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Failure to consider population structure when managing harvested fishes increases the risk of stock depletion, yet empirical estimates of population structure are often lacking for important fishery species. In this study, we characterise genetic variation in single nucleotide polymorphisms (SNPs) to assess population structure for three harvested species of tropical snappers across the broad (up to 300 km wide) and extensive (~ 4000 km) continental shelf of north-western Australia. Comparisons across ~ 300 individuals per species, showed remarkably similar patterns of genetic structure among Lutjanus sebae (red emperor), L. malabaricus (saddletail snapper) and Pristipomoides multidens (goldband snapper) despite subtle differences in biological and ecological traits. Low levels of genetic subdivision were reflected in an isolation by distance relationship where genetic connectivity increased with geographic proximity. This indicates extensive but not unlimited dispersal across the north-western Australian shelf. Our findings provide evidence of connectivity between current management areas, violating the assumption of multiple independent stocks. Spatial stock assessment models may be more suitable for the management of these species however demographic connectivity rates cannot be accurately estimated from the conventional population genetic approaches applied in this study. We recommend that managers aim to maintain adequate spawning biomass across current management areas, and assess stocks at finer scales, where practical., (© 2024. Crown.)

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple approaches have been tried to achieve adequate decongestion rapidly while minimizing adverse effects, no single diuretic strategy has shown superiority, and there is a paucity of data and guidelines to utilize in making these decisions. Observational cohort studies have shown associations between urine sodium excretion and outcomes after hospitalization for ADHF. Urine chemistries (urine sodium ± urine creatinine) may guide diuretic titration during ADHF, and multiple randomized clinical trials have been designed to compare a strategy of urine chemistry-guided diuresis to usual care. This review will summarize current literature for diuretic monitoring and titration strategies, outline evidence gaps, and describe the recently completed and ongoing clinical trials to address these gaps in patients with ADHF with a particular focus on the utility of urine sodium-guided strategies., (© 2024. The Author(s).)

Introduction: Understanding the pneumococcal serotypes causing community-acquired pneumonia (CAP) is essential for evaluating the impact of pneumococcal vaccines., Methods: We conducted a prospective surveillance study of adults aged ≥18 years hospitalized with CAP at 3 hospitals in Tennessee and Georgia between 1 September 2018 and 31 October 2022. We assessed for pneumococcal etiology with cultures, the BinaxNOW urinary antigen detection test, and serotype-specific urinary antigen detection assays that detect 30 pneumococcal serotypes contained in the investigational pneumococcal conjugate vaccine V116, as well as licensed vaccines PCV15 and PCV20 (except serotype 15B). The distribution of pneumococcal serotypes was calculated based on serotype-specific urinary antigen detection results., Results: Among 2917 hospitalized adults enrolled with CAP, 352 (12.1%) patients had Streptococcus pneumoniae detected, including 51 (1.7%) patients with invasive pneumococcal pneumonia. The 8 most commonly detected serotypes were: 3, 22F, 19A, 35B, 9N, 19F, 23A, and 11A. Among 2917 adults with CAP, 272 (9.3%) had a serotype detected that is contained in V116, compared to 196 (6.7%) patients with a serotype contained in PCV20 (P < .001), and 168 (5.8%) patients with a serotype contained in PCV15 (P < .001). A serotype contained in V116 but not PCV15 or PCV20 was detected in 120 (4.1%) patients, representing 38.0% of serotype detections., Conclusions: Approximately 12% of adults hospitalized with CAP had S. pneumoniae detected, and approximately one-third of the detected pneumococcal serotypes were not contained in PCV15 or PCV20. Development of new pneumococcal vaccines with expanded serotype coverage has the potential to prevent a substantial burden of disease., Competing Interests: Potential conflicts of interest . This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Additionally, the following authors made the following disclosures. K. D. J. reports being an employee and shareholder with stock options of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. C. G. G. reports consulting fees from Merck & Co., Inc and research funding outside the submitted work from NIH, CDC, AHRQ, FDA, and Campbell Alliance/Syneos Health. C. A. R. reports research funding outside the submitted work from BioFire, GSK, MedImmune, Micron, Merck, Novavx, PaxVax, Regeneron, Pfizer, Sanofi-Pasteur, Janssen, Moderna, NIH, and CDC, reports royalties from Meissa Vaccines, and reports 2 planned patents for RSV vaccines. I. Y. reports research funding outside the submitted work from Merck, and consulting fees from Sanofi Pasteur and Merck. T. W. reports being an employee and shareholder with stock options of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. C. R. reports being an employee and shareholder with stock options of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. N. R. reports research funding outside the submitted work from Merck, Sanofi, Pfizer, Vaccine Company, Immorna, Quidel and Lilly, reports consulting fees from Krog, reports honoraria from Virology Education and Medscape, reports support for attending a meeting from Sanofi and Moderna, reports participation in advisory boards for Moderna, Sanofi, Seqirus, Pfizer, EMMES, ICON, and Micron, and reports leadership roles with ARLG, TMRC, CDC-Pertussis challenge, and Clinical Infectious Diseases. The other authors reported no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Despite decades of research on yoga and depression, subjective experiences of participants in these studies have rarely been reported, and never in individuals receiving heated yoga for depression. We examined patient-reported qualitative findings from an 8-week randomized controlled trial of heated yoga for depression. Eighty medically healthy participants with moderate-to-severe depression were randomized to 8 weeks of at least twice-weekly heated yoga classes, derived from Bikram yoga, or a waitlist control. Fifty-seven participants received a clinician-administered exit interview at intervention completion/study withdrawal. The exit interview assessed: (1) how participants felt immediately following the heated yoga sessions (acute effects), (2) what they liked or found helpful about heated yoga over the 8-week intervention (positive effects), and (3) what they disliked/did not find helpful over the 8-week intervention (negative effects). Qualitative data were analyzed using thematic analysis. Acute improvements in depressive symptoms (i.e., immediately following yoga) were the most commonly reported (n = 44, 77.2%), followed by overall positive effects on depressive symptoms (i.e., over the course of the 8-week intervention; n = 33, 57.9%), including improvements in sleep (n = 10, 17.5%), energy (n = 13, 22.8%), mood (n = 18, 31.6%), motivation (n = 2, 3.5%), and concentration/decision-making (n = 5, 8.8%). Overall negative effects (i.e., over the course of the 8-week intervention) included dislike of various aspects of the intervention (n = 19, 33.3%), such as instruction (n = 7, 12.3%), difficulty (n = 7, 12.3%), repetitiveness (n = 3, 5.3%), class length (n = 2, 3.5%), and boredom (n = 7, 12.3%). Most participants reported both overall positive and negative effects (n = 37, 64.9%). Of the rest, 19 (33.3%) reported only overall positive effects, and 1 (1.8%) reported only overall negative effects. Most participant experiences were positive. Negative effects were less common and primarily involved dislike of different aspects of the heated yoga. The findings support strong acceptability and subjective improvement in depressive symptoms in depressed individuals.

Importance: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care; however, accompanying immune-related adverse events (irAEs) confer substantial morbidity and occasional mortality. Life-threatening irAEs may require permanent cessation of ICI, even in patients with positive tumor response. Therefore, it is imperative to comprehensively define the spectrum of irAEs to aid individualized decision-making around the initiation of ICI therapy., Objective: To define incidence, risk factors, and clinical spectrum of an irreversible and life-threatening irAE: ICI-induced diabetes., Design, Setting, and Participants: This cohort study, conducted at an academic integrated health care system examined 14 328 adult patients treated with ICIs, including 64 patients who developed ICI-induced diabetes, from July 2010 to January 2022. The data were analyzed from 2022 to 2023. Cases of ICI-induced diabetes were manually confirmed; detailed clinical phenotyping was performed at diagnosis and 1-year follow-up. For 862 patients, genotyping data were available, and polygenic risk for type 1 diabetes was determined., Main Outcomes and Measures: For ICI-induced diabetes cases and controls, demographic characteristics, comorbidities, tumor category, and ICI category were compared. Among ICI-induced diabetes cases, markers of glycemic physiology were examined at diagnosis and 1-year follow-up. For patients with available genotyping, a published type 1 diabetes polygenic score (T1D GRS2) was calculated., Results: Of 14 328 participants, 6571 (45.9%) were women, and the median (range) age was 66 (8-106) years. The prevalence of ICI-induced diabetes among ICI-treated patients was 0.45% (64 of 14 328), with an incidence of 124.8 per 100 000 person-years. Preexisting type 2 diabetes (odds ratio [OR], 5.91; 95% CI, 3.34-10.45) and treatment with combination ICI (OR, 2.57; 95% CI, 1.44-4.59) were significant clinical risk factors of ICI-induced diabetes. T1D GRS2 was associated with ICI-induced diabetes risk, with an OR of 4.4 (95% CI, 1.8-10.5) for patients in the top decile of T1D GRS2, demonstrating a genetic association between spontaneous autoimmunity and irAEs. Patients with ICI-induced diabetes were in 3 distinct phenotypic categories based on autoantibodies and residual pancreatic function, with varying severity of initial presentation., Conclusions and Relevance: The results of this analysis of 14 328 ICI-treated patients followed up from ICI initiation determined the incidence, risk factors and clinical spectrum of ICI-induced diabetes. Widespread implementation of this approach across organ-specific irAEs may enhance diagnosis and management of these conditions, and this becomes especially pertinent as ICI treatment rapidly expands to treat a wide spectrum of cancers and is used at earlier stages of treatment.

Background: Falls are a significant public health problem and constitute a major cause of injuries and mortality. Risk factors for falls are multifactorial and include medication use., Aim: To develop and investigate the content validity of the Medication-Related fall (MRF) screening and scoring tool., Method: The MRF tool was developed from clinical practice guidelines addressing medication-related problems, and additional medications identified by specialist pharmacists across a region of the United Kingdom (Northern Ireland). Medication classes were categorised according to their 'potential to cause falls' as: high-risk (three points), moderate-risk (two points) or low-risk (one point). The overall medication-related falls risk for the patient was determined by summing the scores for all medications. The MRF was validated using Delphi consensus methodology, whereby three iterative rounds of surveys were conducted using SurveyMonkey ® . Twenty-two experts from 10 countries determined their agreement with the falls risk associated with each medication on a 5-point Likert scale. Only medications with at least 75% of respondents agreeing or strongly agreeing were retained in the next round., Results: Consensus was reached for 19 medications/medication classes to be included in the final version of the MRF tool; ten were classified as high-risk, eight as moderate-risk and one as low-risk., Conclusion: The MRF tool is simple and has the potential to be integrated into medicines optimisation to reduce falls risk and negative fall-related outcomes. The score from the MRF tool can be used as a clinical parameter to assess the need for medication review and clinical interventions., (© 2024. The Author(s).)

Immune checkpoint inhibitors have revolutionized cancer therapy but are associated with a risk of endocrine immune-related adverse events, including pituitary complications. Autoimmune hypophysitis, traditionally a rare diagnosis, has become a more frequently encountered clinical entity with the emergence of antitumor immunotherapy. This mini-review aims to consolidate current knowledge, encompassing the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of pituitary complications of immune checkpoint inhibitor use., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Pegfilgrastim-cbqv/CHS-1701 (UDENYCA ® ) (hereafter referred to as pegfilgrastim-cbqv) was approved in 2018 by the US Food and Drug Administration as a biosimilar for pegfilgrastim (Neulasta ® ) (hereafter referred to as pegfilgrastim). Both pegfilgrastim-cbqv and pegfilgrastim are conjugates of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) with a 20 kDa polyethylene glycol (PEG) indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients receiving myelosuppressive anticancer drugs. The demonstration of analytical similarity for PEG-protein conjugates presents unique challenges since both the protein and PEG attributes must be characterized., Objective: The current study demonstrates the analytical similarity of pegfilgrastim-cbqv and the reference product, pegfilgrastim. In addition to the physicochemical and functional characterization of the protein, the study assessed attributes specific to PEGylation including PEG size and polydispersity, site of attachment, linker composition, and PEGylation process-related variants., Methods: The structural, functional, and stability attributes of pegfilgrastim-cbqv and pegfilgrastim were compared using state-of-the-art analytical methods. For the protein, the primary structure, disulfide structure, and secondary and tertiary structures were assessed using traditional protein characterization techniques such as mass spectrometry (MS), circular dichroism (CD), intrinsic fluorescence, and differential scanning calorimetry (DSC), as well as more advanced techniques such as two-dimensional (2D) nuclear magnetic resonance (NMR) and hydrogen deuterium exchange (HDX). For the PEG moiety, the site of attachment, occupancy, linker composition, size and polydispersity were compared using mass spectrometry (both intact and after endoprotease digestion), multiangle light scattering detection (MALS), and Edman degradation. Purity assessments included the assessment of both protein variants and PEGylation variants using chromatographic and electrophoretic analytical separation techniques. The functional similarity between pegfilgrastim-cbqv and pegfilgrastim was compared using both a cell-based bioassay and surface plasmon resonance (SPR). The degradation rates and stability profiles were compared under accelerated and stressed conditions., Results: Biosimilarity was demonstrated by a thorough assessment of physiochemical and functional attributes, as well as comparative stability, of pegfilgrastim-cbqv relative to pegfilgrastim. These studies demonstrated identical primary structure and disulfide structure, highly similar secondary and tertiary structure, as well as functional similarity. The impurity profile of pegfilgrastim-cbqv was comparable to that of pegfilgrastim with only minor differences in PEGylation variants and a slight offset in the PEG molar mass. These differences were not clinically relevant. The degradation profiles were qualitatively and quantitatively similar under accelerated and stress conditions., Conclusion: The structural, functional, and stability data demonstrate that pegfilgrastim-cbqv is highly similar to the reference product, pegfilgrastim., (© 2024. The Author(s).)

Objective: Mid-life cardiovascular risk factors are associated with later cognitive decline. Whether repetitive head injury among professional athletes impacts cardiovascular risk is unknown. We investigated associations between concussion burden and postcareer hypertension, high cholesterol, and diabetes among former professional American-style football (ASF) players., Methods: In a cross-sectional study of 4080 professional ASF players conducted between January 2015 and March 2022, we used an mulitsymptom concussion symptom score (CSS) and the number of loss-of-consciousness (LOC) episodes as a single severe symptom to quantify football-related concussion exposure. Primary outcomes were hypertension, dyslipidemia, and diabetes, defined by current or recommended prescription medication use., Results: The prevalence of hypertension, high cholesterol, and diabetes among former players (52 ± 14 years of age) was 37%, 34%, and 9%. Concussion burden was significantly associated with hypertension (lowest vs. highest CSS quartile, odds ratio (OR) = 1.99; 95%CI: 1.33-2.98; p < 0.01) and high cholesterol (lowest vs. moderate CSS, OR = 1.46, 95%CI, 1.11-1.91; p < 0.01), but not diabetes. In fully adjusted models, the prevalence of multiple CVD was associated with CSS. These results were driven by younger former players (≤ 40 year of age) in which the odds of hypertension were over three times higher in those in the highest CSS quartile (OR = 3.29, 95%CI: 1.39-7.61; p = 0.01). Results were similar for LOC analyses., Interpretation: Prior concussion burden is associated with postcareer atherogenic cardiovascular risk profiles among former professional American football players., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

MEK signaling pathway targeting has emerged as a valuable addition to the options available for the treatment of advanced cancers including melanoma and non-small cell lung cancer. Ophthalmologic monitoring of patients taking part in clinical trials of MEK inhibitors has shown that while ocular effects are common, generally emerging during the first days to weeks of treatment, the majority are either asymptomatic or have minimal visual impact and are benign, resolving without intervention or the need to reduce or stop MEK inhibitor therapy. However rare cases of serious, potentially vision-threatening ocular toxicities have been reported during MEK inhibitor therapy. There is currently no recommendation for routine ophthalmologic screening or monitoring of patients with advanced cancer who are initiating MEK inhibitor therapy. However, baseline ophthalmologic examination may be useful for all patients initiating MEK inhibitor therapy to allow the differentiation of preexisting pathology versus the development of MEK inhibitor-associated retinopathy in the event of the emergence of symptomatic ocular events. Regular ophthalmologic examination may be appropriate for patients at increased risk for ocular events, such as patients with a history of ocular inflammation, infection, or underlying macular/retinal disease. All patients reporting visual disturbance should be referred for prompt ophthalmologic review to determine the potential seriousness of any underlying abnormalities and whether there is a need for treatment modification or specific intervention. Understanding the potential consequences of ocular toxicities is of particular importance in the context of decision-making for the continuation of potentially life-prolonging medications such as MEK inhibitors., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The primary goals during acute heart failure (AHF) hospitalization are decongestion and guideline-directed medical therapy (GDMT) optimization. Unlike diuretics or other GDMT, early dapagliflozin initiation could achieve both AHF goals., Objectives: The authors aimed to assess the diuretic efficacy and safety of early dapagliflozin initiation in AHF., Methods: In a multicenter, open-label study, 240 patients were randomized within 24 hours of hospital presentation for hypervolemic AHF to dapagliflozin 10 mg once daily or structured usual care with protocolized diuretic titration until day 5 or hospital discharge. The primary outcome, diuretic efficiency expressed as cumulative weight change per cumulative loop diuretic dose, was compared across treatment assignment using a proportional odds model adjusted for baseline weight. Secondary and safety outcomes were adjudicated by a blinded committee., Results: For diuretic efficiency, there was no difference between dapagliflozin and usual care (OR: 0.65; 95% CI: 0.41-1.02; P = 0.06). Dapagliflozin was associated with reduced loop diuretic doses (560 mg [Q1-Q3: 260-1,150 mg] vs 800 mg [Q1-Q3: 380-1,715 mg]; P = 0.006) and fewer intravenous diuretic up-titrations (P ≤ 0.05) to achieve equivalent weight loss as usual care. Early dapagliflozin initiation did not increase diabetic, renal, or cardiovascular safety events. Dapagliflozin was associated with improved median 24-hour natriuresis (P = 0.03) and urine output (P = 0.005), expediting hospital discharge over the study period., Conclusions: Early dapagliflozin during AHF hospitalization is safe and fulfills a component of GDMT optimization. Dapagliflozin was not associated with a statistically significant reduction in weight-based diuretic efficiency but was associated with evidence for enhanced diuresis among patients with AHF. (Efficacy and Safety of Dapagliflozin in Acute Heart Failure [DICTATE-AHF]; NCT04298229)., Competing Interests: Funding Support and Author Disclosures This study was funded by AstraZeneca as an investigator-initiated study. The authors designed the protocol, conducted the trial according to the protocol and statistical analysis plan, analyzed the data, and attest to the accuracy and completeness of the data. The REDCap database is supported by a grant from National Center for Advancing Translational Sciences/National Institutes of Health (NIH) (UL1 TR000445). Dr Cox has received research funding from AstraZeneca; and has received consulting fees from Roche and Translational Catalyst. Dr Collins has performed consulting for Boehringer Ingelheim, Reprieve Cardiovascular, Siemens, and Abbott; and has received research support from the Patient-Centered Outcomes Research Institute, NIH, U.S. Department of Defense, Agency for Healthcare Research and Quality, and Beckman Coulter. Dr Lindsell has received funding from AstraZeneca, bioMerieux, Entegrion, Endpoint Health, NIH, the U.S. Department of Defense, and the Centers for Disease Control and Prevention. Dr Stubblefield has received funding from the NIH/National Heart, Lung, and Blood Institute. Dr Lindenfeld has received research funding from AstraZeneca, Volumetrix, and NIH; and has received consulting fees from AstraZeneca, Abbott, Alleviant, Axon, Boston Scientific, CVRx, Edwards Lifesciences, Medtronic, Merck, Vascular Dynamics, VWave, and Whiteswell. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Canonical α/β T-cell receptors (TCRs) bind to human leukocyte antigen (HLA) displaying antigenic peptides to elicit T cell-mediated cytotoxicity. TCR-engineered T-cell immunotherapies targeting cancer-specific peptide-HLA complexes (pHLA) are generating exciting clinical responses, but owing to HLA restriction they are only able to target a subset of antigen-positive patients. More recently, evidence has been published indicating that naturally occurring α/β TCRs can target cell surface proteins other than pHLA, which would address the challenges of HLA restriction. In this proof-of-concept study, we sought to identify and engineer so-called HLA-independent TCRs (HiTs) against the tumor-associated antigen mesothelin., Methods: Using phage display, we identified a HiT that bound well to mesothelin, which when expressed in primary T cells, caused activation and cytotoxicity. We subsequently engineered this HiT to modulate the T-cell response to varying levels of mesothelin on the cell surface., Results: The isolated HiT shows cytotoxic activity and demonstrates killing of both mesothelin-expressing cell lines and patient-derived xenograft models. Additionally, we demonstrated that HiT-transduced T cells do not require CD4 or CD8 co-receptors and, unlike a TCR fusion construct, are not inhibited by soluble mesothelin. Finally, we showed that HiT-transduced T cells are highly efficacious in vivo, completely eradicating xenografted human solid tumors., Conclusion: HiTs can be isolated from fully human TCR-displaying phage libraries against cell surface-expressed antigens. HiTs are able to fully activate primary T cells both in vivo and in vitro. HiTs may enable the efficacy seen with pHLA-targeting TCRs in solid tumors to be translated to cell surface antigens., Competing Interests: This study was funded by Adaptimmune. Adaptimmune contributed to study design, data analysis, decision to publish, and preparation of the manuscript. Writing and editorial support was funded by Adaptimmune. All authors are employees of Adaptimmune or were at the time of the study. Authors may hold stock in Adaptimmune. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Hiscox et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Anorexia nervosa is associated with low bone mineral density (BMD) and deficits in bone microarchitecture and strength. Low BMD is common in atypical anorexia nervosa, in which criteria for anorexia nervosa are met except for low weight. We investigated whether women with atypical anorexia nervosa have deficits in bone microarchitecture and estimated strength at the peripheral skeleton., Method: Measures of BMD and microarchitecture were obtained in 28 women with atypical anorexia nervosa and 27 controls, aged 21-46 years., Results: Mean tibial volumetric BMD, cortical thickness, and failure load were lower, and radial trabecular number and separation impaired, in atypical anorexia nervosa versus controls (p < .05). Adjusting for weight, deficits in tibial cortical bone variables persisted (p < .05). Women with atypical anorexia nervosa and amenorrhea had lower volumetric BMD and deficits in microarchitecture and failure load versus those with eumenorrhea and controls. Those with a history of overweight/obesity or fracture had deficits in bone microarchitecture versus controls. Tibial deficits were particularly marked. Less lean mass and longer disease duration were associated with deficits in high-resolution peripheral quantitative computed tomography (HR-pQCT) variables in atypical anorexia nervosa., Discussion: Women with atypical anorexia nervosa have lower volumetric BMD and deficits in bone microarchitecture and strength at the peripheral skeleton versus controls, independent of weight, and particularly at the tibia. Women with atypical anorexia nervosa and amenorrhea, less lean mass, longer disease duration, history of overweight/obesity, or fracture history may be at higher risk. This is salient as deficits in HR-pQCT variables are associated with increased fracture risk., Public Significance: Atypical anorexia nervosa is a psychiatric disorder in which psychological criteria for anorexia nervosa are met despite weight being in the normal range. We demonstrate that despite weight in the normal range, women with atypical anorexia nervosa have impaired bone density, structure, and strength compared to healthy controls. Whether this translates to an increased risk of incident fracture in this population requires further investigation., (© 2023 Wiley Periodicals LLC.)

Importance: Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown., Objective: To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD., Design, Setting, and Participants: This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023., Interventions: Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months., Main Outcomes and Measures: The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified., Results: Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn., Conclusions and Relevance: In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT04031729.

Introduction: Adopting healthy lifestyle behaviors has the potential to slow cognitive decline in older adults by reducing risks associated with dementia. Curriculum-based group health coaching may aid in establishing behavior change centered for dementia risk factors., Methods: In this pilot clinical care patient group study ( n = 6), we examined the effects of a six-month online Cognitive Health Program combined with a weekly telehealth support group led by the course creator, and personalized health optimization by a collaborating physician, in older adults with subjective cognitive decline. Cognition was assessed at baseline and post-intervention using a computerized battery., Results: Cognitive changes were estimated with nonparametric tests and effect sizes (Cohen's d). Results showed significant improvements in global cognition ( p < 0.03, d = 1.6), spatial planning ( p < 0.01, d = 2.3), and visuospatial processing ( p < 0.05, d = 1.1) compared to baseline. Participants reported high levels of satisfaction with the virtual group format and online curriculum., Conclusions: This small pilot study suggests that a virtual six-month personalized health coaching group with self-paced online health education is feasible and potentially efficacious for improving cognition in participants with subjective cognitive complaints. This format may facilitate behavior change to slow cognitive decline. Future studies should include a control group, a larger, more diverse sample as well as assessing mood and other subjective measures.

The study of molecular drivers of cancer is an area of rapid growth and has led to the development of targeted treatments, significantly improving patient outcomes in many cancer types. The identification of actionable mutations informing targeted treatment strategies are now considered essential to the management of cancer. Traditionally, this information has been obtained through biomarker assessment of a tissue biopsy which is costly and can be associated with clinical complications and adverse events. In the last decade, blood-based liquid biopsy has emerged as a minimally invasive, fast, and cost-effective alternative, which is better suited to the requirement for longitudinal monitoring. Liquid biopsies allow for the concurrent study of multiple analytes, such as circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA), from a single blood sample. Although ctDNA assays are commercially more advanced, there is an increasing awareness of the clinical significance of the transcriptome and proteome which can be analysed using CTCs. Herein, we review the literature in which the microfluidic, label-free Parsortix ® system is utilised for CTC capture, harvest and analysis, alongside the analysis of ctDNA from a single blood sample. This detailed summary of the literature demonstrates how these two analytes can provide complementary disease information.

Background: Adalimumab-aqvh/CHS-1420 (YUSIMRY TM ) (hereafter referred to as adalimumab-aqvh) was recently approved by the US Food and Drug Administration as a biosimilar for adalimumab., Objective: The current study was conducted to investigate the analytical similarity of adalimumab-aqvh and the reference product, adalimumab., Methods: The structural, functional, and stability attributes of adalimumab-aqvh and adalimumab were compared using state-of-the-art assays. The primary structure, disulfide structure, glycan profile, secondary and tertiary structures, molar mass, size variants, free thiol, charge variants, hydrophobic variants, post-translational modifications, subvisible particles, host cell proteins, and protein concentration were investigated. The functional similarity between adalimumab-aqvh and adalimumab was demonstrated by comparing fragment antigen-binding (Fab)-associated and fragment crystallizable (Fc)-associated biological activities. The stability of adalimumab-aqvh and of adalimumab was compared through forced degradation., Results: The structural attributes of adalimumab-aqvh were identical to those of adalimumab or met the similarity criteria, with a few exceptions. Adalimumab-aqvh and adalimumab exhibited comparable stability profiles and functional activities. Any observed differences in the physiochemical attributes did not impact the conclusion of similarity because they did not influence any functional activities related to the adalimumab mechanism of action., Conclusion: The structural, functional, and stability data provide convincing evidence of biosimilarity between adalimumab-aqvh and the reference product, adalimumab., (© 2023. The Author(s).)

Context: Overweight and obesity are associated with relative growth hormone (GH) deficiency, which has been implicated in the development of nonalcoholic fatty liver disease (NAFLD). NAFLD is a progressive disease without effective treatments., Objective: We hypothesized that GH administration would reduce hepatic steatosis in individuals with overweight/obesity and NAFLD., Methods: In this 6-month randomized, double-blind, placebo-controlled trial of low-dose GH administration, 53 adults aged 18 to 65 years with BMI ≥25 kg/m2 and NAFLD without diabetes were randomized to daily subcutaneous GH or placebo, targeting insulin-like growth factor 1 (IGF-1) to the upper normal quartile. The primary endpoint was intrahepatic lipid content (IHL) by proton magnetic resonance spectroscopy (1H-MRS) assessed before treatment and at 6 months., Results: Subjects were randomly assigned to a treatment group (27 GH; 26 placebo), with 41 completers (20 GH and 21 placebo) at 6 months. Reduction in absolute % IHL by 1H-MRS was significantly greater in the GH vs placebo group (mean ± SD: -5.2 ± 10.5% vs 3.8 ± 6.9%; P = .009), resulting in a net mean treatment effect of -8.9% (95% CI, -14.5 to -3.3%). All side effects were similar between groups, except for non-clinically significant lower extremity edema, which was more frequent in the GH vs placebo group (21% vs 0%, P = .02). There were no study discontinuations due to worsening of glycemic status, and there were no significant differences in change in glycemic measures or insulin resistance between the GH and placebo groups., Conclusion: GH administration reduces hepatic steatosis in adults with overweight/obesity and NAFLD without worsening glycemic measures. The GH/IGF-1 axis may lead to future therapeutic targets for NAFLD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple clinical trials have investigated initial diuretic strategies for a designated period of time, there is a paucity of evidence to guide diuretic titration strategies continued until decongestion is achieved. The use of urine chemistries (urine sodium and creatinine) in a natriuretic response prediction equation accurately estimates natriuresis in response to diuretic dosing, but a randomized clinical trial is needed to compare a urine chemistry-guided diuresis strategy with a strategy of usual care. The urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE) trial is designed to test the hypothesis that protocolized diuretic therapy guided by spot urine chemistry through completion of intravenous diuresis will be superior to usual care and improve outcomes over the 14 days following randomization. ESCALATE will randomize and obtain complete data on 450 patients with acute heart failure to a diuretic strategy guided by urine chemistry or a usual care strategy. Key inclusion criteria include an objective measure of hypervolemia with at least 10 pounds of estimated excess volume, and key exclusion criteria include significant valvular stenosis, hypotension, and a chronic need for dialysis. Our primary outcome is days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and intravenous diuresis. CLINICAL TRIAL REGISTRATION: NCT04481919., Competing Interests: Disclosures ZC receives research funding from AstraZeneca and Cumberland Pharmaceuticals and consulting fees from Roche and Translational Catalyst. JHH receives research funding from the NIA, Boehringer Ingelheim and Merck. JL receives research funding from AstraZeneca, Volumetrix, Sensible Medical, NIH and consulting fees from AstraZeneca, Abbott, Alleviant, Boehringer Ingelheim, Boston Scienrific, CVRx, Edwards Lifesciences, Medtronic, Merck, Vascular Dynamics, VWave, WHiteswell. CJL reports research grants and contracts to institution from NIH, CDC, DoD, AbbVie, Entegrion, Endpoint Health, bioMerieux, and patents for risk stratification in septic shock unrelated to the current work. JOW receives research funding from Bristol Myers Squibb. EDS receives personal fees as an Associate Editor for the Clinical Journal of the American Society of Nephrology and royalties as an author for UptoDate. JT reports grants and/or personal fees from 3ive labs, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Astra Zeneca, Novartis, Cardionomic, MagentaMed, Reprieve inc., FIRE1, W.L. Gore, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon pharmaceuticals, Precardia, Relypsa, Regeneron, BD, Edwards life sciences, and Lilly. In addition, JMT has a patent Treatment of diuretic resistance issued to Yale and Corvidia Therapeutics Inc, a patent Methods for measuring renalase issued to Yale, and a patent Treatment of diuretic resistance pending with Reprieve inc. SPC reports consulting with Boehringer Ingelheim, Reprieve Cardiovascular, Aboott and research support from PCORI, NIH, DOD, and Beckman Coulter., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To evaluate feasibility, acceptability, and preliminary efficacy of heated yoga to treat moderate-to-severe depression., Design: An 8-week randomized controlled trial (RCT) of heated yoga versus waitlist control was conducted from March 2017 to August 2019., Methods: Participants in the yoga condition were asked to attend heated yoga classes at 2 community heated yoga studios at least twice weekly. We assessed acceptability and feasibility using exit interview and attendance data, respectively. The primary intervention efficacy outcome variable was change in the Inventory of Depressive Symptomatology-Clinician Rated (IDS-CR) score from baseline to post-intervention (week 8)., Results: We randomized 80 participants and included 65 (mean [± SD] age 32.7 [± 11.7] years; 81.5% female) in the analyses (yoga n = 33, waitlist n = 32). The mean IDS-CR score at baseline was 35.6 (± 7.9) for the full sample, 36.9 (± 8.8) for yoga participants, and 34.4 (± 6.7) for waitlist participants. Participants attended an average of 10.3 (± 7.1) total classes over the 8-week intervention period. Yoga participants had a significantly greater pre- to post-intervention reduction in IDS-CR scores than waitlist participants (Cohen d  = 1.04, P  < .001). More yoga participants (59.3%; n = 16) than waitlist participants (6.3%; n = 2) evidenced larger treatment responses (IDS-CR ≥ 50% decrease in symptoms). Participants rated the heated yoga and its aftereffects positively in exit interviews., Conclusions: Approximately 1 heated yoga session per week (mean of 10.3 classes over 8 weeks) was associated with significantly greater reduction in depression symptoms than a waitlist control. Participants rated heated yoga positively. Taken together, results suggest feasibility, acceptability, and preliminary efficacy for patients with depression and warrant further research using active control conditions., Trial Registration: ClinicalTrials.gov identifier: NCT02607514., (© Copyright 2023 Physicians Postgraduate Press, Inc.)

Physician parents encounter unique challenges in balancing new parenthood with work responsibilities, especially upon their return from parental leave. We designed a pilot program that incorporated 1:1 parental coaching to expectant and new physician parents and provided stipends for lactation support and help at home. Additional initiatives included launching a virtual new parent group during the COVID-19 pandemic and starting an emergency backup pump supplies program. There was positive feedback for our Parental Wellness Program (PWP), which was used to secure expanded funding. Pilot results showed that our program had a meaningful impact on parental wellness, morale, productivity, and lactation efforts., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023.)

Context: Female athletes, particularly runners, with insufficient caloric intake for their energy expenditure [low energy availability (EA) or relative energy deficiency] are at risk for impaired skeletal integrity. Data are lacking in male runners., Objective: To determine whether male runners at risk for energy deficit have impaired bone mineral density (BMD), microarchitecture, and estimated strength., Design: Cross-sectional., Setting: Clinical research center., Participants: 39 men (20 runners, 19 controls), ages 16-30 years., Main Outcome Measures: Areal BMD (dual-energy x-ray absorptiometry); tibia and radius volumetric BMD and microarchitecture (high-resolution peripheral quantitative computed tomography); failure load (microfinite element analysis); serum testosterone, estradiol, leptin; energy availability., Results: Mean age (24.5 ± 3.8 y), lean mass, testosterone, and estradiol levels were similar; body mass index, percent fat mass, leptin, and lumbar spine BMD Z-score (-1.4 ± 0.8 vs -0.8 ± 0.8) lower (P < .05); and calcium intake and running mileage higher (P ≤ .01) in runners vs controls. Runners with EA

Our objective was to characterize bone outcomes in adolescent and young adult women with atypical anorexia nervosa (AAN) compared to typical AN and normal-weight healthy controls (HC) based on DSM-5 criteria. Four hundred thirty-two participants (141 AN, 131 AAN and 160 HC), ages 12-21 years, underwent dual-energy X-ray absorptiometry for areal BMD, and a subset had high-resolution peripheral quantitative CT assessment of the distal radius and tibia for volumetric BMD (vBMD), bone geometry and microarchitecture, and microfinite element analysis for estimated strength. The groups did not differ for age, pubertal stage, menarcheal age or physical activity. BMI and bone outcomes overall were intermediate in AAN compared with AN and HC. This applied to spine, total hip and femoral neck BMD measures and many distal tibial measures. However, the mean whole-body less head BMD Z-score did not differ between AAN and AN, and it was lower in both vs. HC. Similarly, many distal radius measures did not differ between AAN vs. AN or HC but were lower in AN than HC. Lower BMI, lean mass and bone age, older menarcheal age and longer illness duration correlated with greater impairment of bone outcomes. These data indicate that individuals with AAN overall have bone outcomes that are intermediate between AN and HC.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease worldwide. There are limited biomarkers that can detect progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The purpose of our study was to utilize CT texture analysis to distinguish steatosis from NASH., Methods: 16 patients with NAFLD (38% male, median (interquartile range): age 57 (48-64) years, BMI 37.5 (35.0-46.8) kg/m 2 ) underwent liver biopsy and abdominal non-contrast CT. CT texture analysis was performed to quantify gray-level tissue summaries (e.g., entropy, kurtosis, skewness, and attenuation) using commercially available software (TexRad, Cambridge England). Logistic regression analyses were performed to quantify the association between steatosis/NASH status and CT texture. ROC curve analysis was performed to determine sensitivity, specificity, AUC, 95% CIs, and cutoff values of texture parameters to differentiate steatosis from NASH., Results: By histology, 6/16 (37%) of patients had simple steatosis and 10/16 (63%) had NASH. Patients with NASH had lower entropy (median, interquartile range (IQR): 4.3 (4.1, 4.8) vs. 5.0 (4.9, 5.2), P  = 0.013) and lower mean value of positive pixels (MPP) (34.4 (21.8, 52.2) vs. 66.5 (57.0, 70.7), P  = 0.009) than those with simple steatosis. Entropy values below 4.73 predict NASH with 100% (95%CI: 67-100%) specificity and 80% (50-100%) sensitivity, AUC: 0.88. MPP values below 54.0 predict NASH with 100% (67-100%) specificity and 100% (50-100%) sensitivity, AUC 0.90., Conclusion: Our study provides preliminary evidence that CT texture analysis may serve as a novel imaging biomarker for disease activity in NAFLD and the discrimination of steatosis and NASH., (© 2023 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Key ecological features (KEFs) are elements of Australia's Commonwealth marine environment considered to be important for biodiversity or ecosystem function, yet many KEFs are poorly researched, which can impede effective decision-making about future development and conservation. This study investigates a KEF positioned over the Last Glacial Maximum (LGM) shoreline on the northwest shelf of Australia (known as the 'Ancient Coastline at ~125m depth contour'; AC125). Seafloor bathymetry, sedimentology and benthic habitats were characterised within five study areas using multibeam sonar, sediment samples and towed video imagery. Direct evidence for the existence of a palaeoshoreline formed during the LGM was not found, however candidate areas to find palaeoshoreline material at or just below the modern seabed were discovered. Approximately 98% of the seabed surveyed was comprised of unconsolidated soft sediment habitat (mud/sand/silt) supporting negligible epibenthic biota. The prevalence of soft sediment suggests that post-glacial sediments have infilled parts of the palaeoshoreline, with cross-shelf, probably tidal currents in the northern section of the study area responsible for some of the sediment mobilisation and southern study areas more influenced by oceanic conditions. Within study areas, total biotic cover ranged from 0.02% to 1.07%. Of the biota encountered, most comprised filter feeder organisms (including gorgonians, sponges, and whip corals) whose distribution was associated with pockets of consolidated hard substrate. Benthic community composition varied with both study area and position in relation to the predicted AC125. In general, consolidated substrate was proportionally higher in water shallower than the AC125 compared to on the AC125 or deeper than the AC125. Spatially continuous maps of predicted benthic habitat classes (pre-determined benthic communities) in each study area were developed to characterise biodiversity. Spatial modelling corroborated depth and large-scale structural complexity of the seafloor as surrogates for predicting likely habitat class. This study provides an important assessment of the AC125 and shows that if a distinct coastline exists in the areas we surveyed, it is now largely buried and as such does not provide a unique hard substrate habitat. However, much work remains to fully locate and map the ancient coastline within the vast region of the AC125 and additional surveys in shallow waters adjacent to the AC125 may identify whether some sections lie outside the currently defined KEF., Competing Interests: Santos is the commercial funder of this research yet they had no role in the study design, data collection and analysis, the decision to publish or the preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Wakeford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: The quality of life (QoL) impact of multidisciplinary treatment for patients with nonfunctioning pituitary macroadenomas (NFPMA) is unclear. We sought to investigate associations between patient factors, clinical data, and patient-reported QoL in patients with NFPMA., Methods: Patients with treated NFPMA and > 1 year of follow up after transsphenoidal surgery (TSS) and with no evidence of progressive disease were evaluated utilizing the following patient-reported outcome measures: RAND-36-Item Health Survey, Multidimensional Fatigue Inventory, Cognitive Failures Questionnaire., Results: 229 eligible patients completed QoL questionnaires a median of 7.7 years after initial transsphenoidal surgery (TSS). 25% of participants received radiation therapy (RT) a median of 2.0 years (0.1-22.5) after initial TSS. Patients who received RT were younger (median age 46 v 58, p < 0.0001), had larger tumors (28 mm v 22 mm, p < 0.0001), were more likely to have visual symptoms (65% v 34%, p = 0.0002), and were more likely to have hypopituitarism (93% v 62%, p < 0.0001). Patients with hypopituitarism reported worse energy and fatigue and cognitive function (p < 0.03). Patients who received RT reported significantly worse general health, physical health, physical fatigue and cognitive functioning (p < 0.05). The largest QoL differences were in patients who experienced a financial stressor, independent of treatment type., Conclusion: Hypopituitarism, radiation therapy after TSS, and financial stressors are associated with more impaired QoL in patients with NFPMA. Awareness of these factors can better guide use and timing of radiation therapy in addition to identifying patients who can benefit from multidisciplinary surveillance., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To compare visual acuity (VA) changes using standardized ETDRS best-corrected visual acuity (BCVA) and nonstandardized Snellen VA among subjects enrolled in clinical trials., Design: Retrospective study., Participants: Patients enrolled in prospective clinical trials at 3 urban retina practices., Methods: Best available Snellen VA at the clinic visit before study entry and after exit were compared with the ETDRS BCVA at trial entry and exit. The correlation and discrepancies between Snellen VA and ETDRS methods as well as the VA changes from trial entry to exit were evaluated., Main Outcome Measures: The discrepancy between VA change from trial entry to exit using Snellen VA versus ETDRS BCVA methods., Results: A total of 273 eyes were included. The mean (standard deviation [SD]) Snellen VA was 58.1 (20) ETDRS-equivalent letters (Snellen 20/69) at the clinic visit before trial entry and 61.6 (21) ETDRS-equivalent letters (Snellen 20/59) at the visit after trial exit. The mean (SD) ETDRS BCVA was 65.5 (16) letters (Snellen 20/49) at trial entry and 70.5 (17) letters (Snellen 20/39) at trial exit. The mean VA change from trial entry to exit was not significantly different for ETDRS (5 letters of vision gain) compared with Snellen (3.6 letters of vision gain) methods ( P  = 0.061). Eyes with baseline Snellen VA 20/50 or worse gained significantly more letters using Snellen (9.3 ± 22.3 letters) compared with ETDRS (5.2 ± 18.7 letters; P  = 0.012). Among eyes with baseline Snellen VA of > 20/50, VA gain was significantly greater with the ETDRS method (4.9 ± 12.3 letters) compared with Snellen (-1.5 ± 12.3 letters; P < 0.001)., Conclusions: The mean VA change from clinical trial entry to exit was similar between the ETDRS and Snellen methods. However, among patients with worse baseline Snellen vision, the magnitude of VA change was greater with Snellen compared with ETDRS, whereas among those with better baseline vision, this magnitude was greater with the ETDRS method. Understanding the proportion of the study population with varying VA levels may have implications for interpreting VA outcomes from retrospective clinic-based studies compared with those reported in clinical trials., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2023 by the American Academy of Ophthalmology.)

Chronic caloric deprivation and obesity are complicated by hypercortisolemia. The effects of acute overfeeding and fasting on circulating free cortisol levels and conversion of cortisone to free cortisol are unknown. We hypothesized that serum-free cortisol and free cortisol-to-cortisone ratio would increase after both overfeeding and fasting. This is a prospective study of 22 healthy volunteers who completed a 10-day high-calorie protocol followed by a 10-day fast, separated by a 2-wk washout. Morning free and total cortisol and free cortisone levels (LC/MS) were measured at baseline and after 10 days of each intervention. Both high-calorie feeding and fasting increased total and free cortisol and the free cortisol-to-free cortisone ratio ( P = 0.001 to P = 0.046). There were sex interactions, with significant effects in men ( P < 0.001), but not in women ( P = 0.898 and 1.000, respectively) in subset analyses examining the effects of fasting on free cortisol and the free-to-total cortisol ratio. Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. Further study is warranted to determine whether elevated cortisol levels contribute to complications of starvation and obesity, such as bone fragility. NEW & NOTEWORTHY Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. The effect of fasting on free cortisol levels is modified by sex. Further study is needed to determine the mechanisms driving the increases in cortisol.

Importance: Pituitary adenomas are neoplasms of the pituitary adenohypophyseal cell lineage and include functioning tumors, characterized by the secretion of pituitary hormones, and nonfunctioning tumors. Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons., Observations: Pituitary adenomas are classified as either macroadenomas (≥10 mm) (48% of tumors) or microadenomas (<10 mm). Macroadenomas may cause mass effect, such as visual field defects, headache, and/or hypopituitarism, which occur in about 18% to 78%, 17% to 75%, and 34% to 89% of patients, respectively. Thirty percent of pituitary adenomas are nonfunctioning adenomas, which do not produce hormones. Functioning tumors are those that produce an excess of normally produced hormones and include prolactinomas, somatotropinomas, corticotropinomas, and thyrotropinomas, which produce prolactin, growth hormone, corticotropin, and thyrotropin, respectively. Approximately 53% of pituitary adenomas are prolactinomas, which can cause hypogonadism, infertility, and/or galactorrhea. Twelve percent are somatotropinomas, which cause acromegaly in adults and gigantism in children, and 4% are corticotropinomas, which secrete corticotropin autonomously, resulting in hypercortisolemia and Cushing disease. All patients with pituitary tumors require endocrine evaluation for hormone hypersecretion. Patients with macroadenomas additionally require evaluation for hypopituitarism, and patients with tumors compressing the optic chiasm should be referred to an ophthalmologist for formal visual field testing. For those requiring treatment, first-line therapy is usually transsphenoidal pituitary surgery, except for prolactinomas, for which medical therapy, either bromocriptine or cabergoline, is usually first line., Conclusions and Relevance: Clinically manifest pituitary adenomas affect approximately 1 in 1100 people and can be complicated by syndromes of hormone excess as well as visual field defects and hypopituitarism from mass effect in larger tumors. First-line therapy for prolactinomas consists of bromocriptine or cabergoline, and transsphenoidal pituitary surgery is first-line therapy for other pituitary adenomas requiring treatment.

Introduction: This study aimed to investigate the level of patient involvement in medication reconciliation processes and factors associated with that involvement in patients with cardiovascular disease presenting to the emergency department., Methods: An observational and cross-sectional design was used. Patients with cardiovascular disease presenting to the adult emergency department of an academic medical center completed a structured survey inclusive of patient demographics and measures related to the study concepts. Data abstracted from the electronic health record included the patient's medical history and emergency department visit data. Our multivariable model adjusted for age, gender, education, difficulty paying bills, health status, numeracy, health literacy, and medication knowledge and evaluated patient involvement in medication discussions as an outcome., Results: Participants' (N = 93) median age was 59 years (interquartile range 51-67), 80.6% were white, 96.8% were not Hispanic, and 49.5% were married or living with a partner. Approximately 41% reported being employed and 36.9% reported an annual household income of <$25,000. Almost half (n = 44, 47.3%) reported difficulty paying monthly bills. Patients reported moderate medication knowledge (median 3.8, interquartile range 3.4-4.2) and perceived involvement in their care (41.8 [SD = 9.1]). After controlling for patient characteristics, only difficulty paying monthly bills (b = 0.36, P = .005) and medication knowledge (b = 0.30, P = .009) were associated with involvement in medication discussions., Discussion: Some patients presenting to the emergency department demonstrated moderate medication knowledge and involvement in medication discussions, but more work is needed to engage patients., (Copyright © 2022 Emergency Nurses Association. Published by Elsevier Inc. All rights reserved.)

Purpose: To report a case of bilateral serous retinal detachments in a patient with preeclampsia without hypertension using multimodal ophthalmic imaging., Methods: Case report., Results: This case demonstrates the rare presentation of bilateral serous retinal detachment in a patient with preeclampsia without hypertension. Characteristic subretinal fluid was seen on examination and optical coherence tomography. No leakage was noted on fluorescein angiography. Treatment was deferred, and the subretinal fluid resolved within 3 weeks., Conclusion: Practitioners should be aware of the rare presentation of serous retinal detachments in preeclampsia, even in the absence of hypertension. Long-term sequelae are uncommon and usually only seen in severe disease. Delivery should be considered once serous retinal detachment develops.

Introduction: This phase 1 trial assessed the safety, pharmacokinetics, and preliminary antitumor activity of RO7297089, an anti-BCMA/CD16a bispecific antibody., Methods: RO7297089 was administered weekly by intravenous infusion to patients with relapsed/refractory multiple myeloma. The starting dose was 60 mg in this dose-escalation study utilizing a modified continual reassessment method with overdose control model., Results: Overall, 27 patients were treated at doses between 60 and 1850 mg. The maximally administered dose was 1850 mg due to excipients in the formulation that did not allow for higher doses to be used. The maximum tolerated dose was not reached. The most common adverse events irrespective of grade and relationship to the drug were anemia, infusion-related reaction, and thrombocytopenia. Most common treatment-related grade ≥ 3 toxicities were ALT/AST increase and reduced lymphocyte count. Pharmacokinetic studies suggested non-linear pharmacokinetics and target-mediated drug disposition, with a trend of approaching linear pharmacokinetics at doses of 1080 mg and higher. Partial response was observed in two patients (7%), minimal response in two patients (7%), and stable disease in 14 patients (52%)., Conclusions: RO7297089 was well tolerated at doses up to 1850 mg, and the efficacy data supported activity of RO7297089 in multiple myeloma. Combination with other agents may further enhance its potential as an innate immune cell engager in multiple myeloma., Trial Registration: ClinicalTrials.gov: NCT04434469; Registered June 16, 2020; https://www., Clinicaltrials: gov/ct2/show/NCT04434469 ., (© 2023. Genentech, Inc.)

Objective: Anorexia nervosa (AN) is commonly associated with depression, anxiety, and deficits in socioemotional functioning. Basal levels of oxytocin, a neurohormone with antidepressant, anxiolytic, and prosocial properties, are low in women with AN. However, the relationship between oxytocin and psychopathology of AN/atypical AN has not been examined in individuals with primarily food restriction (AN/AtypAN-R) or those with restriction plus binge/purge behaviors (AN/AtypAN-BP) alone, which is important to further elucidate the neurobiology of different AN presentations. We investigated whether oxytocin levels are related to eating, affective, and socioemotional psychopathology in women with AN/AtypAN-R and separately AN/AtypAN-BP., Methods: In a cross-sectional study of 53 women with low-weight AN or atypical AN based on DSM-5 (AN/AtypAN-R: n=21, AN/AtypAN-BP: n=32), we obtained fasting serum oxytocin levels and self-report measures of psychopathology, including the Eating Disorder Examination-Questionnaire (EDE-Q), Beck Depression Inventory-IA (BDI), State-Trait Anxiety Inventory (STAI), and Toronto Alexithymia Scale (TAS-20)., Results: In individuals with AN/AtypAN-R, oxytocin levels were negatively associated with eating psychopathology (EDE-Q Global Score: r=-0.49, p=0.024), depressive and anxiety symptoms (BDI Total Score: r=-0.55, p=0.009; STAI Trait Score: r=-0.63, p=0.002), and socioemotional symptoms (TAS-20 Difficulty Identifying Feelings Score: r=-0.49, p=0.023). In contrast, in those with AN/AtypAN-BP oxytocin levels were negatively associated with depressive symptoms only (BDI Total Score: r=-0.52, p=0.049)., Conclusions: These findings support the notion that AN/AtypAN-R and AN/AtypAN-BP might have divergent underlying neurobiology. Understanding these differences is crucial to develop targeted treatments for a population with high levels of chronicity, for which no specific pharmacological treatments are currently available., Clinical Trial Registration: https://clinicaltrials.gov, identifier: NCT01121211., Competing Interests: KM has received study medication from Pfizer and an investigator-initiated research grant from Amgen. She has had equity in Bristol-Myers Squibb, General Electric, Boston Scientific, Amgen, and Becton Dickinson. EL was on the scientific advisory board and has/had a financial interest in OXT Therapeutics, a company that developed oxytocin-based therapeutics for obesity and metabolic disease. She also received an investigator-initiated grant from Tonix Pharmaceuticals. The remaining 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 Plessow, Galbiati, Eddy, Misra, Miller, Klibanski, Aulinas and Lawson.)

Background: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI)., Objective: To model the relationships between handgrip strength, mobility, and MRI volumetry., Methods: We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance., Results: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes., Conclusion: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

Background and Aims: Although lower lean mass is associated with greater diabetes prevalence in cross-sectional studies, prospective data specifically in middle-aged Black and White adults are lacking. Relative appendicular lean mass (ALM), such as ALM adjusted for body mass index (BMI), is important to consider since muscle mass is associated with overall body size. We investigated whether ALM/BMI is associated with incident type 2 diabetes in the Coronary Artery Risk Development in Young Adults study., Methods and Results: 1893 middle-aged adults (55% women) were included. ALM was measured by DXA in 2005-06. Incident type 2 diabetes was defined in 2010-11 or 2015-16 as fasting glucose ≥7 mmol/L (126 mg/dL), 2-h glucose on OGTT ≥11.1 mmol/L (200 mg/dL) (2010-11 only), HbA 1C  ≥48 mmol/mol (6.5%) (2010-11 only), or glucose-lowering medications. Cox regression models with sex stratification were performed. In men and women, ALM/BMI was 1.07 ± 0.14 (mean ± SD) and 0.73 ± 0.12, respectively. Seventy men (8.2%) and 71 women (6.8%) developed type 2 diabetes. Per sex-specific SD higher ALM/BMI, unadjusted diabetes risk was lower by 21% in men [HR 0.79 (0.62-0.99), p = 0.04] and 29% in women [HR 0.71 (0.55-0.91), p = 0.008]. After adjusting for age, race, smoking, education, physical activity, and waist circumference, the association was no longer significant. Adjustment for waist circumference accounted for the attenuation in men., Conclusion: Although more appendicular lean mass relative to BMI is associated with lower incident type 2 diabetes in middle-aged men and women over 10 years, its effect may be through other metabolic risk factors such as waist circumference, which is a correlate of abdominal fat mass., Competing Interests: Declaration of competing interest KKM is the recipient of an investigator-initiated grant from Amgen, has received study medication from Pfizer, and has had equity in Amgen, Bristol-Myers Squibb, General Electric, Boston Scientific, and Becton Dickinson. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Understanding how follicular helper T cells (TFH) regulate the specialization, maturation, and differentiation of adaptive B cell immunity is crucial for developing durable high-affinity immune protection. Using indexed single-cell molecular strategies, we reveal a skewed intraclonal assortment of higher-affinity T cell receptors and the distinct molecular programming of the localized TFH compartment compared with emigrant conventional effector T H cells. We find a temporal shift in B cell receptor class switch, which permits identification of inflammatory and anti-inflammatory modules of transcriptional programming that subspecialize TFH function before and during the germinal center (GC) reaction. Late collapse of this local primary GC reaction reveals a persistent post-GC TFH population that discloses a putative memory TFH program. These studies define subspecialized antigen-specific TFH transcriptional programs that progressively change with antibody class-specific evolution of high-affinity B cell immunity and a memory TFH transcriptional program that emerges upon local GC resolution.

Objective: Anorexia nervosa is complicated by high bone resorption, low bone mineral density (BMD), and increased fracture risk. We investigated whether off-label antiresorptive therapy with denosumab increases BMD in women with anorexia nervosa., Design: Twelve-month, randomized, double-blind, placebo-controlled study., Methods: Thirty ambulatory women with anorexia nervosa and areal BMD (aBMD) T-score <-1.0 at ≥1 sites were randomized to 12 months of denosumab (60 mg subcutaneously q6 months)(n = 20) or placebo (n = 10). Primary end point was postero-anterior (PA) lumbar spine aBMD by dual-energy x-ray absorptiometry. Secondary end points included femoral neck aBMD, tibia and radius volumetric BMD and bone microarchitecture by high-resolution peripheral quantitative CT, tibia and radius failure load by finite element analysis (FEA), and markers of bone turnover., Results: Baseline mean (±s.d.) age (29 ± 8 (denosumab) vs 29 ± 7 years (placebo)), BMI (19.0 ± 1.7 vs 18.0 ± 2.0 kg/m2), and aBMD (PA spine Z-score -1.6±1.1 vs -1.7±1.4) were similar between groups. PA lumbar spine aBMD increased in the denosumab vs placebo group over 12 months (P = 0.009). The mean (95% CI) increase in PA lumbar spine aBMD was 5.5 (3.8-7.2)% in the denosumab group and 2.2 (-0.3-4.7)% in the placebo group. The change in femoral neck aBMD was similar between groups. Radial trabecular number increased, radial trabecular separation decreased, and tibial cortical porosity decreased in the denosumab vs placebo group (P ≤ 0.006). Serum C-terminal telopeptide of type I collagen and procollagen type I N-terminal propeptide decreased in the denosumab vs placebo group (P < 0.0001). Denosumab was well tolerated., Conclusions: Twelve months of antiresorptive therapy with denosumab reduced bone turnover and increased spine aBMD, the skeletal site most severely affected in women with anorexia nervosa.

Background: Preparation for exploration class space flight requires planning to support human life in many circumstances including healthcare emergencies such as the need for acute surgical care, a notable example of which is appendicitis. Although performing a laparoscopic appendectomy on Earth is routine for a trained general surgeon, it is far from routine for a non-surgeon working in microgravity where IVs do not drip, drains do not drain, and gaseous anesthetic is out of the question. Because the procedure for laparoscopic appendectomy is so well documented, it was the ideal procedure on which to base a study on how to deconstruct a surgical procedure to examine all actions, skills, equipment, and supplies needed for success by non-surgeons working in an extreme environment. Study Design : Our challenge was to develop a task analysis model robust enough to include 3 performers (in the roles of surgeon, assistant, and anesthesiologist) including each action and instrument or supply item needed in chronological order, while indicating which actions were completed independently and which were done in tandem. We also had to indicate where variations in the actions would be determined by the negative response of the patient (failure mode), and which actions and supply items needed further research to accommodate working in microgravity. We opted to begin with a hierarchical task analysis model (HTA) because the steps in the task are sequential; but we expanded the typical linear presentation of data to a multi-column spread sheet with active links to instructional video clips where needed. Content development was an iterative process beginning with a scoping review of literature to select a baseline task analysis of the procedure. The SAGES 2010 approach was selected as most comprehensive, but logically focused on the surgeon's performance with few references to the assistant or anesthesiologist. Those gaps were filled using content from training materials developed for surgical technicians and nurse anesthetists. The second step was an expert review of the spread sheet to identify gaps and inadequacies. The third step was a minute comparison of spread sheet content to actions and equipment as documented on 2 videotapes of the procedure performed by our team surgeon on otherwise healthy patients. The final review was accomplished by replicating the procedure on 360° video (with narration) using the spread sheet as a guide, then cross checking and correcting the spread sheet to correspond with the 360° video. This test procedure was performed on a lightly preserved, fresh cadaver since working at that very slow, deliberate pace would not be in the best interest of an actual patient. Results: In this study, simulation was actually used to test the expanded HTA rather than to evaluate a learner. The final spread sheet included 178 lines, 13 columns, 13 illustrations, and 4 active links to instructional video clips. Thirteen items or issues were identified as needing further research, 8 action sequences were identified as generalizable skills, and 27 supply or equipment items were identified as multipurpose. Excluding the pharmaceuticals necessary for IV general anesthesia (that research is on-going), we were able to replicate a laparoscopic appendectomy on a fresh cadaver using no more than 30 items. The procedure was done using 3 trocars with very few instrument exchanges through the trocars since the surgical assistant assumed the role of laparoscopic camera operator during the procedure. Conclusion: An expanded HTA of a surgical procedure can produce many useful outcomes including integrated training for all team members, review of instrumentation and supplies and, in our case, identifying areas for adapting to an extreme environment. Using an interdisciplinary team including instructional designers, subject matter experts from medicine and biomedical engineering, and media production enriched the process.

Context: Obesity is a state of relative growth hormone (GH) deficiency, and GH has been identified as a candidate disease-modifying target in nonalcoholic fatty liver disease (NAFLD) because of its lipolytic and anti-inflammatory properties. However, the GH/IGF-1 axis has not been well characterized in NAFLD., Objective: We aimed to investigate serum GH and IGF-1 levels in relation to intrahepatic lipid content (IHL) and markers of hepatocellular damage and fibrosis in NAFLD., Methods: This cross-sectional study included 102 adults (43% women; age 19-67; BMI ≥ 25 kg/m2) without type 2 diabetes. IHL was measured by magnetic resonance spectroscopy; NAFLD was defined by ≥ 5% IHL. Peak-stimulated GH in response to GH releasing hormone and arginine was assessed as was serum IGF-1 (LC/MS)., Results: There was no difference in mean age, BMI, or sex distribution in NAFLD vs controls. Mean (± SD) IHL was higher in NAFLD vs controls (21.8 ± 13.3% vs 2.9 ± 1.1%, P < 0.0001). Mean peak-stimulated GH was lower in NAFLD vs controls (9.0 ± 6.3 vs 15.4 ± 11.2 ng/mL, P = 0.003), including after controlling for age, sex, visceral adipose tissue, and fasting glucose. In a stepwise model, peak-stimulated GH predicted 14.6% of the variability in IHL (P = 0.004). Higher peak-stimulated GH was also associated with lower ALT. Higher serum IGF-1 levels were associated with lower risk of liver fibrosis by Fibrosis-4 scores., Conclusion: Individuals with NAFLD have lower peak-stimulated GH levels but similar IGF-1 levels as compared to controls. Higher peak-stimulated GH levels are associated with lower IHL and less hepatocellular damage. Higher IGF-1 levels are associated with more favorable fibrosis risk scores. These data implicate GH and IGF-1 as potential disease modifiers in the development and progression of NAFLD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Anorexia nervosa (AN) is a serious condition characterized by undernutrition, complicated by endocrine dysregulation, and with few predictors of recovery. Urinary free cortisol (UFC) is a predictor of weight gain, but 24-h urine samples are challenging to collect. We hypothesized that serum dehydroepiandrosterone sulfate (DHEAS), which like cortisol is regulated by adrenocorticotropic hormone (ACTH), would predict weight gain and increases in fat mass in women with AN., Methods: We prospectively studied 34 women with AN and atypical AN, mean age 27.4 ± 7.7 years (mean ± SD), who received placebo in a 6-month randomized trial. Baseline DHEAS and 24-h UFC were measured by liquid chromatography with tandem mass spectrometry. Body composition was assessed at baseline and 6 months by DXA and cross-sectional abdominal CT at L4., Results: Mean baseline DHEAS level was 173 ± 70 μg/dl (0.7 ± 0.3 times the mean normal range for age) and mean baseline UFC (n = 15) was 20 ± 18 μg/24 h (normal: 0-50 μg/24 h). Higher DHEAS levels predicted weight gain over 6 months (r = 0.61, p < .001). DHEAS levels also predicted increases in fat mass (r = 0.40, p = .03), appendicular lean mass (r = 0.38, p = .04), and abdominal adipose tissue (r = 0.60, p < .001). All associations remained significant after controlling for age, baseline BMI, OCP use, duration of AN, and SSRI/SNRI use. DHEAS levels correlated with UFC (r = 0.61, p = .02)., Discussion: In women with AN, higher serum DHEAS predicts weight gain and increases in fat and muscle mass. Additional studies are needed to confirm these findings and further elucidate the association between DHEAS and weight gain., Public Significance: Anorexia nervosa is a severe psychiatric condition, and predictors of weight recovery are needed to improve prognostication and guide therapeutic decision making. While urinary cortisol is a predictor of weight gain, 24-h urine collections are challenging to obtain. Like cortisol, dehydroepiandrosterone sulfate (DHEAS) is a hormone produced by the adrenal glands. As a readily available blood test, DHEAS holds promise as more practical biomarker of weight gain in anorexia nervosa., (© 2022 Wiley Periodicals LLC.)

Younger patients (18 to 65 years old) are often excluded from delirium outcome studies. We sought to determine if delirium was associated with short-term adverse outcomes in a diverse cohort of younger and older patients with acute heart failure (AHF). We conducted a multi-center prospective cohort study that included adult emergency department patients with confirmed AHF. Delirium was ascertained using the Brief Confusion Assessment Method (bCAM). The primary outcome was a composite outcome of 30-day all-cause death, 30-day all-cause rehospitalization, and prolonged index hospital length of stay. Multivariable logistic regression was performed, adjusting for demographics, cognitive impairment without delirium, and HF risk factors. Older age (≥ 65 years old)*delirium interaction was also incorporated into the model. Odds ratios (OR) with their 95% confidence intervals (95%CI) were reported. A total of 1044 patients with AHF were enrolled; 617 AHF patients were < 65 years old and 427 AHF patients were ≥ 65 years old, and 47 (7.6%) and 40 (9.4%) patients were delirious at enrollment, respectively. Delirium was significantly associated with the composite outcome (adjusted OR = 1.64, 95%CI: 1.02 to 2.64). The older age*delirium interaction p-value was 0.47. In conclusion, delirium was common in both younger and older patients with AHF and was associated with poorer short-term outcomes in both cohorts. Younger patients with acute heart failure should be included in future delirium outcome studies., Competing Interests: Jin H. Han receives research support from Bristol Myers Squibb, Boehringer Ingelheim, and Merck. Candace D. McNaughton receives research support from Pfizer. Phillip D. Levy is a consultant for Apex Innovations, AstraZeneca, Bristol Myers Squibb, Mespere, Novartis, Cardionomics, Baim Institute, Ortho Clinical Diagnostics, Roche Diagnostics, Siemens, and Hospital Quality Foundation. Dr. Levy also receives research support from Amgen, Arterez, Bristol Myers Squibb, Beckman Coulter, and the Blue Cross Blue Shield of Michigan Foundation (BCBSMF). Peter S. Pang is a consultant for Baxter, Bristol Myers Squibb, Heart Initiative (DSMB). He also receives research support from Bristol Myers Squibb, Roche, Novartis, OrthoDiagnostics, Beckman Coulter, and Abbott. Mette L. Cole is employed by Roche. Sean P. Collins is a consultant for Ortho Clinical Diagnostics, Boehringer Ingelheim, Roche, and Bristol Myers Squibb. He receives research support from Ortho Clinical Diagnostics, Bristol Myers Squibb, Novartis, Astra Zeneca. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Antibodies are produced across multiple isotypes with distinct properties that coordinate initial antigen clearance and confer long-term antigen-specific immune protection. Here, we interrogate the molecular programs of isotype-specific murine plasma cells (PC) following helper T cell-dependent immunization and within established steady-state immunity. We developed a single-cell-indexed and targeted molecular strategy to dissect conserved and divergent components of the rapid effector phase of antigen-specific IgM + versus inflammation-modulating programs dictated by type 1 IgG2a/b + PC differentiation. During antibody affinity maturation, the germinal center (GC) cycle imparts separable programs for post-GC type 2 inhibitory IgG1 + and type 1 inflammatory IgG2a/b + PC to direct long-term cellular function. In the steady state, two subsets of IgM + and separate IgG2b + PC programs clearly segregate from splenic type 3 IgA + PC programs that emphasize mucosal barrier protection. These diverse isotype-specific molecular pathways of PC differentiation control complementary modules of antigen clearance and immune protection that could be selectively targeted for immunotherapeutic applications and vaccine design.

Background: While physiologic estrogen replacement results in increases in areal bone mineral density (aBMD) in hypoestrogenic adolescent girls and young adult women with AN, data are lacking regarding its impact on measures of volumetric BMD (vBMD), bone geometry, and structure. Methods: 23 young women with anorexia nervosa (AN) and 27 normal-weight healthy controls (HC) between 14−25 years old were followed for 12 months. AN participants received transdermal 17β-estradiol (continuously) with 10 days of cyclic oral progesterone (100 mg daily) every month for the study duration (AN-E+). DXA was used to measure aBMD and body composition, high resolution peripheral quantitative CT (HRpQCT) to assess vBMD, bone geometry and structure at the distal radius and tibia, and microfinite element analysis to estimate strength. Results: Groups did not differ for age. Median baseline BMI z-scores were −1.13 (−1.58, −0.38) in AN-E+ vs. 0.08 (−0.40, 0.84) in HC (p < 0.0001). For most HRpQCT parameters and strength estimates, young women with AN receiving physiologic estrogen replacement demonstrated similar changes over 12 months as did normoestrogenic HC. Additionally, radial cortical tissue mineral density, cortical vBMD, and failure load increased (p = 0.01; p = 0.02; p = 0.004 respectively) over 12 months in AN-E+ compared to HC. Conclusions: With physiologic estrogen replacement, bone accrual improved in AN to approximate changes observed in normoestrogenic controls followed without any intervention, with additional benefits observed for cortical tissue mineral density, cortical vBMD, and failure load at the radius in AN vs. controls. Thus, this strategy for estrogen replacement effectively mimics the effects of endogenous estrogen on bone structure and estimated strength.

Offshore platforms, subsea pipelines, wells and related fixed structures supporting the oil and gas (O&G) industry are prevalent in oceans across the globe, with many approaching the end of their operational life and requiring decommissioning. Although structures can possess high ecological diversity and productivity, information on how they interact with broader ecological processes remains unclear. Here, we review the current state of knowledge on the role of O&G infrastructure in maintaining, altering or enhancing ecological connectivity with natural marine habitats. There is a paucity of studies on the subject with only 33 papers specifically targeting connectivity and O&G structures, although other studies provide important related information. Evidence for O&G structures facilitating vertical and horizontal seascape connectivity exists for larvae and mobile adult invertebrates, fish and megafauna; including threatened and commercially important species. The degree to which these structures represent a beneficial or detrimental net impact remains unclear, is complex and ultimately needs more research to determine the extent to which natural connectivity networks are conserved, enhanced or disrupted. We discuss the potential impacts of different decommissioning approaches on seascape connectivity and identify, through expert elicitation, critical knowledge gaps that, if addressed, may further inform decision making for the life cycle of O&G infrastructure, with relevance for other industries (e.g. renewables). The most highly ranked critical knowledge gap was a need to understand how O&G structures modify and influence the movement patterns of mobile species and dispersal stages of sessile marine species. Understanding how different decommissioning options affect species survival and movement was also highly ranked, as was understanding the extent to which O&G structures contribute to extending species distributions by providing rest stops, foraging habitat, and stepping stones. These questions could be addressed with further dedicated studies of animal movement in relation to structures using telemetry, molecular techniques and movement models. Our review and these priority questions provide a roadmap for advancing research needed to support evidence-based decision making for decommissioning O&G infrastructure., (© 2022 Crown copyright and Commonwealth of Australia. Global Change Biology published by John Wiley & Sons Ltd. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Purpose: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis)., Methods: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA)., Results: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD., Conclusion: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

An understanding of stock recruitment dynamics in fisheries is fundamental to successful management. Pinctada maxima is a bivalve mollusc widely distributed throughout the Indo-Pacific and is the main species targeted for cultured pearl and pearl shell production in Australia. Pearl production in Australia relies heavily on wild-caught individuals, the majority of which come from the Eighty Mile Beach region near Broome in Western Australia. In this study, we used a genotyping by sequencing approach to explore fine-scale patterns of genetic connectivity among inshore shallow and offshore deep populations of P. maxima near Eighty Mile Beach. Our results revealed high-levels of gene flow among inshore and offshore sites and no differences in genetic diversity between depths. Global estimates of genetic differentiation were low ( F ST = 0.006) but significantly different from zero, and pairwise estimates of genetic differentiation among sites were significant in only 3% of comparisons. Moreover, Bayesian clustering detected no separation of inshore and offshore sample sites, and instead showed all samples to be admixed among sites, locations and depths. Despite an absence of any clear spatial clustering among sites, we identified a significant pattern of isolation by distance. In a dynamic environment like Eighty Mile Beach, genetic structure can change from year-to-year and successive dispersal and recruitment events over generations likely act to homogenize the population. Although we cannot rule out the null hypothesis of panmixia, our data indicate high levels of dispersal and connectivity among inshore and offshore fishing grounds., Competing Interests: The authors declare that they have no competing interests., (© 2022 Thomas and Miller.)

Background/objectives: Although relatively less muscle mass has been associated with greater diabetes prevalence, whether there is an association between muscle mass and diabetes prevalence independent of body fat distribution is unknown. The objective was to determine whether less skeletal muscle mass is associated with greater diabetes prevalence in young men and women independent of body fat distribution., Subjects/methods: One thousand seven hundred and sixty-four adults, aged 20-49 years old, from the United States National Health and Nutrition Examination Survey (2005-2006). Body composition, including appendicular lean mass (ALM), was measured by dual-energy x-ray absorptiometry. Diabetes was defined as fasting blood glucose ≥7 mmol/l, 2-h blood glucose ≥11.1 mmol/l on 75 g OGTT, HbA1c ≥ 48 mmol/mol (6.5%), use of diabetes medications, or self-reported diagnosis of diabetes., Results: The odds of diabetes were 1.31 times higher in men [OR 1.31 (1.18-1.45), p = 0.0001], and 1.24 times higher in women [OR 1.24 (1.05-1.46), p = 0.01], per percent decrease in ALM/weight after controlling for age, race, height, smoking, and education. After additionally controlling for android/gynoid fat, the odds of diabetes were 1.20 times higher per percent decrease in ALM/weight in men [OR 1.20 (1.04-1.37), p = 0.01]; an inverse association was also observed in women, albeit was not statistically significant [OR 1.08 (0.90-1.30), p = 0.42]., Conclusions: Less muscle mass was associated with greater diabetes prevalence independent of body fat distribution in young men. The association was not statistically significant in women after controlling for android and gynoid adiposity. Low muscle mass could be a causal factor in the development of type 2 diabetes or a correlated marker of higher metabolic risk., (© 2022. The Author(s).)

Introduction: Angiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors., Materials and Methods: 219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated in vitro with the endothelial tube formation assay and in vivo in RbΔ19 mice., Results: 71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFβ). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice., Conclusion: Human pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors., 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 © 2022 Zhou, Hu, Zhu, Nie, Zhao, Faje, Labelle, Swearingen, Lee, Hedley-Whyte, Zhang, Jones, Miller, Klibanski, Zhou and Soberman.)