatigue and pain interference scores similar to those in the reference population, but 15.6% reported severe fatigue and 7.3% reported severe pain interference, with wide variation across JIA categories. Fatigue was strongly correlated with pain interference (r = 0.72, P < 0.001) and with physical disability (r = 0.60, P < 0.001). Pain interference (β = 0.027, P < 0.001) and fatigue (β = 0.013, P < 0.001) were both associated with physical disability after controlling for each other and potential confounders. SEM supported our hypothesis that fatigue partially mediates the relationship between pain interference and physical disability., Conclusion: Our findings suggest both fatigue and pain interference are independently associated with physical disability in children newly diagnosed with JIA, and the effect of pain interference may be partly mediated by fatigue., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus, 12/15-LOX is an important target to prevent delayed cerebral ischemia. SAH was induced in C57BL/6 and 12/15-LOX -/- mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro. C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day 5 to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. In SAH mice, 12/15-LOX was upregulated in brain vascular cells, and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH., (© 2024. The Author(s).)

Immigrants are highly entrepreneurial. But, what is the broader relationship between high-skilled immigration and regional entrepreneurship activity beyond the ventures that immigrants establish themselves? Using administrative data on newly awarded H-1B visas in the United States, we document a positive relationship between high-skilled immigration and regional entrepreneurship. A doubling of immigrants to a metropolitan statistical area is followed by a 6% increase in entrepreneurship within three years. In contrast, continuing H-1Bs and the arrival of unskilled immigrants (H-2B visas) do not increase regional entrepreneurship. Focusing on Indian immigrants (representing about 70% of all H-1B visas), we find the effect is stronger in metropolitan statistical areas with a larger local Indian population, but not other nationalities, suggesting that presence of conationals facilitates the relationship between high-skilled immigration and regional entrepreneurship. We present this and other evidence as consistent with a knowledge transfer mechanism., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing 2005-2010 and 2017-2021 inception cohorts., Methods: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan-Meier survival analysis and multivariable Cox regression., Results: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for good health-related quality of life (≥9/10)., Conclusion: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient-reported outcomes were smaller than improvements in disease activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Prostate cancer progression is driven by androgen receptor (AR) activity, which is a target for therapeutic approaches. Enzalutamide is an AR inhibitor that prolongs the survival of patients with advanced prostate cancer. However, resistance mechanisms arise and impair its efficacy. One of these mechanisms is the expression of AR-V7, a constitutively active AR splice variant. The Mediator complex is a multisubunit protein that modulates gene expression on a genome-wide scale. MED12 and cyclin-dependent kinase (CDK)8, or its paralog CDK19, are components of the kinase module that regulates the proliferation of prostate cancer cells. In this study, we investigated how MED12 and CDK8/19 influence cancer-driven processes in prostate cancer cell lines, focusing on AR activity and the enzalutamide response. We inhibited MED12 expression and CDK8/19 activity in LNCaP (AR+, enzalutamide-sensitive), 22Rv1 (AR-V7+, enzalutamide-resistant), and PC3 (AR-, enzalutamide-insensitive) cells. Both MED12 and CDK8/19 inhibition reduced cell proliferation in all cell lines, and MED12 inhibition reduced proliferation in the respective 3D spheroids. MED12 knockdown significantly inhibited c-Myc protein expression and signaling pathways. In 22Rv1 cells, it consistently inhibited the AR response, prostate-specific antigen (PSA) secretion, AR target genes, and AR-V7 expression. Combined with enzalutamide, MED12 inhibition additively decreased the AR activity in both LNCaP and 22Rv1 cells. CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Poorly cohesive carcinoma (PCC) is an uncommon neoplasm characterized by tumorous cells exhibiting a lack of adhesion. PCC has been reported rarely in the small intestine other than at the ampulla of Vater. We present a 40-year-old man with recurrent abdominal pain and small bowel obstruction. Imaging revealed an abnormal appearing distal small bowel, with only nonspecific mucosal changes discovered on antegrade and retrograde enteroscopy. On subsequent diagnostic laparoscopy, an ileal mass was found and resected with histopathology showing PCC with signet ring formation. This is an aggressive cancer with a worse prognosis than other small bowel adenocarcinomas., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Here we present the Multisite Assembly of Gateway Induced Clones (MAGIC) system, which harnesses site-specific recombination-based cloning via Gateway technology for rapid, modular assembly of between 1 and 3 "Entry" vector components, all into a fourth, standard high copy "Destination" plasmid backbone. The MAGIC toolkit spans a range of in vitro and in vivo uses, from directing tunable gene expression, to driving simultaneous expression of microRNAs and fluorescent reporters, to enabling site-specific recombinase-dependent gene expression. All MAGIC system components are directly compatible with existing multisite gateway Tol2 systems currently used in zebrafish, as well as existing eukaryotic cell culture expression Destination plasmids, and available mammalian lentiviral and adenoviral Destination vectors, allowing rapid cross-species experimentation. Moreover, herein we describe novel vectors with flanking piggyBac transposon elements for stable genomic integration in vitro or in vivo when used with piggyBac transposase. Collectively, the MAGIC system facilitates transgenesis in cultured mammalian cells, electroporated mouse and chick embryos, as well as in injected zebrafish embryos, enabling the rapid generation of innovative DNA constructs for biological research due to a shared, common plasmid platform.

Covering: September 1964 to June 2023Bacteria and fungi living in symbiosis with insects have been studied over the last sixty years and found to be important sources of bioactive natural products. Not only classic producers of secondary metabolites such as Streptomyces and other members of the phylum Actinobacteria but also numerous bacteria from the phyla Proteobacteria and Firmicutes and an impressive array of fungi (usually pathogenic) serve as the source of a structurally diverse number of small molecules with important biological activities including antimicrobial, cytotoxic, antiparasitic and specific enzyme inhibitors. The insect niche is often the exclusive provider of microbes producing unique types of biologically active compounds such as gerumycins, pederin, dinactin, and formicamycins. However, numerous insects still have not been described taxonomically, and in most cases, the study of their microbiota is completely unexplored. In this review, we present a comprehensive survey of 553 natural products produced by microorganisms isolated from insects by collating and classifying all the data according to the type of compound (rather than the insect or microbial source). The analysis of the correlations among the metadata related to insects, microbial partners, and their produced compounds provides valuable insights into the intricate dynamics between insects and their symbionts as well as the impact of their metabolites on these relationships. Herein, we focus on the chemical structure, biosynthesis, and biological activities of the most relevant compounds.

The telencephalon of the mammalian brain comprises multiple regions and circuit pathways that play adaptive and integrative roles in a variety of brain functions. There is a wide array of GABAergic neurons in the telencephalon; they play a multitude of circuit functions, and dysfunction of these neurons has been implicated in diverse brain disorders. In this study, we conducted a systematic and in-depth analysis of the transcriptomic and spatial organization of GABAergic neuronal types in all regions of the mouse telencephalon and their developmental origins. This was accomplished by utilizing 611,423 single-cell transcriptomes from the comprehensive and high-resolution transcriptomic and spatial cell type atlas for the adult whole mouse brain we have generated, supplemented with an additional single-cell RNA-sequencing dataset containing 99,438 high-quality single-cell transcriptomes collected from the pre- and postnatal developing mouse brain. We present a hierarchically organized adult telencephalic GABAergic neuronal cell type taxonomy of 7 classes, 52 subclasses, 284 supertypes, and 1,051 clusters, as well as a corresponding developmental taxonomy of 450 clusters across different ages. Detailed charting efforts reveal extraordinary complexity where relationships among cell types reflect both spatial locations and developmental origins. Transcriptomically and developmentally related cell types can often be found in distant and diverse brain regions indicating that long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons. Additionally, we find various spatial dimensions of both discrete and continuous variations among related cell types that are correlated with gene expression gradients. Lastly, we find that cortical, striatal and some pallidal GABAergic neurons undergo extensive postnatal diversification, whereas septal and most pallidal GABAergic neuronal types emerge simultaneously during the embryonic stage with limited postnatal diversification. Overall, the telencephalic GABAergic cell type taxonomy can serve as a foundational reference for molecular, structural and functional studies of cell types and circuits by the entire community., Competing Interests: Competing Interests H.Z. is on the scientific advisory board of MapLight Therapeutics, Inc. The other authors declare no competing interests.

Background and Purpose: Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus 12/15-LOX is an important target to prevent delayed cerebral ischemia., Methods: SAH was induced in C57BL/6 and 12/15-LOX -/- mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and in vitro . C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day five to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and for development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay., Results: In SAH mice, 12/15-LOX was upregulated in brain vascular cells and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples., Conclusions: Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH., Competing Interests: Potential conflict of interests The authors declare no competing interests.

Purpose: To examine the estimated effects of substituting 30 min of sedentary time with low-light physical activity (LLPA) and high-light physical activity (HLPA) on episodic memory, executive functioning, and working memory among middle-aged and older Latinos., Design: A cross-sectional study., Setting: Chicago and Chicagoland suburbs., Subjects: Middle-aged and older Latinos (n = 61)., Measures: Accelerometer-assessed physical activity. A cognitive battery was administered to assess episodic memory, executive function, and working memory., Analysis: Isotemporal substitution analyses were conducted, where unstandardized coefficients from linear regression models were used to examine the substitution effect of replacing sedentary time with LLPA and HLPA., Results: Substitution of sedentary time with LLPA was associated with better episodic memory (Immediate recall, B = .947, P = .008; Delayed recall, B = .857, P = .013). No other significant substitution effects were present., Conclusion: Middle-aged and older Latinos who replace sedentary time with LLPA may have better episodic memory. Future studies may target light physical activity to address cognition disparities and can inform the development of physical activity interventions that are appealing and accessible for Latinos., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Primary graft dysfunction (PGD) is the leading cause of morbidity and mortality early after heart transplantation (HT). The International Consortium on PGD is a multicenter collaboration dedicated to identifying the clinical risk factors for PGD in the contemporary era of HT. The objectives of the current report were (1) to assess the incidence of severe PGD in an international cohort; (2) to evaluate the performance of the most strongly validated PGD risk tool, the RADIAL score, in a contemporary cohort; and (3) to redefine clinical risk factors for severe PGD in the current era of HT., Methods: This is a retrospective, observational study of consecutive adult HT recipients between 2010 and 2020 in 10 centers in the United States, Canada and Europe. Patients with severe PGD were compared to those without severe PGD (comprising those with no, mild and moderate PGD). The RADIAL score was calculated for each transplant recipient. The discriminatory power of the RADIAL score was evaluated using receiver operating characteristic (ROC) analysis, and its calibration was assessed by plotting the percentage of PGD predicted vs that which was observed. To identify clinical risk factors associated with severe PGD, we performed multivariable mixed-effects logistic regression modeling to account for among-center variability., Results: A total of 2746 patients have been enrolled in the registry to date, including 2015 (73.4%) from North America, and 731 (26.6%) from Europe; 215 participants (7.8%) met the criteria for severe PGD. There was an increase in the incidence of severe PGD over the study period (P value for trend by difference sign test = 0.004). The Kaplan-Meier estimate for 1-year survival was 75.7% (95% CI 69.4-80.9%) in patients with severe PGD as compared to 94.4% (95% CI 93.5-95.2%) in those without severe PGD (log-rank P value < 0.001). The RADIAL score performed poorly in our contemporary cohort and was not associated with severe PGD; it had an AUC of 0.53 (95% CI 0.48-0.58). In the multivariable regression model, acute preoperative dialysis (OR 2.41, 95% CI 1.31-4.43), durable left ventricular assist device support (OR 1.77, 95% CI 1.13-2.77), and total ischemic time (OR 1.20 for each additional hour, 95% CI 1.02-1.41) were associated with an increased risk of severe PGD., Conclusions: Our consortium has identified an increasing incidence of PGD in the modern transplant era. We identified contemporary risk factors for this early post-transplant complication, which confers a high mortality risk. These results may enable the identification of patients at high risk for developing severe PGD in order to inform peri-transplant donor and recipient management practices., Competing Interests: Disclosures None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This paper pioneers a novel approach in electromagnetic (EM) system analysis by synergistically combining Bayesian Neural Networks (BNNs) informed by Latin Hypercube Sampling (LHS) with advanced thermal-mechanical surrogate modeling within COMSOL simulations for high-frequency low-pass filter modeling. Our methodology transcends traditional EM characterization by integrating physical dimension variability, thermal effects, mechanical deformation, and real-world operational conditions, thereby achieving a significant leap in predictive modeling fidelity. Through rigorous evaluation using Mean Squared Error (MSE), Maximum Learning Error (MLE), and Maximum Test Error (MTE) metrics, as well as comprehensive validation on unseen data, the model's robustness and generalization capability is demonstrated. This research challenges conventional methods, offering a nuanced understanding of multiphysical phenomena to enhance reliability and resilience in electronic component design and optimization. The integration of thermal variables alongside dimensional parameters marks a novel paradigm in filter performance analysis, significantly improving simulation accuracy. Our findings not only contribute to the body of knowledge in EM diagnostics and complex-environment analysis but also pave the way for future investigations into the fusion of machine learning with computational physics, promising transformative impacts across various applications, from telecommunications to medical devices.

Intestinal allografts are the most immunologically complex and carry the highest risk of rejection among solid organ transplantation, necessitating complex immunosuppressive management. We evaluated the latest information regarding induction immunosuppression, with an emphasis on established, novel, and emergent therapies. We also reviewed classic and novel induction immunosuppression strategies for highly sensitized recipients. Comparable progress has been made in intestinal transplantation clinical outcomes since the implementation of induction strategies. This review shows a clear diversity of induction protocols can be observed across different centers. The field of intestinal transplantation is still in its early stages, which is further complicated by the limited number of institutions capable of intestinal transplantation and their geographical variation, which further hinders the development of adequately powered studies in comparison to other organs. As the implementation of institution-specific induction protocols becomes more refined and results are disseminated, future research efforts should be directed towards the development of efficacious induction strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Using Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) juvenile idiopathic arthritis (JIA) registry data, we describe (1) clinical characteristics of patients with JIA transitioning to adult care, (2) prevalence of disease-related damage and complications, and (3) changes in disease activity during the final year prior to transfer., Methods: Registry participants who turned 17 years between February 2017 and November 2021 were included. Clinical characteristics and patient-reported outcomes (PROs) at the last recorded pediatric rheumatology visit, and changes observed in the year prior to that visit were analyzed. Physicians completed an additional questionnaire characterizing cumulative disease-related damage and adverse events by age 17 years., Results: At their last visit, 88 of 131 participants (67%) had inactive and 42 (32%) had active disease. Overall, 96 (73%) were on medications and 41 (31%) were on biologic disease-modifying antirheumatic drugs. Among 80 participants for whom the additional questionnaire was completed, 26% had clinically detected joint damage, 31% had joint damage on imaging, 14% had uveitis, and 7.5% had experienced at least 1 serious adverse event. During the final year, 44.2% of patients were in remission, 28.4% attained inactive disease, and 27.4% became or remained active. Mean scores of PROs were stable overall during that last year, but a minority reported marked worsening., Conclusion: A substantial proportion of youth with JIA transitioning to adult care in Canada had a high disease burden, which was reflected by their degree of disease activity, joint damage, or ongoing medication use. These results will inform pediatric and adult providers of anticipated needs during transition of care., (Copyright © 2024 by the Journal of Rheumatology.)

Background: The androgen/androgen receptor (AR)-signaling axis plays a central role in prostate cancer (PCa). Upon androgen-binding the AR dimerizes with another AR, and translocates into the nucleus where the AR-dimer activates/inactivates androgen-dependent genes. Consequently, treatments for PCa are commonly based on androgen deprivation therapy (ADT). The clinical benefits of ADT are only transitory and most tumors develop mechanisms allowing the AR to bypass its need for physiological levels of circulating androgens. Clinical failure of ADT is often characterized by the synthesis of a constitutively active AR splice variant, termed AR-V7. AR-V7 mRNA expression is considered as a resistance mechanism following ADT. AR-V7 no longer needs androgenic stimuli for nuclear entry and/or dimerization., Methods: Our goal was to mechanistically decipher the interaction between full-length AR (AR-FL) and AR-V7 in AR-null HEK-293 cells using the NanoLuc Binary Technology under androgen stimulation and deprivation conditions., Results: Our data point toward a hypothesis that AR-FL/AR-FL homodimers form in the cytoplasm, whereas AR-V7/AR-V7 homodimers localize in the nucleus. However, after androgen stimulation, all the AR-FL/AR-FL, AR-FL/AR-V7 and AR-V7/AR-V7 dimers were localized in the nucleus., Conclusions: We showed that AR-FL and AR-V7 form heterodimers that localize to the nucleus, whereas AR-V7/AR-V7 dimers were found to localize in the absence of androgens in the nucleus., (© 2024. The Author(s).)

Competing Interests: Competing interests: Prior to contributing to this piece, MS and KT were employees of HTAIn.

Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA neurons following BFc circuit manipulations. Furthermore, in vivo acetylcholine sensor and genetically encoded calcium indicator imaging within the BLA (using GACh3 and GCaMP, respectively) revealed selective response patterns of activity during feeding. Finally, through optogenetic manipulations in vivo, we found that increased cholinergic signaling from the BFc to the BLA suppresses appetite and food intake. Together, these data support a model in which cholinergic signaling from the BFc to the BLA directly influences appetite and feeding behavior., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Ortiz-Guzman et al.)

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Background: The Hispanic/Latino population has greater risk (estimated >50%) of developing type 2 diabetes (T2D) and developing it at a younger age. The American Diabetes Association estimates costs of diagnosed diabetes in 2017 was $327 billion; with medical costs 2.3x higher than patients without diabetes. The purpose of this manuscript is to describe the methodology utilized in a randomized controlled trial aimed at evaluating the efficacy of a diabetes telemanagement (DTM) program for Hispanic/Latino patients with T2D. The intent is to provide information for future investigators to ensure that this study can be accurately replicated., Methods: This study was a randomized controlled trial with 240 participants. Eligible patients (Hispanic/Latino, aged 18+, living with T2D) were randomized to Comprehensive Outpatient Management (COM) or DTM. DTM was comprised of usual care, including routine clinic visits every three months, as well as: Biometrics (a tablet, blood glucose meter, blood pressure monitor, and scale); Weekly Video Visits (facilitated in the patient's preferred language); and Educational Videos (including culturally congruent diabetes self-management education and quizzes). COM consisted of usual care including routine clinic visits every three months. For this study, COM patients received a glucometer, glucose test strips, and lancets. Establishing a therapeutic nurse-patient relationship was a fundamental component of our study for both groups. First contact (post-enrollment) centered on ensuring that patients and caregivers understood the program, building trust and rapport, creating a non-judgmental environment, determining language preference, and establishing scheduling availability (including evenings and weekends). DTM were provided with a tablet which allowed for self-paced education through videos and weekly video visits. The research team and Community Advisory Board identified appropriate educational video content, which was incorporated in diabetes educational topics. Video visits allowed us to assess patient involvement, motivation, and nonverbal communication. Communicating in Spanish, and awareness of diverse Hispanic/Latino backgrounds was critical, as using relevant and commonly-used terms can increase adherence and improve outcomes. Shared decision-making was encouraged to make realistic health care choices., Conclusion: Key elements discussed above provide a framework for future dissemination of an evidence-based DTM intervention to meet the needs of underserved Hispanic/Latino people living with T2D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Martinez, Nouryan, Williams, Patel, Barbero, Correa Gomez, Marino, Goris, Cigaran, Granville, Murray, Harris, Myers, Guzman, Makaryus, McFarlane, Zeltser, Pena, Sison, Lesser, Kline, DiClemente and Pekmezaris.)

Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptations remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA) in mice. Glutamatergic neurons in both regions displayed correlated responses to various stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BF → VTA circuit reduces appetite, increases locomotion, and elicits avoidance. Consistently, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of anxiety, all hallmarks of typical anorexia symptoms. Importantly, activation of BF glutamatergic terminals in the VTA reduced dopamine release in the nucleus accumbens. Collectively, our results point to overactivation of the glutamatergic BF → VTA circuit as a potential cause of anorexia-like phenotypes involving reduced dopamine release., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Diffuse large B-cell lymphoma comprises nearly 30% of non-Hodgkin lymphoma cases and patients with relapsed or refractory diffuse large B-cell lymphoma who are ineligible for stem-cell transplantation have few treatment options and poor prognoses. We aimed to determine whether the novel combination of polatuzumab vedotin in combination with rituximab and lenalidomide (Pola+R+Len) would provide a tolerable treatment option with enhanced antitumour response in patients with relapsed or refractory diffuse large B-cell lymphoma., Methods: This completed phase 1b/2, open-label, multicentre, single-arm study (GO29834) evaluated the safety and efficacy of Pola+R+Len in patients with relapsed or refractory diffuse large B-cell lymphoma at 19 sites in three countries (USA, Spain, and UK). Patients (≥18 years old) were eligible for inclusion if they had histologically documented CD20-positive relapsed or refractory diffuse large B-cell lymphoma and Eastern Cooperative Oncology Group performance status of 2 or lower, had received at least one previous line of chemoimmunotherapy, including an anti-CD20 agent, and were ineligible for stem-cell transplantation. The dose-escalation phase (1b) used escalating doses of lenalidomide to find the recommended phase 2 dose. Patients received six 28-day cycles of induction treatment with intravenous rituximab 375 mg/m 2 and intravenous polatuzumab vedotin 1·8 mg/kg (all cohorts) plus oral lenalidomide at the following doses: 10 mg (cohort A); 15 mg (cohort B); and 20 mg (cohort C). Rituximab and polatuzumab vedotin were administered on day 1 and lenalidomide on days 1-21 of each 28-day cycle. During the dose-expansion phase (2), patients received six 28-day cycles of Pola+R+Len at the recommended phase 2 dose established during dose escalation. In both phases, patients with a complete response or partial response at the end of induction were eligible for post-induction therapy with rituximab 375 mg/m 2 on day 1 and lenalidomide 10 mg/day on days 1-21 of each 28-day cycle for a maximum of 6 cycles. The primary safety objective of the dose-escalation phase was identification of the maximum tolerated dose through incidence of dose-limiting toxic effects. The primary efficacy outcome of the dose-expansion phase was Independent Review Committee-assessed complete response rate at end of induction, based on PET-CT. Analyses were conducted in the safety population, which included all patients who received at least one dose of any study drug, and the efficacy population, which included all patients who received at least one dose of any study drug at the recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02600897., Findings: Between July 11, 2017 and Feb 3, 2020, 57 patients were enrolled (median age 71 years [IQR 60-75]; 38 [67%] were male and 19 (33%) were female; 47 [82%] were not Hispanic or Latino; and the median previous lines of therapy was 2 [IQR 1-3]). 18 participants were included in phase 1b and 39 were included in phase 2. Phase 1b confirmed a 20 mg recommended phase 2 dose for lenalidomide. After a median follow-up of 11·8 months (IQR 4·7-25·8), the complete response rate, as assessed by the Independent Review Committee, was 31% (90% CI 20-43). The most common grade 3-4 adverse events were neutropenia (35 [61%] of 57) and thrombocytopenia (eight [14%] of 57). Serious adverse events were reported in 23 (40%) of 57 patients and one patient died due to a treatment-related adverse event (neutropenic sepsis)., Interpretation: Although the combination of Pola+R+Len did not meet the prespecified activity threshold, some patients derived clinical benefit and the regimen had a tolerable safety profile in patients with relapsed or refractory diffuse large B-cell lymphoma., Funding: Genentech/F Hoffmann-La Roche., Competing Interests: Declaration of interests PA has held consultancy for and received honoraria from Janssen, AstraZeneca, Bristol Myers Squibb, AbbVie, Genmab and F Hoffmann-La Roche; and has received honoraria from Gilead and Incyte and expenses for travel from AbbVie, Janssen, and F Hoffmann-La Roche. CP has received honoraria from Celgene/Bristol Myers Squibb, Novartis, F Hoffmann-La Roche, AbbVie, Janssen, and Gilead/Kite; received expenses for travel from F Hoffmann-La Roche, Gilead/Kite, and AbbVie; and participated on a Data Safety Monitoring Board or Advisory Board with F Hoffmann-La Roche, Incyte, and BeiGene. JMAP has received honoraria from F Hoffmann-La Roche, Janssen, AbbVie, AstraZeneca, and Amgen. AM has received honoraria for advisory boards from SOBI, Amgen, F Hoffmann-La Roche, and Takeda; received payment or honoraria for lectures, presentations, or speaker bureaus from F Hoffmann-La Roche and Takeda; received payment for expert testimony from Delphi Study: Prosthetics; and received support for attending meetings and/or travel from F Hoffmann-La Roche and Takeda. ES reports expenses for travel and attending meetings from Flatiron Health and BeiGene, and stock or stock options from F Hoffmann-La Roche and BeiGene; is an employee of BeiGene; and was an employee of Wayne State University/Karmanos Cancer institute from September, 2017 to February, 2021, and of Flatiron Health from February, 2021, to March, 2023. HYJ, JH, and LM are employees of Genentech and own F Hoffmann-La Roche stock options. JdG was an employee of Genentech at the time of this analysis. CD has held consultancy for Genentech/F Hoffmann-La Roche; and participated on a Data Safety Monitoring Board or Advisory Board with Genentech/F Hoffmann-La Roche and Celgene (BMS). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: Competing interests: Dr Shankar Prinja and Dr Sitanshu Sekhar Kar are Principal Investigators of HTAIn Regional Resource Centers.

Background: Urban areas in the US are increasingly focused on mass casualty incident (MCI) response. We simulated prehospital triage scenarios and hypothesized that using hospital-based blood product inventories for on-scene triage decisions would minimize time to treatment., Study Design: Discrete event simulations modeled MCI casualty injury and patient flow after a simulated blast event in Boston, MA. Casualties were divided into moderate (Injury Severity Score 9 to 15) and severe (Injury Severity Score >15) based on injury patterns. Blood product inventories were collected from all hospitals (n = 6). The primary endpoint was the proportion of casualties managed with 1:1:1 balanced resuscitation in a target timeframe (moderate, 3.5 U red blood cells in 6 hours; severe, 10 U red blood cells in 1 hour). Three triage scenarios were compared, including unimpeded casualty movement to proximate hospitals (Nearest), equal distribution among hospitals (Equal), and blood product inventory-based triage (Supply-Guided)., Results: Simulated MCIs generated a mean ± SD of 302 ± 7 casualties, including 57 ± 2 moderate and 15 ± 2 severe casualties. Nearest triage resulted in significantly fewer overall casualties treated in the target time (55% vs Equal 86% vs Supply-Guided 91%, p < 0.001). These differences were principally due to fewer moderate casualties treated, but there was no difference among strategies for severe casualties., Conclusions: In this simulation study comparing different triage strategies, including one based on actual blood product inventories, nearest hospital triage was inferior to equal distribution or a Supply-Guided strategy. Disaster response leaders in US urban areas should consider modeling different MCI scenarios and casualty numbers to determine optimal triage strategies for their area given hospital numbers and blood product availability., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

In the pursuit of universal health coverage, countries are invariably confronted with questions about which services to pay with public funds, to whom, and at what cost. Such priority-setting processes have major ramifications for the costs and benefits of care delivered. These processes are not just technical, but also highly political and organizational in nature and expressions of social values. This special issue focuses on building institutions for priority setting in health. These institutions serve a public purpose and are primarily concerned with conducting or using health technology assessment (HTA) to inform resource allocation decisions. We first define the concept of institutions for priority setting in health and the methodological considerations of assessing and evaluating these institutions. Next, we present key common themes and summarize key messages across the articles, including lessons learned and future challenges in building these institutions.

Countries pursuing universal health coverage must set priorities to determine which benefits to add to a national health program, but the roles that organizations play are less understood. This article investigates the case of the formation of an organization with a mandate for choice of technology for public health interventions and priorities, the Health Technology Assessment India. First, we narrate a chronology of agenda setting and adoption of national policy for organizational formation drawing on historical documentation, publicly available literature, and lived experiences from coauthors. Next, we conduct a thematic analysis that examines windows of opportunity, enabling factors, barriers and conditions, roles of stakeholders, messaging and framing, and specific administrative and bureaucratic tools that facilitated organization formation. This case study shows that organizational formation relied on the identification of multiple champions with sufficient seniority and political authority across a wide group of organizations, forming a coalition of broad base support, who were keen to advance health technology assessment policy development and organizational placement or formation. The champions in turn could use their roles for policy decisions that used private and public events to raise priority and commitment to the decisions, carefully considered organizational placement and formation, and developed the network of organizations for the generation of technical evidence and capacity building for health technology assessment, strengthened by international networks and organizations with financing, expertise, and policymaker relationships.

Health benefits packages in Colombia-what is covered, by whom, and at what cost-have evolved over the past thirty years. Coverage changed from two explicit health benefits packages (with benefits linked to ability to contribute) to an implicit approach that covers, in theory, everything for everyone, excluding a narrow negative list of services and health technologies. This article explores the evolution of priority setting in Colombia during two periods of major reform. Each period had its own advantages and disadvantages associated with different institutional arrangements, processes, and methodologies. Colombia's evolution provides several lessons for other low- and middle-income countries interested in institutionalizing evidence-based priority-setting.

All health systems must set priorities. Evidence-informed priority-setting (EIPS) is a specific form of systematic priority-setting which involves explicit consideration of evidence to determine the healthcare interventions to be provided. The international Decision Support Initiative (iDSI) was established in 2013 as a collaborative platform to catalyze faster progress on EIPS, particularly in low- and middle-income countries. This article summarizes the successes, challenges, and lessons learned from ten years of iDSI partnering with countries to develop EIPS institutions and processes. This is a thematic documentary analysis, structured by iDSI's theory of change, extracting successes, challenges, and lessons from three external evaluations and 19 internal reports to funders. We identified three phases of iDSI's work-inception (2013-15), scale-up (2016-2019), and focus on Africa (2019-2023). iDSI has established a global platform for coordinating EIPS, advanced the field, and supported regional networks in Asia and Africa. It has facilitated progress in securing high-level commitment to EIPS, strengthened EIPS institutions, and developed capacity for health technology assessments. This has resulted in improved decisions on service provision, procurement, and clinical care. Major lessons learned include the importance of sustained political will to develop EIPS; a clear EIPS mandate; inclusive governance structures appropriate to health financing context; politically sensitive and country-led support to EIPS, taking advantage of policy windows for EIPS reforms; regional networks for peer support and long-term sustainability; utilization of context appropriate methods such as adaptive HTA; and crucially, donor-funded global health initiatives supporting and integrating with national EIPS systems, not undermining them.

Co-transmission of multiple neurotransmitters from a single neuron increases the complexity of signaling information within defined neuronal circuits. Superficial short-axon cells in the olfactory bulb release both dopamine and γ-aminobutyric acid (GABA), yet the specific targets of these neurotransmitters and their respective roles in olfaction have remained unknown. Here, we implement intersectional genetics in mice to selectively block GABA or dopamine release from superficial short-axon cells to identify their distinct cellular targets, impact on circuit function, and behavioral contribution of each neurotransmitter toward olfactory behaviors. We provide functional and anatomical evidence for divergent superficial short-axon cell signaling onto downstream neurons to shape patterns of mitral cell firing that contribute to olfactory-related behaviors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties 1-3 . Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain., (© 2023. The Author(s).)

Introduction: Deep sternal wound infection (DSWI) is a rare complication associated with high mortality. Seasonal variability in surgical site infections has been demonstrated, however, these patterns have not been applied to DSWI. The purpose of this study was to assess temporal clustering of DSWIs., Methods: All cardiac surgery patients who underwent sternotomy were queried from a regional Society of Thoracic Surgeons database from 17 centers from 2001 to 2019. All patients with the diagnosis of DSWI were then identified. Cluster analysis was performed at varying time intervals (monthly, quarterly, and yearly) at the hospital and regional level. DSWI rates were calculated by year and month, and compared using mixed-effects negative binomial regression., Results: A total of 134,959 patients underwent a sternotomy for cardiac surgery, of whom 469 (0.35%) developed a DSWI. Rates of DSWI per hospital across all years ranged from 0.12% to 0.69%. Collaborative-level rates of DSWIs were the greatest in September (0.44%) and the lowest in January (0.30%). Temporal clustering was not seen across seasonal quarters (high rate in preceeding quarter was not associated with a high rate in the next quarter) (P = 0.39). There were yearly differences across all institutions in the DSWI rates. A downward trend in DSWI rates was seen from 2001 to 2019 (P < 0.001). A difference among hospitals in the cohort was observed (P < 0.001)., Conclusions: DSWI are a rare event within our region. Unlike other surgical site infection, there does not appear to be a seasonal pattern associated with DSWI., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Dietary nitrate (NO 3 - ) is a widely used supplement purported to provide beneficial effects during exercise. Most studies to date include predominantly males. Therefore, the present study aimed to investigate if there is a sex-dependent effect of NO 3 - supplementation on exercise outcomes. We hypothesized that both sexes would exhibit improvements in exercise economy and exercise capacity following NO 3 - supplementation, but males would benefit to a greater extent. In a double-blind, randomized, crossover study, twelve females (24 ± 4 yr) and fourteen males (23 ± 4 yr) completed two 4-min moderate-intensity (MOD) exercise bouts followed by a time-to-exhaustion (TTE) task after following 3 days of NO 3 - supplementation (beetroot juice or BRJ) or NO 3 - -depleted placebo (PL). Females were tested during the early follicular phase of the menstrual cycle. During MOD exercise, BRJ reduced the steady-state V̇o 2 by ∼5% in males (M: Δ -87 ± 115 mL·min -1 ; P < 0.05) but not in females (F: Δ 6 ± 195 mL·min -1 ). Similarly, BRJ extended TTE by ∼15% in males ( P < 0.05) but not in females. Dietary NO 3 - supplementation improved exercise economy during moderate-intensity exercise and exercise capacity during severe-intensity TTE in males but not in females. These differences could be related to estrogen levels, antioxidant capacity, nitrate-reducing bacteria, or a variety of known physiologic differences such as skeletal muscle calcium handling, and/or fiber type. Overall, our data suggests the ergogenic benefits of oral NO 3 - supplementation found in studies predominantly on male subjects may not be applicable to females. NEW & NOTEWORTHY While inorganic nitrate (NO 3 - ) supplementation has increased in popularity as an ergogenic aid to improve exercise performance, the role of sex in NO 3 - supplementation on exercise outcomes is lacking despite known physiological differences during exercise between sex. This study revealed that males, but not females, improved exercise economy during submaximal exercise and exercise capacity during exercise within the severe-intensity domain following NO 3 - supplementation.

Oral inorganic nitrate (NO 3 - ) supplementation has been shown to increase bioavailable NO and provide potential ergogenic benefits in males; however, data in females is scarce. Estrogen is known to increase endogenous NO bioavailability and to fluctuate throughout the menstrual cycle (MC), being lowest in the early follicular (EF) phase and highest during the late follicular (LF) phase. This study examined the effects of oral NO 3 - supplementation on exercise economy, endurance capacity, and vascular health in young females across the MC. Ten normally menstruating females' MCs were tested in a double-blinded, randomized design during both the EF and LF phases of the MC. Participants consumed ∼13 mmol NO 3 - , in the form of 140 mL beetroot juice (BRJ) or an identical NO 3 - -depleted placebo (PL) for ∼3 days before lab visits and 2 h before testing on lab visits. Plasma nitrate, nitrite, and estradiol were assessed, as was blood pressure and pulse wave velocity. Moderate-intensity exercise economy and severe intensity time to exhaustion (TTE) were tested on a cycle ergometer. As expected, plasma estradiol was elevated in the LF phase, and plasma nitrite and nitrate were elevated in the BRJ condition. Exercise economy was unaltered by BRJ or the MC, however TTE was significantly worsened by 48 s (∼10%) after BRJ supplementation ( P = 0.04), but was not different across the MC with no interaction effects. In conclusion, NO 3 - supplementation did not affect exercise economy or vascular health and worsened aerobic endurance capacity (TTE), suggesting healthy females should proceed with caution when considering supplementation with BRJ. NEW & NOTEWORTHY Although inorganic nitrate (NO 3 - ) supplementation has increased in popularity as a means of improving exercise performance, data in females at different phases of the menstrual cycle are lacking despite known interactions of estrogen with NO. This study revealed neither NO 3 - supplementation nor the menstrual cycle influenced exercise economy or vascular health in healthy young naturally menstruating females, while NO 3 - supplementation significantly worsened endurance capacity (10%) independent of the menstrual cycle phase.

Single-cell transcriptomic studies have identified a conserved set of neocortical cell types from small postmortem cohorts. We extended these efforts by assessing cell type variation across 75 adult individuals undergoing epilepsy and tumor surgeries. Nearly all nuclei map to one of 125 robust cell types identified in the middle temporal gyrus. However, we found interindividual variance in abundances and gene expression signatures, particularly in deep-layer glutamatergic neurons and microglia. A minority of donor variance is explainable by age, sex, ancestry, disease state, and cell state. Genomic variation was associated with expression of 150 to 250 genes for most cell types. This characterization of cellular variation provides a baseline for cell typing in health and disease.

Background: Telemonitoring (TM) plays an important role in the self-management of chronic diseases. This study aimed to assess the feasibility of TM in early stages of chronic care for self-management and recognition of signs and symptoms of exacerbation, with a view to completing the TM program in an optimal timeframe to encourage independence and self-management., Methods: This study was conducted from 2019 to 2020. Included in the study were patients with chronic conditions at an early stage of their disease residing in the South Western Sydney region. Eligible patients were allocated a TM device for 6months. Their routine tests data were sent in real time to health care professionals. Following assessment by a TM coordinator, suitable patients were off-boarded (deactivation of monitoring device) after 6months. Data on hospitalisation/emergency department presentation and surveys were collected to assess the impact of TM on the level of the patient's understanding of their signs and symptoms of exacerbation, self-care, and quality of life., Results: Out of 44 patients approached, seven were off-boarded at the 6-month timeframe. The follow-up data on the hospitalisation/emergency department presentation during monitoring and 12months post off-boarding showed a reduction in the frequency of hospitalisation/nil admissions. Patients reported an increased understanding of their health condition and confidence in managing their own health with the support of TM., Conclusion: The result demonstrates the feasibility of TM as a tool for health education and self-management in the coordination of care for chronic disease patients; however, the small sample size was a limitation.

cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways-the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway-affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications. However, whether MC1R genotype affects melanosomal pH is poorly understood. We now report that loss of function MC1R does not affect melanosomal pH. Thus, sAC signaling appears to be the only cAMP signaling pathway that regulates melanosomal pH. We also addressed whether MC1R genotype affects sAC-dependent regulation of melanin synthesis. Although sAC loss of function in wild-type human melanocytes stimulates melanin synthesis, sAC loss of function has no effect on melanin synthesis in MC1R nonfunctional human and mouse melanocytes or skin and hair melanin in e/e mice. Interestingly, activation of transmembrane adenylyl cyclases, which increases epidermal eumelanin synthesis in e/e mice, leads to enhanced production of eumelanin in sAC-knockout mice relative to that in sAC wild-type mice. Thus, MC1R- and sAC-dependent cAMP signaling pathways define distinct mechanisms that regulate melanosomal pH and pigmentation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Health technology assessment (HTA) is an established mechanism for explicit priority setting to support universal health coverage. However, full HTA requires significant time, data, and capacity for each intervention, which limits the number of decisions it can inform. Another approach systematically adapts full HTA methods by leveraging HTA evidence from other settings. We call this "adaptive" HTA (aHTA), although in settings where time is the main constraint, it is also called "rapid HTA.", Methods: The objectives of this scoping review were to identify and map existing aHTA methods, and to assess their triggers, strengths, and weaknesses. This was done by searching HTA agencies' and networks' websites, and the published literature. Findings have been narratively synthesized., Results: This review identified 20 countries and 1 HTA network with aHTA methods in the Americas, Europe, Africa, and South-East Asia. These methods have been characterized into 5 types: rapid reviews, rapid cost-effectiveness analyses, rapid manufacturer submissions, transfers, and de facto HTA. Three characteristics "trigger" the use of aHTA instead of full HTA: urgency, certainty, and low budget impact. Sometimes, an iterative approach to selecting methods guides whether to do aHTA or full HTA. aHTA was found to be faster and more efficient, useful for decision makers, and to reduce duplication. Nevertheless, there is limited standardization, transparency, and measurement of uncertainty., Conclusions: aHTA is used in many settings. It has potential to improve the efficiency of any priority-setting system, but needs to be better formalized to improve uptake, particularly for nascent HTA systems., (Copyright © 2023. Published by Elsevier Inc.)

Dormant bacterial cells do not divide and are not immediately culturable, but they persist in a state of low metabolic activity, a physiological state having clinical relevance, for instance in latent tuberculosis. Resuscitation-promoting factors (Rpfs) are proteins that act as signalling molecules mediating growth and replication. In this study we aimed to test the effect of Rpfs from Micrococcus luteus on the number and diversity of cultured bacteria using insect and soil samples, and to examine if the increase in culturability could be reproduced with the putative reaction product of Rpf, 1,6-anhydro- N -acetylmuramic acid (1,6-anhydro-MurNAc). The rpf gene from Micrococcus luteus was amplified and cloned into a pET21b expression vector and the protein was expressed in Escherichia coli BL21(DE3) cells and purified by affinity chromatography using a hexa-histidine tag. 1,6-Anhydro-MurNAc was prepared using reported chemical synthesis methods. Recombinant Rpf protein or 1,6-anhydro-MurNAc were added to R2A cultivation media, and their effect on the culturability of bacteria from eight environmental samples including four cockroach guts and four soils was examined. Colony-forming units, 16S rRNA gene copies and Illumina amplicon sequencing of the 16S rRNA gene were measured for all eight samples subjected to three different treatments: Rpf, 1,6-anhydro-MurNAc or blank control. Both Rpf and 1,6-anhydro-MurNAc increased the number of colony-forming units and of 16S rRNA gene copies across the samples although the protein was more effective. The Rpf and 1,6-anhydro-MurNAc promoted the cultivation of a diverse set of bacteria and in particular certain clades of the phyla Actinomycetota and Bacillota . This study opens the path for improved cultivation strategies aiming to isolate and study yet undescribed living bacterial organisms., Competing Interests: The authors have no conflicts of interest., (© 2023 The Authors.)

Background: To identify baseline predictors of persisting pain in children with Juvenile Idiopathic Arthritis (JIA), relative to patients with JIA who had similar baseline levels of pain but in whom the pain did not persist., Methods: We used data from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) inception cohort to compare cases of 'moderate persisting pain' with controls of 'moderate decreasing pain'. Moderate pain was defined as a Visual Analogue Scale (VAS) for pain measurement score of > 3.5 cm. Follow-up was minimum 3 years. Univariate and Multivariate logistic regression models ascertained baseline predictors of persisting pain., Results: A total of 31 cases and 118 controls were included. Mean pain scores at baseline were 6.4 (SD 1.6) for cases and 5.9 (1.5) for controls. A greater proportion of cases than controls were females (77.4% vs 65.0%) with rheumatoid factor positive polyarthritis (12.9% vs 4.2%) or undifferentiated JIA (22.6% vs 8.5%). Oligoarthritis was less frequent in cases than controls (9.7% vs 33%). At baseline, cases had more active joints (mean of 11.4 vs 7.7) and more sites of enthesitis (4.6 vs 0.7) than controls. In the final multivariate regression model, enthesitis count at baseline (OR 1.40, CI 95% 1.19-1.76), female sex (4.14, 1.33-16.83), and the overall Quality of My Life (QoML) baseline score (0.82, 0.69-0.98) predicted development of persisting pain., Conclusions: Among newly diagnosed children with JIA with moderate pain, female sex, lower overall quality of life, and higher enthesitis counts at baseline predicted development of persisting pain. If our findings are confirmed, patients with these characteristics may be candidates for interventions to prevent development of chronic pain., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Hispanic women have the highest rates of incident cervical cancer in the United States (U.S.) and are 1.9 times more likely to die from cervical cancer than non-Hispanic Whites. Objective: Assess the impact of text message reminders on cervical cancer screening attendance and completion. Design: Pragmatic non-randomized study design using propensity matched analysis. Setting: Community-dwelling low-income females in the U.S./Mexico border community. A total of 2,255 mainly Hispanic females aged 21-65. Methods: Text message reminders in addition to usual care (telephone call reminders). Results: After adjusting for significant factors and propensity score matching, individuals in the text reminder group had 11% lower screening incidence than individuals without text reminders (risk difference [RD] = -0.11, 95% CI : -0.16, -0.05; p  < .001). Conclusion: Participants with text reminders were less likely to complete cervical screening than usual practice in a predominantly Hispanic population. Our study demonstrates that reminders' content rather than method may be vital to improving our population's cancer screening rates.

Background: A glomus vagale tumor is an infrequent paraganglioma primarily characterized by auditory symptoms, cranial nerve involvement, or autonomic symptoms. However, visual involvement is not commonly observed, and to date, no cases have been reported in the literature., Observations: The case involves a 62-year-old female patient with a history of right carotid body tumor resection. She presented to the emergency department with a sudden decrease in visual acuity and bitemporal hemianopsia, accompanied by a left parietal headache. Initial brain magnetic resonance imaging (MRI) revealed a pituitary macroadenoma, which was completely resected. However, postoperatively, the patient developed left amaurosis. Subsequent brain MRI showed the presence of hemostatic material mixed with blood in the sellar region, causing displacement of the optic chiasm. A repeat intervention was performed, identifying bleeding from both cavernous sinuses. Head and neck angiography demonstrated a right glomus vagale tumor with abundant blood drainage into the right cavernous sinus. Embolization of the glomus vagale tumor was performed, resulting in no further bleeding and improvement of symptoms., Lessons: The aim of this case report is to describe a rare occurrence of bilateral visual disturbances caused by bleeding in both cavernous sinuses due to venous hypertension caused by a right glomus vagale tumor.

Background and Objectives : During the COVID-19, the demand for non-invasive ventilatory support equipment significantly increased. In response, a novel non-invasive ventilatory support model called CPAP-AirFlife™ was developed utilizing existing technologies. This model offers technological advantages, including an aerosol-controlled helmet suitable for high-risk environments such as ambulances. Additionally, it is cost-effective and does not require medical air, making it accessible for implementation in low-level hospitals, particularly in rural areas. This study aimed to assess the efficacy of CPAP-AirFlife™ by conducting a non-inferiority comparison with conventional ventilation equipment used in the Intensive Care Unit. Materials and Methods : A clinical study was conducted on normal subjects in a randomized and sequential manner. Parameters such as hemoglobin oxygen saturation by pulse oximetry, exhaled PCO 2 levels, vital signs, and individual tolerance were compared between the CPAP-AirFlife™ and conventional equipment. The study population was described in terms of demographic characteristics and included in the analysis. Results : It was shown that the CPAP-AirFlife™ was not inferior to conventional equipment in terms of efficacy or tolerability. Hemoglobin oxygen saturation levels, exhaled PCO 2 levels, vital signs, and individual tolerance did not significantly differ between the two models. Conclusions : The findings suggest that CPAP-AirFlife™ is a practical and cost-effective alternative for non-invasive ventilatory support. Its technological advantages, including the aerosol-controlled helmet, make it suitable for high-risk environments. The device's accessibility and affordability make it a promising solution for implementation in low-level hospitals, particularly in rural areas. This study supports using CPAP-AirFlife™ as a practical option for non-invasive ventilatory support, providing a valuable contribution to respiratory care during the COVID-19 pandemic and beyond.

In addition to their role in promoting feeding and obesity development, hypothalamic arcuate agouti-related protein/neuropeptide Y (AgRP/NPY) neurons are widely perceived to be indispensable for maintaining normal feeding and body weight in adults, and consistently, acute inhibition of AgRP neurons is known to reduce short-term food intake. Here, we adopted complementary methods to achieve nearly complete ablation of arcuate AgRP/NPY neurons in adult mice and report that lesioning arcuate AgRP/NPY neurons in adult mice causes no apparent alterations in ad libitum feeding or body weight. Consistent with previous studies, loss of AgRP/NPY neurons blunts fasting refeeding. Thus, our studies show that AgRP/NPY neurons are not required for maintaining ad libitum feeding or body weight homeostasis in adult mice., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals., (© 2023. The Author(s).)

Introduction: Medical clearance for patients with primary psychiatric complaints presenting to the emergency department has been debated for decades. Emergency physicians have argued that clearance labs are unnecessary, yet psychiatrists may still order or require them. A retrospective review was conducted to evaluate the continued need for labs of psychiatric patients and help identify high risk groups that may need additional intervention prior to medical clearance., Methods: Charts of 163 patients from Ochsner LSU Shreveport Psychiatric Crisis Unit (PCU) were reviewed with data collected of history, physical examination, review of systems, vitals and routine lab work including complete blood count (CBC), comprehensive metabolic panel (CMP), urine drug screen (UDS), serum ethanol level (EtOH), urinalysis (UA), creatine kinase (CK), urine pregnancy test (UPT), and rapid COVID-19., Results: Review identified 82 patients (50.3%) that received interventions prior to medical clearance. Most common intervention was intravenous (IV) fluids ( n = 59; 45%) followed by admission to other service ( n = 15; 8.4%), imaging ( n = 10; 7.6%), antihypertensive medication ( n = 3; 3.1%), cardiac workup ( n = 3; 2.3%), antibiotics ( n = 3; 2.3%), lorazepam for undocumented reasons ( n = 2; 1.5%). Additional interventions completed once included immunizations, antiseizure medication, pain medication, and additional lab work. Causes for IV fluids were reviewed with elevated creatine kinase (CK) ( n = 31; 50.8%) being most common. Additional causes included undocumented ( n = 12; 19.7%), tachycardia ( n = 6; 9.8%), elevated EtOH level ( n = 3; 4.9%), dehydration ( n = 2; 3.3%), acute kidney injury (AKI) ( n = 2; 3.3%), leukocytosis following a seizure ( n = 1; 1.6%), elevated CK and leukocytosis ( n = 1; 1.6%), and AKI and elevated CK ( n = 1; 1.6%). Most common cause for medical admission was elevated CK being cited in 8 out of 15 admissions (53.3%). Additional causes for admission included AKI ( n = 2; 14.3%), seizures and leukocytosis ( n = 1; 6.7%), rule out of acute coronary syndrome (ACS) ( n = 1; 6.7%), alcohol withdrawal ( n = 1; 6.7%), encephalopathy with drop in hemoglobin and white blood cell count ( n = 1; 6.7%), and encephalopathy with elevated CK ( n = 1; 6.7%)., Discussion: Our results support the recommended guidelines set by AAEP for laboratory testing in addition to history, vital signs and physical examination prior to medical clearance. Certain laboratory testing such as CK and CMP were identified to have higher utility for medical intervention while other lab work such as UA and UDS had less of an impact. Further, we suggest that specifically a CK and CMP be obtained on patients presenting with any of the following: agitation, abnormal vital signs, intoxication, or a history of or current stimulant use as these were factors correlated with lab abnormalities that led to interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Casey, Guzman, Salard, Wu, Rieger, Mangham and Patterson.)