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Simple Summary: The incidence and mortality rates of cancer in the Surveillance, Epidemiology, and End Results (SEER) Program for adolescent and young adult (AYA) patients show distinct patterns among early-onset cancers. For some cancers, AYA cancer rates varied by age group, sex, race, ethnicity and geography. Monitoring the rates and time trends of AYA cancer emphasizes the distinct health concern for this age group. (1) Background: The incidence rate of early onset-cancer (<50) has increased since 1995. Among younger people, cancers in AYAs (aged 15–39 y) are often biologically distinct tumors from those treated in the pediatric and older adult population. The current study describes trends in the United States for the most recent years including the first year of the COVID-19 epidemic. We aimed to describe the recent incidence and mortality trends of cancers in AYAs (aged 15–39 y). (2) Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER 22) from 1 January 2016 to 31 December 2021. Age-adjusted incidence and mortality rates were assessed by SEER*Stat 8.4.3 for major cancer types by sex, race/ethnicity, age, and metropolitan/nonmetropolitan status. Time trends of age-adjusted incidence and mortality rates were examined by sex and metropolitan/nonmetropolitan status. (3) Results: Age-adjusted overall cancer incidence and mortality rates were stable during this study period. The age-adjusted incidence rates declined significantly for ependymoma, melanoma, carcinomas of lung, bronchus, and trachea, unspecified malignant neoplasms, and non-Hodgkin's lymphoma. Significant increases were found for gastrointestinal tract cancers and non-Kaposi sarcomas. The age-adjusted mortality rate decreased for acute myeloid leukemia, melanoma, carcinomas of liver and intrahepatic bile ducts, kidney and, in women, leukemia. For some cancers, rates differed by sex, race, ethnicity, and geography. Monitoring the rates and time trends of AYA cancer emphasizes the distinct health concern for this age group. [ABSTRACT FROM AUTHOR]

Background and Aims: Exercise is recommended for the management of metabolic dysfunction‐associated steatotic liver disease (MASLD), yet effects on liver histology remain unknown, especially without significant weight loss. We aimed to examine changes in surrogate measures of liver histological response with exercise training. Methods: We conducted a post hoc pooled analysis of three randomised controlled trials (duration: 12–20 weeks) comparing aerobic exercise interventions with controls. The primary outcome measure was a ≥30% relative reduction in (MRI‐measured) liver fat, as a surrogate measure of liver histological response (the threshold necessary for fibrosis improvement). Secondary outcome measures were changes in other biomarkers of liver fibrosis, anthropometry, body composition and aerobic fitness. Results: Eighty‐eight adults (exercise: 54, control: 34; male: 67%) were included with mean (SD) age 51 (11) years and body mass index 33.3 (5.2) kg/m2. Following the intervention, exercise had ~5‐fold (OR [95%CI]: 4.86 [1.72, 13.8], p =.002) greater odds of ≥30% relative reduction in MRI‐measured liver fat compared with control. This paralleled the improvements in anthropometry (waist and hip circumference reduction), body composition (body fat, visceral and subcutaneous adipose tissue) and aerobic fitness (V̇O2peak, ventilatory threshold and exercise capacity). Importantly, these effects were independent of clinically significant body weight loss (<3% body weight). Conclusion: Exercise training led to clinically meaningful improvements in surrogate serum‐ and imaging‐based measures of liver histological change, without clinically meaningful body weight reduction. These data reinforce the weight‐neutral benefit of exercise training and suggest that aerobic training may improve liver fibrosis in patients with MASLD. [ABSTRACT FROM AUTHOR]

The identification of prognostic and predictive biomarker signatures is crucial for drug development and providing personalized treatment to cancer patients. However, the discovery process often involves high-dimensional candidate biomarkers, leading to inflated family-wise error rates (FWERs) due to multiple hypothesis testing. This is an understudied area, particularly under the survival framework. To address this issue, we propose a novel three-stage approach for identifying significant biomarker signatures, including prognostic biomarkers (main effects) and predictive biomarkers (biomarker-by-treatment interactions), using Cox proportional hazard regression with high-dimensional covariates. To control the FWER, we adopt an adaptive group LASSO for variable screening and selection. We then derive adjusted p-values through multi-splitting and bootstrapping to overcome invalid p values caused by the penalized approach's restrictions. Our extensive simulations provide empirical evaluation of the FWER and model selection accuracy, demonstrating that our proposed three-stage approach outperforms existing alternatives. Furthermore, we provide detailed proofs and software implementation in R to support our theoretical contributions. Finally, we apply our method to real data from cancer genetic studies. [ABSTRACT FROM AUTHOR]

Background The association between angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and severe acute respiratory syndrome coronavirus 2 susceptibility, particularly via ACE-2 receptor upregulation in the kidneys, raises concerns about potential kidney disease risks in long coronavirus disease (COVID) patients. This study explores the association of ACEI/ARB therapy on acute kidney injury (AKI), chronic kidney disease (CKD) and all-cause mortality in patients with and without long COVID. Methods A retrospective cohort study using TriNetX datasets was conducted, with diagnoses of long COVID via International Classification of Diseases, Tenth Revision (ICD-10) codes and prescription for ACEI/ARB as the classification of four cohorts: long COVID ACEI/ARB users (LCAUs), long COVID ACEI/ARB non-users (LCANs), non-long COVID ACEI/ARB users (NLCAUs) and non-long COVID ACEI/ARB non-users (NLCANs). Multivariable stratified Cox proportional hazards regression models assessed the adjusted hazard ratios (aHRs) across groups. Additional analyses were conducted, including time-dependent exposure analysis and comparison with an active comparator, calcium channel blockers. Results Our study included 18 168 long COVID and 181 680 propensity score-matched non-long COVID patients from October 2021 to October 2023. ACEI/ARB use did not significantly affect the risk of AKI or CKD when comparing LCAUs with LCANs and NLCAUs with NLCANs. However, a protective effect against all-cause mortality was observed {aHR 0.79 [95% confidence interval (CI) 0.65–0.93]} in the NLCAU group compared with the NLCAN group. Conversely, long COVID was associated with increased risks of CKD [aHR 1.49 (95% CI 1.03–2.14)] and all-cause mortality [aHR 1.49 (95% CI 1.00–2.23)] when comparing LCANs with NLCANs. The additional analyses support the primary findings. Conclusions ACEI/ARB treatment does not increase the incidence of CKD or AKI, regardless of long COVID status. However, long COVID itself is associated with increasing risks of kidney diseases and all-cause mortality. [ABSTRACT FROM AUTHOR]

In clinical and observational studies, secondary outcomes are frequently collected alongside the primary outcome for each subject, yet their potential to improve the analysis efficiency remains underutilized. Moreover, missing data, commonly encountered in practice, can introduce bias to estimates if not appropriately addressed. This article presents an innovative approach that enhances the empirical likelihood-based information borrowing method by integrating missing-data techniques, ensuring robust data integration. We introduce a plug-in inverse probability weighting estimator to handle missingness in the primary analysis, demonstrating its equivalence to the standard joint estimator under mild conditions. To address potential bias from missing secondary outcomes, we propose a uniform mapping strategy, imputing incomplete secondary outcomes into a unified space. Extensive simulations highlight the effectiveness of our method, showing consistent, efficient, and robust estimators under various scenarios involving missing data and/or misspecified secondary models. Finally, we apply our proposal to the Uniform Data Set from the National Alzheimer's Coordinating Center, exemplifying its practical application. [ABSTRACT FROM AUTHOR]

Introduction: Berries are a rich source of antioxidant polyphenols and other nutrients that are associated with good health. Allostatic load (AL) is an aggregate measure of chronic stress-induced physiological dysregulations across cardiovascular, metabolic, autonomic, and immune systems; the extent of these dysregulations, collectively or in each system, can be characterized by a composite score or a domain score assessed by integrated biomarkers. It was hypothesized that the anti-inflammatory and other effects of berries lower AL. The association was determined between berry consumption and AL composite and domain scores in the 2003–2010 National Health and Nutrition Examination Survey (NHANES). Methods: Berry intake was measured using two 24 h dietary recalls collected from US adults in the 2003–2010 NHANES (n = 7684). The association with AL and its specific domains was examined using population weight-adjusted multivariable linear regression. Results: The mean AL composite scores for consumers of any berries (11.9), strawberries (11.6), and blueberries (11.6), respectively, were significantly lower than nonconsumers (12.3), after fully adjusting for sociodemographic, lifestyle, and dietary confounders. A significant dose-response relationship was determined between greater consumption of total berries, strawberries, and blueberries and lower mean AL composite scores (p-trend < 0.05, for all). Consistently, mean cardiovascular and metabolic domain scores remained significantly lower in the consumers of total berries (mean cardiovascular domain score: 4.73 versus 4.97 for nonconsumers; mean metabolic domain score: 2.97 versus 3.1), strawberries (4.73 versus 4.95; 2.99 versus 3.1), and blueberries (4.6 versus 4.95; 2.92 versus 3.11). Berry consumers also had significantly lower mean AL immune scores (1.52 versus 1.56) and lower mean AL autonomic scores (2.49 versus 2.57) than nonconsumers (initial sample: n = 15,620). Conclusions: The current study indicates that consumption of berries lowers the AL composite scores and potentially reduces stress-related disease risks in the US adult population. [ABSTRACT FROM AUTHOR]

Black breast cancer survivors (BCS) in comparison with White BCS are more likely to experience suboptimal quality of life (QoL). QoL is a multi-dimensional concept that focuses on different aspects of well-being (e.g., emotional well-being). There is limited evidence on the perspectives and experiences of QoL (e.g., the influence of breast cancer on QoL) and the QoL concerns (e.g., negative perceptions of body appearance) among Black BCS. The purpose of this study was to explore the QoL experiences and QoL concerns of Black BCS. Primary data was collected in semi-structured interviews and analyzed using a thematic analysis. A narrative approach (detailed stories or life experiences of a small group of people) was used to better understand the research topic among the target group. Ferrell's Conceptual Framework on QoL in Breast Cancer was used to guide the development of the interview questions, codes, and themes. There were 10 Black BCS, averaging 58 years of age. Two coders achieved a moderate level of agreement (i.e., Kappa) of 0.77. Five major themes were identified: defining QoL (what QoL means to them), behavioral changes (e.g., altering behaviors due to cancer), phases of cancer (e.g., breast cancer diagnosis), QoL experiences and factors affecting QoL, and impactful statements from cancer survivors (other meaningful information shared by the participants). The survivors reported multiple QoL concerns and body image issues. The study findings warrant cancer education interventions or programs to address the relevant survivorship issues of Black BCS. [ABSTRACT FROM AUTHOR]

Background and Aims: Exercise training is recommended for all patients with metabolic dysfunction-associated steatotic liver disease and may reverse liver fibrosis. Whether exercise training improves liver fibrosis without body weight loss remains controversial. We further investigated this relationship using serum biomarkers of liver fibroinflammation in a post hoc analysis of an exercise trial where patients did not lose significant body weight. Methods: In the NASHFit trial, patients with metabolic dysfunction-associated steatohepatitis were randomized to receive either moderate-intensity aerobic exercise training or standard clinical care for 20 weeks. Mediterranean-informed dietary counselling was provided to each group. Change in serum biomarkers was measured and compared between the two groups. Results: Exercise training led to improvement in serum biomarkers of liver fibroinflammation, including (1) ≥17 IU/L reduction in alanine aminotransferase (ALT) in 53% of individuals in the exercise training group compared to 13% in the standard clinical care group (p < 0.001; mean reduction 24% vs. 10% respectively) and (2) improvement in CK18 (--61 vs. +71 ng/mL, p = 0.040). ALT improvement ≥17 IU/L was correlated with ≥30% relative reduction in magnetic resonance imaging-measured liver fat and PNPLA3 genotype. Conclusion: Exercise training improves multiple serum biomarkers of liver fibroinflammation at clinically significant thresholds of response without body weight loss. This study provides further evidence that exercise training should be viewed as a weightneutral intervention for which response to intervention can be readily monitored with widely available non-invasive biomarkers that can be applied at the population level. [ABSTRACT FROM AUTHOR]

Purpose: Physical activity (PA) has been shown to improve quality of life (QoL) in predominantly White cancer survivors. Very few studies have examined the association between PA and QoL among Black breast cancer survivors (BCS). We investigated the association between PA and multiple QoL domains and the effects of race on the proposed association in a racially diverse group of BCS. Methods: This was an exploratory study using secondary data from a completed 12-month randomized controlled trial (RCT). Mixed effects models were tested on a subset of participants in the control and exercise groups of the RCT. The primary outcomes were changes in the QoL domains (baseline to 12 months post baseline). Results: There were 173 participants included in this analysis, averaging 59 years of age; about 33% of the participants were Black women. There were no significant differences in the QoL outcomes between the control and exercise groups at 12 months post baseline. Race was not a significant moderator. Exercise improved emotional/mental wellbeing and body image as it relates to social barriers at 12 months post baseline in Black and White BCS, but the changes in these outcomes were only statistically significant in White BCS (p < 0.05). Conclusions: Results show that exercise can improve multiple QoL domains over time in Black BCS. However, the significance of the effect on QoL was isolated to White BCS. The small sample size in Black women could constrain the statistical significance of observed effects. Future studies are warranted to assess associations between exercise and QoL in larger samples of Black women. [ABSTRACT FROM AUTHOR]

The natural direct and indirect effects in causal mediation analysis with survival data having one mediator is addressed by VanderWeele. He derived an approach for (1) an accelerated failure time regression model in general cases and (2) a proportional hazards regression model when the time-to-event outcome is rare. If the outcome is not rare, then VanderWeele did not derive a simple closed-form expression for the log-natural direct and log-natural indirect effects for the proportional hazards regression model because the baseline cumulative hazard function does not approach zero. We develop two approaches to extend VanderWeele's approach, in which the assumption of a rare outcome is not required. We obtain the natural direct and indirect effects for specific time points through numerical integration after we calculate the cumulative baseline hazard by (1) applying the Breslow method in the Cox proportional hazards regression model to estimate the unspecified cumulative baseline hazard; (2) assuming a piecewise constant baseline hazard model, yielding a parametric model, to estimate the baseline hazard and cumulative baseline hazard. We conduct simulation studies to compare our two approaches with other methods and illustrate our two approaches by applying them to data from the ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Consortium. [ABSTRACT FROM AUTHOR]

Introduction: Poor sleep is associated with numerous adverse health outcomes. Berries are rich in micronutrients and antioxidants that may improve sleep quality and duration. We determined the association of berry consumption and sleep duration and sleep difficulty among adult participants in NHANES. Methods: We analyzed the diet of US adults aged ≥ 20 y using two non-consecutive 24 h recalls from the National Health and Nutrition Examination Survey 2005 to 2018 (N = 29,217). Poor sleep quality was measured by sleep duration (short sleep duration: <7 h), long sleep (≥9 h), and reported sleep difficulty. The relative risk of poor sleep outcomes for berry consumers vs. nonconsumers was modelled using population weight-adjusted multivariable general logistic regression. Results: About 46% of participants reported inadequate sleep duration, and 27% reported sleep difficulties. Twenty-two percent reported consuming berries. Berry consumers had a 10–17% decreased risk of short sleep. The findings were consistent for specific berry types including strawberries and blueberries (p < 0.05). No significant associations with long sleep were found for total berries and any berry types. A decreased risk of sleep difficulties was found to be linked to blackberry consumption (adjusted OR = 0.63, 95% CI: 0.40–0.97; p = 0.036) but not for other berries. Conclusions: US adult berry consumers had a decreased risk of reporting short sleep compared to nonconsumers. Berries are underconsumed foods in the US adult population, and increased berry consumption may improve sleep quality. [ABSTRACT FROM AUTHOR]

Background Whether treatment of human immunodeficiency virus (HIV) with antiretroviral therapy (ART) is associated with lower risk of mental health disorders (MHDs) among people with HIV (PWH) remains unknown. We aim to determine the association between HIV and MHDs and whether ART alters the risk of MHDs among PWH in the US adult population. Methods We conducted a real-world study using the Merative MarketScan claims database (2016–2020), identifying individuals with HIV (diagnosed using International Classification of Diseases, Tenth Revision, Clinical Modification codes) and those without HIV. A multivariable stratified Cox proportional hazard regression model was conducted to examine the association of HIV treatment status with MHDs, adjusting for potential confounders. Additionally, we sought to determine the effect modification of ART on the relationship between living with HIV and MHDs. Results A total of 313 539 individuals, with a mean age of 44.2 (standard deviation, 11.4) years, predominantly males (81.2%), residing in the South region of the US (50.9%) were included in the present analysis. During 671 880 person-years of follow-up, 46 235 incident MHD cases occurred. In the multivariable Cox proportional hazard model, living with HIV was associated with higher risk of incident MHDs. Relative to those without HIV, the adjusted hazard ratio was 1.85 (95% confidence interval [CI], 1.79–1.92; P <.001) for those with HIV on treatment, and 2.70 (95% CI, 2.59–2.82; P <.001) for those with HIV without any treatment. Stronger associations between HIV and MHDs were observed in men relative to women, among those aged 18–34 years relative to those aged 55–63 years, and among those with no overweight/obesity relative to obese individuals (P interaction <.001 for all). Conclusions HIV was associated with an increased risk of developing MHDs. However, HIV treatment mitigated the risk. [ABSTRACT FROM AUTHOR]

Establishing intravenous (IV) access in younger patient populations via the traditional cannulation technique for procedures requiring anesthesia is often challenging. Infrared (IR) vein visualization is a modality that aids venous cannulation; however, few reports of this technique exist in the infant and toddler population. The primary aim of this study was to compare the efficacy of IR vein visualization to the standard cannulation technique for obtaining peripheral IV access in infant and toddler populations. Following Institutional Review Board (IRB) approval and written informed consent, children were randomly assigned to either a standard cannulation technique group or an IR vein visualization device group for venous cannulation. The primary outcome variable was the success rate of IV cannulation, and the secondary variables were the total number of attempts and the time to successful cannulation. No difference was noted between either group for first-attempt success rate (standard versus IR: 61.25% vs. 54.4%; p = 0.4) or time to establish IV cannulation (standard versus IR: median [interquartile range], 40 s [24–120] vs. 53 s [26–106]; p = 0.55). The anesthesiologist's grading of the anticipated difficulty of IV cannulation was a significant predictor of cannulation success (p = 0.0016). Our study demonstrated no significant benefit in utilizing the IR vein visualization device in terms of the overall success rate, number of attempts, and time to establish successful IV cannulation when compared to the standard technique. However, in difficult IV access situations, this device proved to be a valuable rescue adjunct. [ABSTRACT FROM AUTHOR]

In the field of cardiovascular disease, recurrent events such as stroke or myocardial infarction (MI) are often encountered, leading to an increase in the risk of death. Accurately evaluating the prognosis of patients and dynamically predicting the risk of death by considering the historical recurrent events can improve medical decisions and lead to better health care outcomes. Recently proposed joint modeling approaches within the Bayesian framework have inspired the development of a dynamic prediction tool, which can be applied for subject‐level prediction of death with implementation in software packages. The prediction model incorporates subject heterogeneity with subject‐level random effects that account for unobserved time‐invariant factors and an extra copula function capturing the part caused by unmeasured time‐dependent factors. Thereafter, given the prespecified landmark time t′$$ {t}^{\prime } $$, the survival probability for a prediction horizon time of interest t$$ t $$ can be estimated for each individual. The prediction accuracy is assessed by time‐dependent receiving operating characteristic curve and the area under the curve and the Brier score with calibration plots is compared to traditional joint frailty models. Finally, the tool is applied to patients with multiple attacks of stroke or MI in the Cardiovascular Health study and the Atherosclerosis Risk in Communities study for illustration. [ABSTRACT FROM AUTHOR]

Background: Evidence on the relative importance of various factors associated with febrile illness in children and their heterogeneity across countries can inform the prevention, identification, and management of communicable diseases in resource-limited countries. The objective of the study is to assess the relative significance of factors associated with childhood febrile illness in 27 sub-Saharan African countries. Methods: This cross-sectional study of 298,327 children aged 0 to 59 months assessed the strengths of associations of 18 factors with childhood fevers, using Demographic and Health Surveys (2010-2018) from 27 sub-Saharan African countries. A total of 7 child level factors (i.e., respiratory illness, diarrhea, breastfeeding initiation; vitamin A supplements; child's age; full vaccination; sex), 5 maternal factors (maternal education; maternal unemployment; antenatal care; maternal age, and maternal marriage status) and 6 household factors (household wealth; water source; indoor pollution, stool disposal; family planning needs and rural residence) were assessed. Febrile illness was defined as the presence of fever in 2 weeks preceding the survey. Results: Among the 298,327 children aged 0 to 59 months included in the analysis, the weighted prevalence of fever was 22.65% (95% CI, 22.31%-22.91%). In the pooled sample, respiratory illness was the strongest factor associated with fever in children (adjusted odds ratio [aOR], 5.46; 95% CI, 5.26-5.67; P <.0001), followed by diarrhea (aOR, 2.96; 95% CI, 2.85-3.08; P <.0001), poorest households (aOR, 1.33; 95% CI,1.23-1.44; P <.0001), lack of maternal education (aOR, 1.25; 95% CI, 1.10-1.41; P <.0001), and delayed breastfeeding (aOR, 1.18; 95% CI, 1.14-1.22; P <.0001. Febrile illnesses were more prevalent in children older than >6 months compared to those 6 months and younger. Unsafe water, unsafe stool disposal, and indoor pollution were not associated with child fever in the pooled analysis but had a large country-level heterogeneity. Conclusions: Major causes of fevers in sub-Saharan Africa could be attributed to respiratory infections and possibly viral infections, which should not be treated by antimalarial drugs or antibiotics. Point-of-care diagnostics are needed to identify the pathogenic causes of respiratory infections to guide the clinical management of fevers in limited-resource countries. [ABSTRACT FROM AUTHOR]

Background: Proton Pump Inhibitors (PPI) are among the most commonly used drugs to treat acid-related gastrointestinal disorders in the USA. Although PPI use has been linked to acute interstitial nephritis, the side effects of post-hospitalization acute kidney injury (AKI) and the progression of kidney disease still are controversial. We conducted a matched cohort study to examine the associations between PPI use and the side effects, especially in post-hospitalization AKI. Methods: We investigated 340 participants from the multicenter, prospective, matched-cohort ASSESS-AKI study, which enrolled participants from December 2009 to February 2015. After the baseline index hospitalization, follow-up visits were conducted every six months, and included a collection of self-reported PPI use by participants. Post-hospitalization AKI was defined as the percentage increase from the nadir to peak inpatient SCr value was ≥ 50% and/or absolute increase ≥ 0.3 mg/dL in peak inpatient serum creatinine compared with baseline outpatient serum creatinine. We applied a zero-inflated negative binomial regression model to test the relationship between PPI use and post-hospitalization AKI. Stratified Cox proportional hazards regression models also were conducted to examine the association between PPI use and the risk of progression of kidney disease. Results: After controlling for demographic variables, baseline co-morbidities and drug use histories, there was no statistically significant association between PPI use and risk of post-hospitalization AKI (risk ratio [RR], 0.91; 95% CI, 0.38 to 1.45). Stratified by AKI status at baseline, no significant relationships were confirmed between PPI use and the risk of recurrent AKI (RR, 0.85; 95% CI, 0.11 to 1.56) or incidence of AKI (RR, 1.01; 95% CI, 0.27 to 1.76). Similar non-significant results also were observed in the association between PPI use and the risk of progression of kidney diseases (Hazard Ratio [HR], 1.49; 95% CI, 0.51 to 4.36). Conclusion: PPI use after the index hospitalization was not a significant risk factor for post-hospitalization AKI and progression of kidney diseases, regardless of the AKI status of participants at baseline. [ABSTRACT FROM AUTHOR]

Background and Aims: Exercise remains a key component of nonalcoholic fatty liver disease (NAFLD) treatment. However, mechanisms underpinning the improvements in NAFLD seen with exercise are unclear. Exercise improved liver fat and serum biomarkers of liver fibrosis in the NASHFit trial. We investigated exercise's mechanism of benefit by conducting a post hoc analysis of these data to determine the relationship between serum fibroblast growth factor (FGF) 21, which is implicated in NAFLD development, and exercise. Methods: In the 20 wk NASHFit trial, patients with nonalcoholic steatohepatitis (NASH) were randomized to receive moderate-intensity aerobic exercise training or standard clinical care. Mediterranean-informed dietary counseling was provided to each group. Change in serum FGF21 was measured after an overnight fast. Results: There was a significant improvement in serum FGF21 with exercise training compared to standard clinical care (p = 0.037) with serum FGF21 reducing by 22% (−243.4 +/−349 ng/mL) with exercise vs. a 34% increase (+88.4 ng/mL +/−350.3 ng/mL) with standard clinical care. There was a large inverse association between change in serum FGF21 and change in cardiorespiratory fitness (VO2peak) (r = −0.62, 95% CI −0.88 to −0.05, p = 0.031), and on multivariable analysis, change in VO2peak remained independently associated with change in FGF21 (β = −44.5, 95% CI −83.8 to −5.11, p = 0.031). Conclusions: Serum FGF21 is markedly decreased in response to aerobic exercise training, offering a novel mechanism to explain the observed reduction in liver fat and improvement in serum biomarkers of liver fibrosis in patients with NASH who do exercise. [ABSTRACT FROM AUTHOR]

Background Corticosteroids confer a survival benefit in individuals hospitalized with coronavirus disease 2019 (COVID-19) who require oxygen. This meta-analysis seeks to determine the duration of corticosteroids needed to optimize this mortality benefit. Methods Electronic databases were searched to 9 March 2022, for studies reporting corticosteroid versus no corticosteroid treatment in hospitalized COVID-19 patients. We estimated the effect of corticosteroids on mortality by random-effects meta-analyses. Subgroup analyses and meta-analyses were conducted to assess the optimal duration of corticosteroid treatment while adjusting for the severity of disease, age, duration of symptoms, and proportion of control group given steroids. Results We identified 27 eligible studies consisting of 13 404 hospitalized COVID-19 patients. Seven randomized controlled trials and 20 observational studies were included in the meta-analysis of mortality, which suggested a protective association with corticosteroid therapy (risk ratio [RR], 0.71 [95% confidence interval {CI},.58–.87]). Pooled analysis of 18 studies showed the greatest survival benefit for a treatment duration up to 6 days (RR, 0.54 [95% CI,.39–.74]). Survival benefit was 0.65 (95% CI,.51–.83) up to 7 days, and no additional survival benefit was observed beyond 7 days of treatment (RR, 0.64 [95% CI,.44–.93]). The survival benefit was not confounded by severity of disease, age, duration of symptoms, or proportion of control group given steroids. Conclusions In this meta-analysis, optimal duration of corticosteroid treatment for hospitalized COVID-19 patients was up to 6 days, with no additional survival benefit with >7 days of treatment. [ABSTRACT FROM AUTHOR]

Background & Aims: Physical activity offers promise to protect against multiple non-hepatic primary cancers. We performed a systematic review to quantify the association between physical activity and hepatocellular carcinoma (HCC) risk. Methods: We searched the Cochrane Library, Embase, Medline and trial registries through December 2020 for studies that measured physical activity levels in adults at risk for HCC. The primary outcome was HCC. Subgroup analysis was performed limiting to vigorous physical activity. Proportions and random-effects odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. Results: Seven studies met inclusion criteria, comprising 777,662 subjects (median age 55 years; 55% female). Greater amounts of physical activity were associated with less HCC (OR 0.65, 95% CI 0.45–0.95, p = 0.03) compared to lower amounts. Vigorous physical activity was associated with even less HCC (OR 0.62, 95% CI 0.49–0.79, p < 0.01). Conclusions: This meta-analysis demonstrates that greater amounts of physical activity are associated with lower odds of HCC. These results support the use of regular physical activity as an effective way to prevent HCC and provide helpful data to support a for future exercise-based interventional study to better define the optimal exercise prescription for patients at risk for primary liver cancer. [ABSTRACT FROM AUTHOR]

Background: Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil‐derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil‐associated diseases treated with mepolizumab, benralizumab, or dexpramipexole. Methods: Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay. Results: Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups. Conclusions: Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA. [ABSTRACT FROM AUTHOR]

Emerging evidence has suggested that mushrooms, which are a rich source of the potent antioxidants ergothioneine and glutathione as well as vitamin D, may have neuroprotective properties. This study investigated the association between mushroom consumption and cognitive performance in a nationally representative sample of US older adults. We analysed data from older adults aged ≥ 60 years from the 2011–2014 National Health and Nutrition Examination Survey. Mushroom intake was measured using up to two 24-h dietary recalls and was categorised into three groups (lowest, middle and highest). Cognitive function tests included the Animal Fluency (AF) Test; Consortium to Establish a Registry for Alzheimer's Disease Delayed Recall (CERAD-DR) and Word Learning (CERAD-WL); and Digit Symbol Substitution Test (DSST). Multivariable linear regression models were developed, adjusting for socio-demographics, major lifestyle factors, self-reported chronic diseases and dietary factors, including the Healthy Eating Index-2015 score and total energy. The study included 2840 participants. Compared with the lowest category of mushroom intake, participants in the highest category (median intake = 13·4 g /4184 KJ (1000 kcal)/d) had higher scores for DSST (β = 3·87; 95 % CI 0·30, 7·45; P for trend = 0·03) and CERAD-WL (β = 1·05; 95 % CI 0·0003, 2·10; P for trend = 0·04). Similar non-significant trends were observed for AF (β = 0·24; 95 % CI −2·26, 2·73; P for trend = 0·92) but not for the CERAD-DR. Greater mushroom intake was associated with certain cognitive performance tests, suggesting regular mushroom consumption may reduce the risk of cognitive decline. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests that coronavirus disease-2019 (COVID-19) may lead to a wide range of post-acute sequelae outcomes, including new onset of diabetes. The aim of this meta-analysis was to estimate the incidence of newly diagnosed diabetes in survivors of COVID-19. We searched MEDLINE, Scopus, Cochrane Central Register of Controlled Trials and the World Health Organization Global Literature on Coronavirus Disease and clinical trial registries for studies reporting the association of COVID-19 and diabetes. Search dates were December 2019–October 16, 2022. Two investigators independently assessed studies for inclusion. Risk of bias was assessed using the Newcastle–Ottawa Scale. We estimated the effect of COVID-19 on incident diabetes by random-effects meta-analyses using the generic inverse variance method. We identified 8 eligible studies consisting of 4,270,747 COVID-19 patients and 43,203,759 controls. Median age was 43 years (interquartile range, IQR 35–49), and 50% were female. COVID-19 was associated with a 66% higher risk of incident diabetes (risk ratio, 1.66; 95% CI 1.38; 2.00). The risk was not modified by age, sex, or study quality. The median risk of bias assessment was 7. In this systematic review and meta-analysis, COVID-19 was associated with higher risk for developing new onset diabetes among survivors. Active monitoring of glucose dysregulation after recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is warranted. [ABSTRACT FROM AUTHOR]

Objective: Dysglycemia influences hospital outcomes and resource utilization. Clinical decision support (CDS) holds promise for optimizing care by overcoming management barriers. This study assessed the impact on hospital length of stay (LOS) of an alert-based CDS tool in the electronic medical record that detected dysglycemia or inappropriate insulin use, coined as gaps in care (GIC).Research Design and Methods: Using a 12-month interrupted time series among hospitalized persons aged ≥18 years, our CDS tool identified GIC and, when active, provided recommendations. We compared LOS during 6-month-long active and inactive periods using linear models for repeated measures, multiple comparison adjustment, and mediation analysis.Results: Among 4,788 admissions with GIC, average LOS was shorter during the tool's active periods. LOS reductions occurred for all admissions with GIC (-5.7 h, P = 0.057), diabetes and hyperglycemia (-6.4 h, P = 0.054), stress hyperglycemia (-31.0 h, P = 0.054), patients admitted to medical services (-8.4 h, P = 0.039), and recurrent hypoglycemia (-29.1 h, P = 0.074). Subgroup analysis showed significantly shorter LOS in recurrent hypoglycemia with three events (-82.3 h, P = 0.006) and nonsignificant in two (-5.2 h, P = 0.655) and four or more (-14.8 h, P = 0.746). Among 22,395 admissions with GIC (4,788, 21%) and without GIC (17,607, 79%), LOS reduction during the active period was 1.8 h (P = 0.053). When recommendations were provided, the active tool indirectly and significantly contributed to shortening LOS through its influence on GIC events during admissions with at least one GIC (P = 0.027), diabetes and hyperglycemia (P = 0.028), and medical services (P = 0.019).Conclusions: Use of the alert-based CDS tool to address inpatient management of dysglycemia contributed to reducing LOS, which may reduce costs and improve patient well-being. [ABSTRACT FROM AUTHOR]

Communication Quality Analysis (CQA) is a rigorous transcript-based coding method for assessing clinical communication quality. We compared the resource-intensive transcript-based version with a streamlined real-time version of the method with respect to feasibility, validity, reliability, and association with traditional measures of communication quality. Simulated conversations between 108 trainees and 12 standardized patients were assessed by 7 coders using the two versions of CQA (transcript and real-time). Participants also completed two traditional communication quality assessment measures. Real-time CQA was feasible and yielded fair to excellent reliability, with some caveats that can be addressed in future work. CQA ratings were moderately correlated with traditional measures of communication quality, suggesting that CQA captures different aspects of communication quality than do traditional measures. Finally, CQA did not exhibit the ceiling effects observed in the traditional measures of communication quality. We conclude that real-time CQA is a user-friendly method for assessing communication quality that has the potential for broad application in training, research, and intervention contexts and may offer improvements to traditional, self-rated communication measures. [ABSTRACT FROM AUTHOR]

In medicine, retrospective cohort studies are used to compare treatments to one another. We hypothesize that the outcomes of retrospective comparative effectiveness research studies can be heavily influenced by biostatistical analytic choices, thereby leading to inconsistent conclusions. We selected a clinical scenario currently under investigation: survival in metastatic prostate, breast or lung cancer after systemic vs systemic + definitive local therapy. We ran >300 000 regression models (each representing a publishable study). Each model had various forms of analytic choices (to account for bias): propensity score matching, left truncation adjustment, landmark analysis and covariate combinations. There were 72 549 lung, 14 904 prostate and 13 857 breast cancer patients included. In the most basic analysis, which omitted propensity score matching, left truncation adjustment and landmark analysis, all of the HRs were <1 (generally, 0.60‐0.95, favoring addition of local therapy), with all P‐values <.001. Left truncation adjustment landmark analysis produced results with nonsignificant P‐values. The combination of propensity score matching, left truncation adjustment, landmark analysis and covariate combinations generally produced P‐values that were >.05 and/or HRs that were >1 (favoring systemic therapy alone). The use of more statistical methods to reduce the selection bias caused reported HR ranges to approach 1.0. By varying analytic choices in comparative effectiveness research, we generated contrary outcomes. Our results suggest that some retrospective observational studies may find a treatment improves outcomes for patients, while another similar study may find it does not, simply based on analytical choices. [ABSTRACT FROM AUTHOR]

Clustered or longitudinal data are commonly encountered in clinical trials and observational studies. This type of data could be collected through a real‐time monitoring scheme associated with some specific event, such as disease recurrence, hospitalization, or emergency room visit. In these contexts, the cluster size could be informative because of its potential correlation with disease status, since more frequency of observations may indicate a worsening health condition. However, for some clusters/subjects, there are no measures or relevant medical records. Under such circumstances, these clusters/subjects may have a considerably lower risk of an event occurrence or may not be susceptible to such events at all, indicating a nonignorable zero cluster size. There is a substantial body of literature using observations from those clusters with a nonzero informative cluster size only, but few works discuss informative nonignorable zero‐sized clusters. To utilize the information from both event‐free and event‐occurring participants, we propose a weighted within‐cluster‐resampling (WWCR) method and its asymptotically equivalent method, dual‐weighted generalized estimating equations (WWGEE) by adopting the inverse probability weighting technique. The asymptotic properties are rigorously presented theoretically. Extensive simulations and an illustrative example of the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS‐AKI) study are performed to analyze the finite‐sample behavior of our methods and to show their advantageous performance compared to the existing approaches. [ABSTRACT FROM AUTHOR]

Background: The temporal evolution of SARS-CoV-2 vaccine efficacy and effectiveness (VE) against infection, symptomatic, and severe COVID-19 is incompletely defined. The temporal evolution of VE could be dependent on age, vaccine types, variants of the virus, and geographic region. We aimed to conduct a systematic review and meta-analysis of the duration of VE against SARS-CoV-2 infection, symptomatic COVID-19 and severe COVID-19. Methods: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, the World Health Organization Global Literature on Coronavirus Disease, and CoronaCentral databases were searched and studies were selected. Independent reviewers selected randomized controlled trials and cohort studies with the outcome of interest. Independent reviewers extracted data, and assessed the risk of bias. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence. Primary outcomes included VE as a function of time against SARS-CoV-2 infection, symptomatic and severe COVID-19. Results: Eighteen studies were included representing nearly 7 million individuals. VE against all SARS-CoV-2 infections declined from 83% in the first month after completion of the original vaccination series to 22% at 5 months or longer. Similarly, VE against symptomatic COVID-19 declined from 94% in the first month after vaccination to 64% by the fourth month. VE against severe COVID-19 for all ages was high overall, with the level being 90% (95% CI, 87–92%) at five months or longer after being fully vaccinated. VE against severe COVID-19 was lower in individuals ≥ 65 years and those who received Ad26.COV2.S. Conclusions: VE against SARS-CoV-2 infection and symptomatic COVID-19 waned over time but protection remained high against severe COVID-19. These data can be used to inform public health decisions around the need for booster vaccination. [ABSTRACT FROM AUTHOR]

Background: Surfactant protein-A (SP-A) plays a critical role in lung innate immunity by regulating alveolar macrophages (AM), expression of inflammatory mediators, and other host defense proteins. The toponome imaging system (TIS), a serial immunostainer, was used to study the AM toponome because it characterizes the localization of multiple markers and identifies marker combinations in each pixel as combinatorial molecular phenotypes (CMPs). We used TIS to study the AM toponome from wild type (WT) and SP-A knockout (KO) mice and changes following Klebsiella pneumoniae exposure. Methods: WT or KO mice received intratracheal K. pneumoniae or vehicle and AM were obtained by bronchoalveolar lavage after one hour. AM were attached to slides and underwent TIS analysis. Images were analyzed to characterize all pixels. AM CMPs from WT vehicle (n=3) and infected (n=3) mice were compared to each other and to AM from KO (n=3 vehicle; n=3 infected). Histograms provided us with a tool to summarize the representation of each marker in a set of CMPs. Results: Using the histograms and other tools we identified markers of interest and observed that: 1) Both comparisons had conserved (present in all group members) CMPs, only in vehicle AM and only in infected AM, or common to both vehicle and infected AM, (i.e., unaffected by the condition). 2) the CMP number decreased with infection in WT and KO versus vehicle controls. 3) More infection-specific CMPs in WT vs KO AM. 4) When AM from WT and KO vehicle or infected were compared, there were more unique CMPs exclusive to the KO AM. 5) All comparisons showed CMPs shared by both groups. Conclusions: The decrease of CMPs exclusive to infected AM in KO mice may underlie the observed susceptibility of KO mice to infection. However, both KO groups had more exclusive CMPs than the corresponding WT groups, perhaps indicating a vigorous effort by KO to overcome deficits in certain proteins and CMPs that are dysregulated by the absence of SP-A. Moreover, the presence of shared CMPs in the compared groups indicates that regulation of these CMPs is not dependent on either infection or the presence or absence of SP-A. [ABSTRACT FROM AUTHOR]

Using the Toponome Imaging System (TIS), a serial immunostainer, we studied the patterns of expression of multiple markers in alveolar macrophages (AM) from female mice lacking surfactant protein A (SP-A knockouts; KO) after "rescue" with exogenous SP-A1. We also used a 7-marker subset to compare with AM from males. AM were harvested 18 h after intrapharyngeal SP-A1 or vehicle, attached to slides, and subjected to serial immunostaining for 12 markers. Expression of the markers in each pixel of the image was analyzed both in the whole image and in individual selected cells. The marker combination in each pixel is referred to as a combinatorial molecular phenotype (CMP). A subset of antibodies was used to compare AM from male mice to the females. We found: (a) extensive AM heterogeneity in females by CMP analysis and by clustering analysis of CMPs in single cells; (b) AM from female KO mice respond to exogenous SP-A1 by increasing CMP phenotypic diversity and perhaps enhancing their potential innate immune capabilities; and (c) comparison of male and female AM responses to SP-A1 revealed that males respond more vigorously than females and clustering analysis was more effective in distinguishing males from females rather than treated from control. [ABSTRACT FROM AUTHOR]

In this study, we used data from the second wave of Midlife in the United States (MIDUS) Study, MIDUS Biomarkers and MIDUS 3. We applied the serial mediation model to explore the serial mediating effects of perceived stress and depressive symptoms on the relationship between sleep quality and life satisfaction. A total of 945 participants were included in our study. The total indirect effect of sleep quality on life satisfaction through perceived stress, depressive symptoms and the combination of perceived stress and depressive symptoms accounted for within the overall model was 45.5%. At the intervention level, programs designed to improve the level of life satisfaction among adults should focus on perceived stress and depressive symptoms. The prevention of perceived stress and depression contributes to improving life satisfaction and wellbeing. The serial mediation results should be confirmed by further longitudinal study. [ABSTRACT FROM AUTHOR]