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Alexander Keenan,1 Hoa H Le,1 Kavita Gandhi,2 Lola Adedokun,3 Eddie Jones,4 Mia Unsworth,4 James Pike,5 Emily Trenholm4 1Scientific Affairs, Janssen Pharmaceuticals Inc., Titusville, NJ, USA; 2Research and Development, Janssen Pharmaceuticals Inc., Titusville, NJ, USA; 3Research and Development, Janssen-Cilag Ltd, High Wycombe, UK; 4Central Nervous System, Adelphi Real World, Bollington, Cheshire, UK; 5Statistics & Data Analytics, Adelphi Real World, Bollington, Cheshire, UKCorrespondence: Mia Unsworth, Adelphi Real World, Adelphi Mill, Grimshaw Lane, Macclesfield, Bollington, Cheshire, SK10 5JB, United Kingdom, Tel +441625578677, Email mia.unsworth@adelphigroup.comIntroduction: Multiple sclerosis (MS) is a neurodegenerative disease characterized by progressive deterioration of cognitive and physical functioning, reducing activities of daily living and quality of life (QoL). Several treatments are available that modify the course of the disease and reduce the frequency of relapses. Although effective, all treatment options are accompanied by adverse events, and this study aimed to assess the extent to which patients were involved in the choice of treatment.Methods: Data were drawn from the Adelphi Multiple Sclerosis Disease Specific Program (DSP)™, a cross-sectional survey of healthcare practitioners (HCP) and their patients with MS in real-world clinical settings in Europe and the United States (US) between December 2020 and July 2021. HCPs reported patient demographics, clinical characteristics, current and previous treatment, and treatment outcomes. Patients voluntarily completed questionnaires reporting the physical and psychological impact of their MS and its treatment. Regression analysis with inverse probability of treatment weighting was used to compare treatment outcomes in patients actively involved in their current treatment choice with those who were not.Results: Of a total of 692 patients, median age 40 years and 64% female, mostly diagnosed with relapsing-remitting MS, those who were involved in shared decision-making tended to choose oral therapies such as dimethyl fumarate more often than HCPs. MS had greater impact on physical and psychological functioning in patients whose HCP made treatment decisions solely. Patients involved in decision-making reported greater satisfaction with their treatment and a better QoL.Discussion: Because no single optimal therapy exists for patients with MS, treatments should be individualized with consideration of patients’ preferences. Our study shows that shared decision-making is under-utilized in the management of MS and supports the benefits of patient involvement.Conclusion: Patients who have an active role in treatment decision-making show improved wellbeing and QoL, and overall treatment satisfaction.Plain Language Summary: Multiple sclerosis (MS) is a disease that affects the brain, causing symptoms such as blurred vision and problems with movements, thoughts, and feelings. MS is a lifelong condition that becomes worse over time and limits the activities that people can do. There are many treatments that can help to reduce relapses (when symptoms become worse), but all have their benefits and drawbacks. It is often the physician who decides which treatment to use, but we wanted to know if patients would feel better if they were involved in the decision.Using our standardized and validated questionnaires, we surveyed physicians and nurses who treat patients with MS in Europe and the United States of America between December 2020 and July 2021, to assess how they felt about the treatment they chose and its effect on the patient. We also asked the patients themselves how they felt about their illness and treatment, whether they were given the chance to choose which treatment to take, and how their treatment affected their symptoms and overall quality of life.The information provided by both the physicians and their patients was used to compare how patients responded when they were involved in the treatment decisions. We found that patients who were involved in choosing their treatment were more satisfied with their treatment and responded better than those whose physicians decided alone. Therefore, it is important for physicians treating patients with MS to consider their patients’ preferences when deciding which treatment is best for them.Keywords: multiple sclerosis, patient preference, decision-making, shared, multinational, survey

CYP24A1 is a multifunctional, P450 mitochondrial enzyme that catabolizes the vitamin D hormone (calcitriol, 1,25(OH)2D3), its precursor (calcifediol, 25(OH)D3), and numerous vitamin D metabolites. In the kidney, Cyp24a1 is induced by 1,25(OH)2D3 and fibroblast growth factor 23 (FGF23) and potently suppressed by PTH to control the circulating levels of 1,25(OH)2D3. Cyp24a1 is controlled by a pair of promoter proximal (PRO) vitamin D response elements (VDREs) that are aided by distal, downstream (DS) enhancers. The downstream 1 region of Cyp24a1 (DS1) enhancer is kidney-specific and responsible for PTH and FGF23 actions, and the downstream 2 region of Cyp24a1 enhancer responds to 1,25(OH)2D3 in all tissues. Despite this knowledge, in vivo contributions of the PRO VDREs to basal expression, FGF23 activation, and PTH suppression of Cyp24a1 remain unknown. In this study, we selectively mutated the PRO VDREs in the mouse to address these questions. We found mutation of the VDREs leads to a dramatic loss of VDR occupancy, a reduction of 1,25(OH)D3-induced kidney Cyp24a1 expression, and near elimination of intestinal Cyp24a1 induction. FGF23 induction of Cyp24a1 was reduced but not eliminated and still showed a synergistic increase with 1,25(OH)2D3. PTH suppression of Cyp24a1 was unchanged, despite minor reductions in total for phosphorylated cAMP-response element binding protein occupancy. Finally, VDR recruitment was dramatically reduced across the DS enhancers in the Cyp24a1 locus. Taken together, our data suggest a cooperative relationship between the DS and PRO enhancers in the regulation of Cyp24a1 by 1,25(OH)2D3 and FGF23 and points to the DS1 region as a crucial basal switch for Cyp24a1 activity that further defines the interconnected genomic control in vitamin D catabolism. [ABSTRACT FROM AUTHOR]

Epidemiological and observational studies suggest that vitamin D has potential for the chemoprevention of ovarian cancer. The anticancer effect of vitamin D in the fallopian tube epithelium (FTE), which is now thought to harbor the precursor cells for high grade ovarian cancer, is not known. The purpose of this study was to investigate whether vitamin D can inhibit carcinogenesis in the mogp-TAg fallopian tube (FT) ovarian cancer mouse model and examine underlying mechanisms. To test this hypothesis, 3 groups of 40 5-week-old female mogp-TAg mice were divided equally into two cohorts of 20 mice, treated with either vehicle (vitamin D solvent) or the active 1,25(OH)2D3 analogue EB1089, delivered via mini-pump or IP injection or cholecalciferol delivered in the feed. The FTs were characterized histologically and pathologically after 3 and 7 weeks of treatment. The effect of vitamin D on cultured human FTE cells was also examined. After 3 weeks, vitamin D, delivered as either cholecalciferol or EB1089 significantly inhibited FT carcinogenesis. After 7 weeks, cholecalciferol significantly reduced p53 signatures, serous tubal epithelial carcinoma, FT cancer, and plasma CA125 while increasing apoptosis in the FTE. EB1089 had no significant effect on FT carcinogenesis at 7 weeks. Cholecalciferol significantly reduced proliferation and increased apoptosis in vitro in p53-altered FTE cells. In conclusion, vitamin D inhibited FT carcinogenesis by clearing cells with p53 alterations. These data suggest that vitamin D has merit for the chemoprevention of fallopian tube/ovarian cancer. The optimal chemopreventive effect may be dependent on the route of vitamin D administration [ABSTRACT FROM AUTHOR]

The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell-derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25- vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor-inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease-mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD., Introduction Vitamin D plays a critical role in bone and mineral metabolism and also controls other physiologic and pathophysiologic processes, including skeletal muscle function, reproductive health, cancer risk and progression, [...]

Background and Objectives: Respiratory syncytial virus (RSV) causes substantial hospitalization in US infants. The Advisory Committee on Immunization Practices recommended nirsevimab in infants younger than 8 months born during or entering their first RSV season and for children aged 8 to 19 months at increased risk of RSV hospitalization in their second season. This study's objective was to evaluate the cost-effectiveness of nirsevimab in all infants in their first RSV season and in high-risk children in their second season., Methods: We simulated healthcare utilization and deaths from RSV with and without nirsevimab among infants aged 0 to 7 months and those 8 to 19 months old over a single RSV season. Data came from published literature, US Food and Drug Administration approval documents, and epidemiologic surveillance data. We evaluated societal outcomes over a lifetime discounting at 3% and reporting in 2022 US dollars. Sensitivity and scenario analyses identified influential variables., Results: We estimated that 107 253 outpatient visits, 38 204 emergency department visits, and 14 341 hospitalizations could be averted each year if half of the US birth cohort receives nirsevimab. This would cost $153 517 per quality-adjusted life year (QALY) saved. Nirsevimab in the second season for children facing a 10-fold higher risk of hospitalization would cost $308 468 per QALY saved. Sensitivity analyses showed RSV hospitalization costs, nirsevimab cost, and QALYs lost from RSV disease were the most influential parameters with cost-effectiveness ratios between cost-saving and $323 788 per QALY saved., Conclusions: Nirsevimab for infants may be cost-effective, particularly among those with higher risks and costs of RSV., (Copyright © 2024 by the American Academy of Pediatrics.)

Background and Objectives: Respiratory syncytial virus (RSV) commonly causes hospitalization among US infants. A maternal vaccine preventing RSV in infants, RSV bivalent prefusion F maternal vaccine (RSVpreF), was approved by the US Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices. Our objective was to evaluate the health benefits and cost-effectiveness of vaccinating pregnant persons in the United States using RSVpreF., Methods: We simulated RSV infection and disease with and without seasonal RSVpreF vaccination in half of the pregnant persons in the annual US birth cohort during weeks 32 through 36 of gestation. Model inputs came from peer-reviewed literature, Food and Drug Administration records, and epidemiological surveillance databases. The results are reported using a societal perspective in 2022 US dollars for a 1-year time frame, discounting future health outcomes and costs at 3%. Sensitivity and scenario analyses were performed., Results: Year-round maternal vaccination with RSVpreF would prevent 45 693 outpatient visits, 15 866 ED visits, and 7571 hospitalizations among infants each year. Vaccination had a societal incremental cost of $396 280 per quality-adjusted life-year (QALY) saved. Vaccination from September through January cost $163 513 per QALY saved. The most influential inputs were QALYs lost from RSV disease, the cost of the vaccine, and RSV-associated hospitalization costs; changes in these inputs yielded outcomes ranging from cost-saving to $800 000 per QALY saved., Conclusions: Seasonal maternal RSV vaccination designed to prevent RSV lower respiratory tract infection in infants may be cost-effective, particularly if administered to pregnant persons immediately before or at the beginning of the RSV season., (Copyright © 2024 by the American Academy of Pediatrics.)

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults. In May 2023, two subunit RSV vaccines (Arexvy [GSK] and Abrysvo [Pfizer]) received approval from the U.S. Food and Drug Administration (FDA). In June 2023, ACIP recommended that adults aged ≥60 years may receive a single dose of RSV vaccine, using shared clinical decision-making. In support of development of this policy, our objective was to assess the cost-effectiveness of RSV vaccination in the general population in this age group. We used a decision-analytical model of RSV over a two-year timeframe using data from published literature, FDA documents, epidemiological databases, and manufacturer data. We tracked RSV-associated outpatient, emergency department, inpatient healthcare utilization, RSV-attributable deaths, quality-adjusted life-years lost (QALYs), and societal costs. The societal cost per QALY saved from RSV vaccination depended on age group and product: adults aged ≥60 years, $196,842 for GSK's vaccine and $176,557 for Pfizer's vaccine; adults ≥65 years, $162,138 for GSK and $146,543 for Pfizer; adults 60- <65 years, $385,829 for GSK and $331,486 for Pfizer. Vaccine efficacy, incidence of RSV hospitalization, and vaccine cost had the greatest influence on cost per QALY. Cost per QALY saved decreased as the age of those vaccinated increased. Inputs such as long-term efficacy are uncertain. RSV vaccination in adults aged ≥60 years may be cost-effective, particularly in those of more advanced age. Lower vaccine acquisition costs and persistent efficacy beyond two RSV seasons would render RSV vaccination more cost-effective for a broader target population. PRIMARY FUNDING SOURCE: US Centers for Disease Control and Prevention., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: David W. Hutton, Lisa A. Prosser, Angela M. Rose, and Kerra Mercon report financial support was provided by Centers for Disease Control and Prevention. If there are other authors, they 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 Elsevier Ltd. All rights reserved.)

This study aimed to quantify U.S. jurisdiction-level costs related to the COVID-19 Vaccination Program by estimating the per-dose-administered cost during December 20, 2020-May 31, 2021, from a combined federal and local government perspective. Costs were limited to vaccine purchase, administration (including operations and wastage), and local redistribution by jurisdictions. Data were collected through publicly available sources, published literature, and a survey of 62 jurisdictions (38 responded). A total of 284.6 million doses of COVID-19 vaccine were distributed to jurisdictions during the study period, of which 284.2 million doses were administered, and 0.4 million doses were wasted. The estimated cost per-dose-administered among the 38 jurisdictions that responded to study survey was $57.45 and imputed cost across all jurisdictions was $63.11. The findings on jurisdiction-level cost per-dose-administered and vaccination cost during the initial period of U.S. COVID-19 Vaccination Program, when demand exceeded supply, may be considered in future pandemic preparedness planning., 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 Ltd.)

This study presents the first genome and transcriptome analyses for Fusarium oxysporum f. sp. lactucae (Fola) which causes Fusarium wilt disease of lettuce. Long-read genome sequencing of three race 1 (Fola1) and three race 4 (Fola4) isolates revealed key differences in putative effector complement between races and with other F. oxysporum ff. spp. following mimp -based bioinformatic analyses. Notably, homologues of Secreted in Xylem ( SIX ) genes, also present in many other F. oxysporum ff. spp, were identified in Fola, with both SIX9 and SIX14 (multiple copies with sequence variants) present in both Fola1 and Fola4. All Fola4 isolates also contained an additional single copy of SIX8 . RNAseq of lettuce following infection with Fola1 and Fola4 isolates identified highly expressed effectors, some of which were homologues of those reported in other F. oxysporum ff. spp. including several in F. oxysporum f. sp. apii . Although SIX8 , SIX9 and SIX14 were all highly expressed in Fola4, of the two SIX genes present in Fola1, only SIX9 was expressed as further analysis revealed that SIX14 gene copies were disrupted by insertion of a transposable element. Two variants of Fola4 were also identified based on different genome and effector-based analyses. This included two different SIX8 sequence variants which were divergently transcribed from a shared promoter with either PSE1 or PSL1 respectively. In addition, there was evidence of two independent instances of HCT in the different Fola4 variants. The involvement of helitrons in Fola genome rearrangement and gene expression is discussed., 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 Bates, Pike, Price, Jenkins, Connell, Legg, Armitage, Harrison and Clarkson.)

Introduction: Early recognition and prompt, appropriate management may reduce mortality in patients with sepsis. The Surviving Sepsis Campaign's guidelines suggest the use of dynamic measurements to guide fluid resuscitation in sepsis; although these methods are rarely employed to monitor cardiac output in response to fluid administration outside intensive care units. This service evaluation investigated the introduction of a nurse led protocolised goal-directed fluid management using a non-invasive cardiac output monitor to the standard assessment of hypotensive ward patients., Methods: We introduced the use of a goal-directed fluid management protocol into our critical care outreach teams' standard clinical assessment. Forty-nine sequential patients before and thirty-nine after its introduction were included in the assessment., Results: Patients in the post-intervention cohort received less fluid in the 6 h following outreach assessment (750mls vs 1200mls). There were no differences in clinical background or rates of renal replacement therapy, but rates of invasive and non-invasive ventilation were reduced (0% vs 31%). Although the groups were similar, the post-intervention patients had lower recorded blood pressures., Conclusion: IV fluid therapy in the patient with hypotension complicating sepsis can be challenging. Excessive IV fluid administration is commonplace and associated with harm, and the use of advanced non-invasive haemodynamic monitoring by trained nurses can provide objective evaluation of individualised response to treatment. Avoiding excessive IV fluid and earlier institution of appropriate vasopressor therapy may improve patient outcomes., Implications for Clinical Practice: Adoption of dynamic measures of cardiac output outside of critical care by trained critical care nurses is feasible and may translate into improved patient outcomes. In hospitals with a nurse-led critical care outreach service, consideration should be given to such an approach., 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 Ltd.)

CYP24A1 is a multifunctional, P450 mitochondrial 24-hydroxylase enzyme that is responsible for catabolism of the most active vitamin D hormone (calcitriol, 1,25(OH) 2 D 3 ), its precursor (calcifediol, 25(OH)D 3 ), and numerous other vitamin D metabolites at the 23- and 24-carbon positions. In the kidney, Cyp24a1 is induced by 1,25(OH) 2 D 3 , induced by FGF23, and potently suppressed by PTH to tightly control the circulating blood levels of 1,25(OH) 2 D 3 . This gene is believed to be under the control of a pair of classic promoter proximal (PRO) vitamin D response elements (VDREs) that are aided by distal, downstream (DS) containing enhancers that we identified more recently. The DS1 enhancer cluster was found to respond to PTH and FGF23 actions in a kidney-specific manner. The DS2 enhancer cluster was found to assist in the response of 1,25(OH) 2 D 3 in kidney, as well as other target tissues. Despite this knowledge, the in vivo contribution of the PRO VDREs to gene expression, what drives Cyp24a1 basal expression in the kidney, how FGF23 activates Cyp24a1 , and importantly, how PTH suppresses Cyp24a1 , all remain unknown. Here in this study, we utilize homology directed CRISPR to mutate one or both VDREs in the PRO region of the Cyp24a1 gene in vivo in the mouse to address these questions. We found that the VDRE (VDRE1) more proximal to the to the transcriptional start site (TSS) is the dominant VDRE of the pair and mutation of both VDREs leads to a dramatic loss of VDR, a reduction of Cyp24a1 gene expression in the kidney, and a near elimination of 1,25(OH) 2 D 3 induction in the intestine. FGF23 induction of Cyp24a1 was reduced with mutation of the PRO VDREs, however, co-treatment of 1,25(OH) 2 D 3 and FGF23 synergistically increased Cyp24a1 expression even with the loss of the PRO VDREs. PTH suppression of Cyp24a1 gene expression was unchanged with PRO VDRE mutations, despite a minor reduction in total pCREB occupancy. Finally, VDR occupancy was dramatically reduced across the DS enhancers in the Cyp24a1 locus after the PRO VDREs mutation. Taken together, our data suggest a cooperative relationship between the DS and PRO enhancers in the regulation of Cyp24a1 by 1,25(OH) 2 D 3 and FGF23, and despite the overall reduction of CREB on the genome it appeared that suppression either does not rely on CREB or that the PRO VDREs are unconnected to PTH suppression altogether. These studies point to the DS1 region as a basal switch for Cyp24a1 expression and help further define the interconnected genomic control of these hormones on vitamin D catabolism., Competing Interests: Conflict of interest: The authors declare no conflicts of interest with the contents of this article.

Multiple sclerosis (MS) is uncommon in China and the standard of care is underdeveloped, with limited utilization of disease-modifying treatment (DMT). An understanding of real-world disease burden (including direct medical, non-medical, and indirect costs, such as loss of productivity), is currently lacking in this population. To investigate the overall burden of managing patients with MS in China, a cross-sectional survey of physicians and their consulting patients with MS was conducted in 2021. Physicians provided information on healthcare resource utilization (HCRU; consultations, hospitalizations, tests, medication) and associated costs. Patients provided data on changes in their life, productivity, and impairment of daily activities due to MS. Results were stratified by disease severity using generalized linear models, with a p value < 0.05 considered statistically significant. Patients with more severe disease had greater HCRU, including hospitalizations, consultations and tests/scans, and incurred higher direct and indirect costs and productivity loss, compared with those with milder disease. However, the use of DMT was higher in patients with mild disease severity. With the low uptake and limited efficacy of non-DMT drugs, Chinese patients with MS experience a high disease burden and significant unmet needs. Therapeutic interventions could help save downstream costs and lessen societal burden., (© 2024. The Author(s).)

The immune benefits of vitamin D3 supplementation beyond calcium and phosphate maintenance are highly clinically debated. Kidney expression of CYP27B1 is the source of endocrine, circulating 1,25(OH)2D3 (active form of vitamin D) that maintains serum calcium and phosphate. 1,25(OH)2D3 may also be made by the CYP27B1 enzyme in nonrenal cells, like immune cells, in a process driven by cellular availability of 25(OH)D3 and inflammation. Due to the endocrine nature of 1,25(OH)2D3 in circulation, it is difficult to discern between these 2 sources. We recently created a regulatory deletion model of Cyp27b1 (M1/M21-DIKO) where mice have normal inflammatory-regulated Cyp27b1 expression in nonrenal tissues (unlike global Cyp27b1-KO) but no expression within the kidney. Here, utilizing on-tissue chemical derivatization and matrix assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI), we investigated the distribution of 1,25(OH)2D3 and 25(OH)D3 in the kidney, liver, spleen, and thymus. MALDI-MSI demonstrated increased 1,25(OH)2D3 in nonrenal tissues such as the spleen after vitamin D3 supplementation in M1/M21-DIKO mice. Additionally, from this, we found increased Il4 and decreased Tnfa in the spleen after vitamin D3 supplementation. Taken together, these data demonstrate nonrenal production of 1,25(OH)2D3 in vivo and provide a consequence of vitamin D3 supplementation and nonrenal 1,25(OH)2D3 production in cytokine changes.

Background: Limited real-world data exists on clinical outcomes in systemic lupus erythematosus (SLE) patients by SLE Disease Activity Index 2000 (SLEDAI-2 K), hereafter, SLEDAI. We aimed to examine the association between SLEDAI score and clinical, patient-reported and economic outcomes in patients with SLE., Methods: Rheumatologists from the United States of America and Europe provided real-world demographic, clinical, and healthcare resource utilization (HCRU) data for SLE patients. Patients provided self-reported outcome data, capturing their general health status using the EuroQol 5-dimension 3-level questionnaire (EQ-5D-3 L), health-related quality of life using the Functional Assessment of Chronic Illness Therapy (FACIT) and work productivity using the Work Productivity and Activity Impairment questionnaire (WPAI). Low disease activity was defined as SLEDAI score ≤ 4 and ≤ 7.5 mg/day glucocorticoids; patients not meeting these criteria were considered to have "higher" active disease. Data were compared between patients with low and higher disease activity. Logistic regression estimated a propensity score for SLE based on demographic and clinical characteristics. Propensity score matched analyses compared HCRU, patient-reported outcomes, income loss and treatment satisfaction in patients with low disease activity versus higher active disease., Results: Data from 296 physicians reporting on 730 patients (46 low disease activity, 684 higher active disease), and from 377 patients' self-reported questionnaires (24 low disease activity, 353 higher active disease) were analyzed. Flaring in the previous 12 months was 2.6-fold more common among patients with higher versus low active disease. Equation 5D-3 L utility index was 0.79 and 0.88 and FACIT-Fatigue scores were 34.78 and 39.79 in low versus higher active disease patients, respectively, indicating better health and less fatigue, among patients with low versus higher active disease. Absenteeism, presenteeism, overall work impairment, and total activity impairment were 47.0-, 2.0-, 2.6- and 1.5-fold greater in patients with higher versus low disease activity. In the previous 12 months there were 28% more healthcare consultations and 3.4-fold more patients hospitalized in patients with higher versus low disease activity., Conclusion: Compared to SLE patients with higher active disease, patients with low disease activity experienced better health status, lower HCRU, less fatigue, and lower work productivity impairment, with work absenteeism being substantially lower in these patients., (© 2024. The Author(s).)

In 1994, the World Health Organization Region of the Americas was declared polio-free. In July 2022, a confirmed case of paralytic polio in an unvaccinated adult resident of Rockland County, New York was reported by the New York State Department of Health (NYSDOH) and Rockland County Department of Health (RCDOH). While only one case was identified, a single case of paralytic polio represents a public health emergency in the United States. The patient's county of residence was identified to have low vaccination coverage indicating that the community was at risk for additional cases. Disease outbreaks are resource-intensive and incur high costs to the patient, local health departments, and to society. These costs are potentially avoidable for vaccine-preventable diseases and thus, highlight the urgency to not only interrupt transmission but to prevent future vaccine-preventable disease outbreaks by improving vaccination coverage. Following case confirmation, an investigation and response was initiated by NYSDOH, along with local health departments and the Centers for Disease Control and Prevention (CDC). After the initial investigation and response, collaborative efforts to mitigate risk and strengthen routine immunization continued, which included provider outreach and immunization record assessments of Head Start and licensed childcare facilities (primarily those with missing or incomplete required vaccination coverage reports from the previous year) in Rockland County. We estimated the costs of (1) provider outreach and (2) childcare and pre-kindergarten immunization record assessments of select licensed childcare and Head Start facilities in Rockland County. The total labor cost incurred for these activities was $138,514 with a total of 2,555 h incurred. Often there are unique opportunities in the midst of an outbreak for public health to implement activities to proactively address low vaccination and strengthen vaccination coverage and possibly prevent future outbreaks. Understanding the cost of these activities might help inform future outbreak planning., 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., (Published by Elsevier Ltd.)

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's "no presumption of advantage" principle disregards this reality. Studies show that transgender women (male-born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of "meaningful competition" is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case-by-case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision-making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Introduction: Part of the difficulty in recruiting and retaining a diverse physician workforce, as well as within medical leadership, is due to racial disparities in medical education. We investigated whether self-identified race-ethnicity is associated with the likelihood of selection as chief resident (CR)., Materials and Methods: We performed a cross sectional analysis using de-identified person-level data from the GME Track, a national resident database and tracking system, from 2015 through 2018. The exposure variable, self-identified race-ethnicity, was categorized as African American or Black, American Indian or Alaskan Native, Asian, Hispanic, Latino or of Spanish Origin, Native Hawaiian or Pacific Islander, White, and Multi-racial. The primary study outcome was CR selection among respondents in their final program year. Logistic regression was used to estimate the adjusted odds ratios (aOR) and 95% confidence intervals (CI) of CR selection for each racial group, as compared to the White referent group., Results: Among the study population (N=121,247), Black, Asian and Hispanic race-ethnicity was associated with a significantly decreased odds of being selected as CR in unadjusted and adjusted analyses. Black, Asian and Hispanic residents had a 26% (aOR=0.74, 95% CI 0.66-0.83), 29% (aOR=0.71, 95% CI 0.66-0.76) and 28% (aOR=0.72, 95% CI 0.66-0.94) decreased likelihood of becoming CR, respectively. Multi-racial residents also had a decreased likelihood, but to a lesser degree (aOR=0.92, 95% CI 0.89-0.95)., Conclusions: In as much as CR is an honor that sets one up for future opportunity, our findings suggest that residents of color are disproportionately disadvantaged compared to their White peers., (Copyright © 2023 National Medical Association. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Author disclosures are available in the supporting information.

Objective: We assessed whether biological age, measured by the epigenetic clock GrimAge, mediates the association of objective and subjective neighborhood disadvantage with incident HF among Black persons., Methods: Participants were 1448 self-reported Black adults (mean age (standard deviation, SD) = 64.3 (5.5)) dually enrolled in two community-based cohorts in Jackson, Mississippi, the ARIC and JHS cohorts, who were free of HF as of January 1, 2000. Incident HF events leading to hospitalization through December 31, 2017, were classified using ICD-9 discharge codes of HF. Multilevel age- and sex-adjusted Cox causal mediation models were used to examine whether biological age (at the person and neighborhood level) mediated the effects of objective (the National Area Deprivation Index, ADI) and subjective (perceived neighborhood problems) neighborhood disadvantage on incident HF., Results: A total of 334 incident hospitalized HF events occurred over a median follow-up of 18.0 years. The total effect of the ADI and perceived neighborhood problems (SD units) on HF was hazard ration (HR) = 1.26 and 95% confidence interval (CI) 0.98-1.56 and HR = 1.26 and 95% CI 1.10-1.41, respectively. GrimAge mediated a majority of the effect of perceived neighborhood problems on HF (person-level indirect effect HR = 1.07; 95% CI 1.02-1.12 and neighborhood-level indirect effect HR = 1.18; 95% CI 1.03-1.34), with the combined indirect effect explaining 94.8% of the relationship. The combined indirect effect of ADI on incident HF was comparable but not statistically significant., Conclusions: Subjective neighborhood disadvantage may confer an increased risk of HF among Black populations., (© 2022. W. Montague Cobb-NMA Health Institute.)

The instability of the surface chemistry in transition metal oxide perovskites is the main factor hindering the long-term durability of oxygen electrodes in solid oxide electrochemical cells. The instability of surface chemistry is mainly due to the segregation of A-site dopants from the lattice to the surface. Here we report that cathodic potential can remarkably improve the stability in oxygen reduction reaction and electrochemical activity, by decomposing the near-surface region of the perovskite phase in a porous electrode made of La 1-x Sr x Co 1-x Fe x O 3 mixed with Sm 0.2 Ce 0.8 O 1.9 . Our approach combines X-ray photoelectron spectroscopy and secondary ion mass spectrometry for surface and sub-surface analysis. Formation of Ruddlesden-Popper phase is accompanied by suppression of the A-site dopant segregation, and exsolution of catalytically active Co particles onto the surface. These findings reveal the chemical and structural elements that maintain an active surface for oxygen reduction, and the cathodic potential is one way to generate these desirable chemistries., (© 2023. The Author(s).)

Background: Despite the known benefits of breastfeeding to infants and mothers, previous studies have demonstrated that underserved women are less likely to exclusively breastfeed. Existing studies on the impact of Special Supplemental Nutritional Program for Women, Infants, and Children enrollment on feeding decisions for infants have conflicting results with low-quality data and metrics., Objective: This study aimed to examine infant feeding trends nationally in the first week postpartum over a 10-year period, comparing breastfeeding rates for primiparous women with low income who used Special Supplemental Nutritional Program for Women, Infants, and Children resources with those women who did not enroll. We hypothesized that although the Special Supplemental Nutritional Program for Women, Infants, and Children is an important resource for new mothers, free formula associated with enrollment in the Special Supplemental Nutritional Program for Women, Infants, and Children may disincentivize women to exclusively breastfeed., Study Design: This was a retrospective cohort study of primiparous women with singleton gestations who gave birth at term and who responded to the Centers for Disease Control and Prevention Pregnancy Risk Assessment Monitoring System between 2009 and 2018. Data were extracted from phases 6, 7, and 8 of the survey. Women with low income were defined as those with a reported annual household income of $35,000 or less. The primary outcome was exclusive breastfeeding after 1 week postpartum. Secondary outcomes included ever breastfeeding, any breastfeeding after 1 week postpartum, and introduction of other liquids within 1 week postpartum. Multivariable logistic regression was used to refine risk estimates with adjustment for mode of delivery, household size, education level, insurance status, diabetes, hypertension, race, age, and BMI., Results: Among the 42,778 women with low income who were identified, 29,289 (68%) of these women reported receiving Special Supplemental Nutritional Program for Women, Infants, and Children resources. There was no significant difference in the rates of exclusive breastfeeding after 1 week postpartum between those enrolled in the Special Supplemental Nutritional Program for Women, Infants, and Children and those not enrolled (adjusted risk ratio, 1.04; 95% confidence interval, 1.00-1.07; P=.10). However, those enrolled were less likely to ever breastfeed (adjusted risk ratio, 0.95; 95% confidence interval, 0.94-0.95; P<.01) and were more likely to introduce other liquids within 1 week postpartum (adjusted risk ratio, 1.16; 95% confidence interval, 1.11-1.21; P<.01)., Conclusion: Although exclusive breastfeeding rates after 1 week postpartum were similar, women enrolled in the Special Supplemental Nutritional Program for Women, Infants, and Children were significantly less likely to ever breastfeed and more likely to introduce formula within the first week postpartum. This suggests that Special Supplemental Nutritional Program for Women, Infants, and Children enrollment may impact the decision to initiate breastfeeding and may represent an important window to test future interventions., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Nonalcoholic steatohepatitis (NASH) is a chronic progression of nonalcoholic fatty liver disease, which can negatively impact the health-related quality of life (HRQoL) of affected individuals. HRQoL in NASH has been assessed using the disease-specific Chronic Liver Disease Questionnaire for NASH (CLDQ-NASH) and the generic EuroQol EQ-5D-5L. As the performance of these instruments relative to each other is unknown, we performed a cross-walk analysis of CLDQ-NASH to EQ-5D-5L using data from a real-world NASH population., Methods: Data were drawn from the Adelphi Real World 2019 NASH Disease Specific Programme, a cross-sectional survey of physicians and their patients in the United States. Patients with physician-diagnosed NASH completed a questionnaire that included the CLDQ-NASH and EQ-5D-5L. Mapping from CLDQ-NASH to EQ-5D-5L was done using tenfold cross-validation; performance was assessed using root-mean squared error as accuracy measure. Subgroup analyses compared performance of the models in obese versus non-obese patients and patients with versus without type 2 diabetes (T2D)., Results: Data from 347 patients were included in this analysis. Overall, 2172 models were tested for predicting EQ-5D-5L index score from CLDQ-NASH score. The best model for this mapping was a generalized linear model using Gaussian distribution and a power link. The best model for mapping from CLDQ-NASH domains to the EQ-5D-5L was a fractional logistic model. Models performed better at predicting upper versus lower values of EQ-5D-5L, for non-obese versus obese patients, and for patients without versus with T2D., Conclusion: We describe a scoring algorithm for cross-walking the CLDQ-NASH to the EQ-5D-5L enabling health status comparisons of HRQoL across studies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: The optimum route for drug administration in cardiac arrest is unclear. Recent data suggest that use of the intraosseous route may be increasing. This study aimed to explore changes over time in use of the intraosseous and intravenous drug routes in out-of-hospital cardiac arrest in England., Methods: We extracted data from the UK Out-of-Hospital Cardiac Arrest Outcomes registry. We included adult out-of-hospital cardiac arrest patients between 2015-2020 who were treated by an English Emergency Medical Service that submitted vascular access route data to the registry. The primary outcome was any use of the intraosseous route during cardiac arrest. We used logistic regression models to describe the association between time (calendar month) and intraosseous use., Results: We identified 75,343 adults in cardiac arrest treated by seven Emergency Medical Service systems between January 2015 and December 2020. The median age was 72 years, 64% were male and 23% presented in a shockable rhythm. Over the study period, the percentage of patients receiving intraosseous access increased from 22.8% in 2015 to 42.5% in 2020. For each study-month, the odds of receiving any intraosseous access increased by 1.019 (95% confidence interval 1.019 to 1.020, p < 0.001). This observed effect was consistent across sensitivity analyses. We observed a corresponding decrease in use of intravenous access., Conclusion: In England, the use of intraosseous access in out-of-hospital cardiac arrest has progressively increased over time. There is an urgent need for randomised controlled trials to evaluate the clinical effectiveness of the different vascular access routes in cardiac arrest., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CDD, RF, CJ, JPN, GDP and KC are co-investigators of the PARAMEDIC-3 trial (a randomised controlled trial of the IV versus IO route for vascular access in out-of-hospital cardiac arrest). JPN is Editor in Chief and GDP is an editor of Resuscitation. CDD and KC are editorial board members of Resuscitation., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)