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OBJECTIVES Studies suggest an association between elevated total serum cholesterol (TC), particularly low-density lipoprotein (LDL), and osteoarthritis (OA). We evaluated the association between total cholesterol, LDL, and high-density lipoprotein (HDL) and risk of knee OA. METHODS We studied participants from the Multicenter Osteoarthritis study (MOST) cohort at risk of developing knee OA. From baseline through 7 years, repeated knee x-rays and MRIs were obtained and knee symptoms were queried. From baseline fasting blood samples, lipids and lipoproteins were analyzed using standard assays. After excluding participants with baseline OA, we defined two sets of cases: those developing radiographic OA and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of: cartilage loss and synovitis on MRI and of knee pain using the WOMAC scale. We carried out logistic regression adjusting for age, sex, BMI, education, baseline pain, and depressive symptoms, testing total cholesterol and lipoproteins as continuous measures and did sensitivity analyses examining whether commonly used thresholds for high cholesterol, LDL or low HDL increased risk. RESULTS We studied 337 cases with incident symptomatic OA and 283 cases with incident radiographic OA. Mean age at baseline was 62 years (55% women). Neither total cholesterol, LDL nor HDL showed a significant association with radiographic or symptomatic OA. Additionally, we found no association of these lipid measures with cartilage loss, worsening synovitis or worsening knee pain. CONCLUSION Our data do not support an association between total cholesterol, LDL or HDL with OA outcomes.

The Systolic Blood Pressure Intervention Trial (SPRINT) results have influenced clinical practice but have also generated discussion regarding the validity, generalizability and importance of the findings. Following the SPRINT primary results manuscript in 2015, additional results and analyses of the data have addressed these concerns. The primary objective of this manuscript is to respond to key questions that have been raised. The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated the effectiveness of treating SBP to levels well below those previously recommended in US and European BP guidelines.(1) The SPRINT results have informed guideline committees in recommending treatment to SBP targets lower than previously advised.(2–4) However, some of the SPRINT findings have generated discussion, and questions have been raised regarding their application in clinical practice. These include generalizability, validity of the outcome measures (especially heart failure), the methods used for event ascertainment, the effect size of the intervention benefit, and safety and tolerability of the

Introduction: Targeted therapy and immune checkpoint inhibitors (ICI) have drastically improved outcomes of metastatic non-small cell lung cancer (NSCLC) patients in outpatient settings. Because trials on critically ill patients are improbable, little is known about their efficacy among patients admitted to intensive care units (ICU). Methods: We retrospectively analyzed the clinical outcomes of critically-ill NSCLC patients receiving either ICI or targeted therapy during ICU admission at the MD Anderson Cancer Center from April 2016 to August 2020. We collected data on ICU admission diagnoses, sequential organ failure assessment (SOFA), previous cancer therapies, tumor gene mutations or translocations, and PD-L1 expression. Overall survival (OS) was calculated from the date of drug initiation using the Kaplan-Meier method. Results: Of 9898 ICU admissions, 9 patients with metastatic NSCLC who received either targeted therapy (5) or PD-1 ICI (4) during ICU admission were included. The most common reasons for ICU admissions were tumor visceral crisis (3/9) and sepsis (3/9). The median (range) admission SOFA was 4 (2-11). Six patients were naïve to systemic therapy. Five patients required mechanical ventilation. The median OS was 77 days (95%CI, 36-NA), and 5 patients were discharged alive (all received targeted therapy). The median OS of patients who received ICI was 25.5 days (95%CI, 8-NA) and for those who received targeted therapy was 218 days (95%CI, 77-NA). At 6 and 12 months follow-up, 3 and 2 patients who received targeted therapy were still alive, respectively. Conclusions: Our exploratory findings indicate a possible benefit of targeted therapy but suggest a lack of clinical utility of PD-1 ICI for critically ill metastatic NSCLC patients. Because of the small sample size, further studies are needed to expand on this topic.

Rationale: Epigenetic aging is a novel measure of biological age, reflecting exposures and disease risks independent of chronological age. It may serve as a useful biomarker of cardiovascular health (CVH) or cardiovascular disease risk for early detection or prevention. Objective: To examine associations between GrimAge acceleration (GrimAA), a measure of epigenetic aging calculated from the residuals of GrimAge regressed on chronological age, and 2 repeated CVH measures: a full score for the AHA Life’s Simple 7 (diet, smoking, physical activity, body mass index, blood pressure, total cholesterol, and glucose) and a clinical CVH score (body mass index, blood pressure, cholesterol, and glucose). Methods and Results: We used Illumina array DNA methylation data from 2 prospective cohort studies, the CARDIA study (Coronary Artery Risk Development in Young Adults) and FHS (Framingham Heart Study), to calculate GrimAA and model associations with CVH. CARDIA randomly selected 1118 participants for assays at Y15 (2000–2001; mean age, 40 years) and Y20 (2005–2006); in FHS, 2106 Offspring participants had DNA methylation measured at exam 8 (2005–2008; mean age, 66 years). We examined multiple cross-sectional and longitudinal models of GrimAA and each CVH score measured at CARDIA Y0 to Y20 and FHS exams 7 to 8. In CARDIA, clinical CVH score from Y0 to Y20 was associated with Y15 and Y20 GrimAA (β range, −0.41 to −0.21 years per 1-point increase in CVH; P range, P P Conclusions: Our data demonstrate that faster GrimAA is associated with the loss of CVH from young age. Epigenetic age may be a useful biomarker of cardiovascular disease risk and provides biological insight into the role of epigenetic mechanisms linking age-related CVH loss and cardiovascular disease.

ObjectiveTo determine the relationship of patellofemoral osteoarthritis (PFOA) to changes in performance-based function over 7 years.MethodsThere were 2666 participants (62.2 ± 8.0 yrs, BMI 30.6 ± 5.9 kg/m2, 60% female) from the Multicenter Osteoarthritis Study with knee radiographs at baseline who completed repeated chair stands and a 20-meter walk test (20MWT) at baseline, 2.5, 5, and 7 years. Generalized linear models assessed the relation of radiographic PFOA and radiographic PFOA with frequent knee pain to longitudinal changes in performance-based function. Analyses were adjusted for age, sex, BMI, tibiofemoral OA, and injury/surgery.ResultsLinear models demonstrated a significant group-by-time interaction for the repeated chair stands (P = 0.04) and the 20MWT (P < 0.0001). Those with radiographic PFOA took 1.01 seconds longer on the repeated chair stands (P = 0.02) and 1.69 seconds longer on the 20MWT (P < 0.0001) at 7 years compared with baseline. When examining the relation of radiographic PFOA with frequent knee pain to performance-based function, there was a significant group-by-time interaction for repeated chair stands (P = 0.05) and the 20MWT (P < 0.0001). Those with radiographic PFOA with frequent knee pain increased their time on the repeated chair stands by 1.12 seconds (P = 0.04) and on the 20MWT by 1.91 seconds (P < 0.0001) over 7 years.ConclusionIndividuals with radiographic PFOA and those with radiographic PFOA with frequent knee pain have worsening of performance-based function over time. This knowledge may present opportunities to plan for early treatment strategies for PFOA to limit functional decline over time.

Upstream therapy of atrial remodeling may decrease atrial fibrillation and associated thromboembolism. We examined the impact of intensive BP lowering on ECG-defined left atrial abnormalities in the SPRINT. SPRINT was a randomized clinical trial comparing outcomes when a systolic BP of 4000 μV × ms. Secondary outcomes were regression of the left atrial abnormality and the change in PTFV1 from baseline across follow-up ECGs. Cox regression was used to examine the associations between treatment assignment and incident left atrial abnormality and its regression. We used linear mixed models to examine the changes in PTFV1. Of 9361 SPRINT participants, 7738 qualified for this analysis, of whom 5544 did not have baseline left atrial abnormalities. Intensive BP management was not associated with incident left atrial abnormality (HR, 0.96; 95% CI, 0.87-1.07) or regression of the baseline left atrial abnormality (HR, 1.09; 95% CI, 0.98-1.21). The change in PTFV1 from baseline through follow-up did not differ significantly between treatment groups (difference in μV × ms per year, 6; 95% CI, -67 to 79). Thus, among patients in a randomized clinical trial, we found no difference in the progression or regression of ECG-defined left atrial abnormalities with intensive BP management compared to standard BP management.

OBJECTIVE The aim of this study was to characterize end-stage renal disease (ESRD) patients with obesity as their only contraindication to listing and to quantify wait-list and transplant access. METHODS Using the US Renal Data System, a retrospective cohort study of incident dialysis cases (2012 to 2014) was performed. The primary outcomes were time to wait-listing and time to transplantation. RESULTS Of 157,572 dialysis patients not already listed, 39,844 had BMI as their only demonstrable transplant contraindication. They tended to be younger, female, and Black. Compared with patients with BMI

Background/Purpose the timing of endorectal pull-through for Hirschsprung disease (HD) is controversial. Neonatal primary endorectal pull-through theoretically prevents preoperative enterocolitis. Delayed primary endorectal pull-through offers the surgeon the benefit of more robust perineal anatomy and allows primary caregivers the time to emotionally process the diagnosis and to gain experience with rectal irrigations. We hypothesized that delayed primary endorectal pull-through would be associated with equivalent perioperative morbidity compared to the neonatal repair and would lead to improved long-term functional outcomes. Methods we analyzed all patients in the Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) registry who had a primary endorectal pull-through for HD and at least three-and-one-half years of follow up in a specialty colorectal clinic. We evaluated patient demographics, operative outcomes, perioperative episodes of enterocolitis, and long-term functional outcomes for the neonatal ( Results eighty-two patients were identified of whom 49 were operated upon in the neonatal period and 33 in a delayed fashion. The median age at operation was 11 days [IQR 7 – 19 days] for the neonatal cohort and 98 days [IQR 61 – 188 days] for the delayed cohort. Thirty-four (69.4%) of the neonatal and 22 (66.7%) of the delayed cohort patients had rectosigmoid transition zones. Four of 49 patients (8.1%) in the neonatal cohort were diagnosed with enterocolitis preoperatively compared to two of 33 (6.0%) in the delayed cohort (p = 0.89). Eighteen of 49 patients (36.7%) in the neonatal cohort and 16 of 33 (48.5%) in the delayed cohort had at least one postoperative episode of enterocolitis (p = 0.38). Fifteen of 49 patients (30.6%) in the neonatal cohort were receiving bowel management for fecal incontinence at most recent follow up compared to five of 33 (15.2%) in the delayed cohort (p = 0.13). Conclusion delayed primary endorectal pull-through offers a safe alternative to operation in the neonatal period and appears to have, at least, equivalent functional outcomes. Level of evidence : Level III, retrospective comparative study

Objective The Action for Health in Diabetes (Look AHEAD) study previously reported that intensive lifestyle intervention (ILI) reduced incident depressive symptoms and improved health-related quality of life (HRQOL) over nearly 10 years of intervention compared with a control group (the diabetes support and education group [DSE]) in participants with type 2 diabetes and overweight or obesity. The present study compared incident depressive symptoms and changes in HRQOL in these groups for an additional 6 years following termination of the ILI in September 2012. Methods A total of 1,945 ILI participants and 1,900 DSE participants completed at least one of four planned postintervention assessments at which weight, mood (via the Patient Health Questionnaire-9), antidepressant medication use, and HRQOL (via the Medical Outcomes Scale, Short Form-36) were measured. Results ILI participants and DSE participants lost 3.1 (0.3) and 3.8 (0.3) kg [represented as mean (SE); p = 0.10], respectively, during the 6-year postintervention follow-up. No significant differences were observed between groups during this time in incident mild or greater symptoms of depression, antidepressant medication use, or in changes on the physical component summary or mental component summary scores of the Short Form-36. In both groups, mental component summary scores were higher than physical component summary scores. Conclusions Prior participation in the ILI, compared with the DSE group, did not appear to improve subsequent mood or HRQOL during 6 years of postintervention follow-up.

Introduction: Traumatic intracranial hemorrhages (TIH) have traditionally been managed in the intensive care unit (ICU) setting with neurosurgery consultation and repeat head CT (HCT) for each patient. Recent publications indicate patients with small TIH and normal neurological examinations who are not on anticoagulation do not require ICU-level care, repeat HCT, or neurosurgical consultation. It has been suggested that these patients can be safely discharged home after a short period of observation in emergency department observation units (EDOU) provided their symptoms do not progress. Methods: This study is a retrospective cross-sectional evaluation of an EDOU protocol for minor traumatic brain injury (mTBI). It was conducted at a Level I trauma center. The protocol was developed by emergency medicine, neurosurgery and trauma surgery and modeled after the Brain Injury Guidelines (BIG). All patients were managed by attendings in the ED with discretionary neurosurgery and trauma surgery consultations. Patients were eligible for the mTBI protocol if they met BIG 1 or BIG 2 criteria (no intoxication, no anticoagulation, normal neurological examination, no or non-displaced skull fracture, subdural or intraparenchymal hematoma up to 7 millimeters, trace to localized subarachnoid hemorrhage), and had no other injuries or medical co-morbidities requiring admission. Protocol in the EDOU included routine neurological checks, symptom management, and repeat HCT for progression of symptoms. The EDOU group was compared with historical controls admitted with primary diagnosis of TIH over the 12 months prior to the initiation of the mTBI protocols. Primary outcome was reduction in EDOU length of stay (LOS) as compared to inpatient LOS. Secondary outcomes included rates of neurosurgical consultation, repeat HCT, conversion to inpatient admission, and need for emergent neurosurgical intervention. Results: There were 169 patients placed on the mTBI protocol between September 1, 2016 and August 31, 2019. The control group consisted of 53 inpatients. Median LOS (interquartile range [IQR]) for EDOU patients was 24.8 (IQR: 18.8 – 29.9) hours compared with a median LOS for the comparison group of 60.2 (IQR: 45.1 – 85.0) hours (P < .001). In the EDOU group 47 (27.8%) patients got a repeat HCT compared with 40 (75.5%) inpatients, and 106 (62.7%) had a neurosurgical consultation compared with 53 (100%) inpatients. Subdural hematoma was the most common type of hemorrhage. It was found in 60 (35.5%) patients, and subarachnoid hemorrhage was found in 56 cases (33.1%). Eleven patients had multicompartment hemorrhage of various classifications. Twelve (7.1%) patients required hospital admission from the EDOU. None of the EDOU patients required emergent neurosurgical intervention. Conclusion: Patients with minor TIH can be managed in an EDOU using an mTBI protocol and discretionary neurosurgical consults and repeat HCT. This is associated with a significant reduction in length of stay.

The CARDIA (Coronary Artery Risk Development in Young Adults) study began in 1985 to 1986 with enrollment of 5,115 Black or White men and women ages 18 to 30 years from 4 US communities. Over 35 years, CARDIA has contributed fundamentally to our understanding of the contemporary epidemiology and life course of cardiovascular health and disease, as well as pulmonary, renal, neurological, and other manifestations of aging. CARDIA has established associations between the neighborhood environment and the evolution of lifestyle behaviors with biological risk factors, subclinical disease, and early clinical events. CARDIA has also identified the nature and major determinants of Black-White differences in the development of cardiovascular risk. CARDIA will continue to be a unique resource for understanding determinants, mechanisms, and outcomes of cardiovascular health and disease across the life course, leveraging ongoing pan-omics work from genomics to metabolomics that will define mechanistic pathways involved in cardiometabolic aging.

Purpose Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance. Methods A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology. Results The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive Aspergillus tracheobronchitis and collection of the best validated specimen for Aspergillus diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients’ clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients. Conclusion CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06449-4.

Heart failure with preserved ejection fraction (HFpEF) affects more women than men. Menopause may influence HFpEF development in women. We assessed cross-sectional and longitudinal associations between menopause and echocardiographic measures of left ventricular (LV) function and cardiac remodeling.We studied 1,723 women with available echo data from at least two of: year 5 (Y5) (1990-1991), Y25 (2010-2011), or Y30 (2015-2016) in the Coronary Artery Risk Development in Young Adults study. Cardiac structure and function were measured using 2D and Doppler echocardiography. Cross-sectional associations between menopausal status and repeated echo measures at Y25 and Y30 were analyzed using linear mixed models. Two-segmented models were used to compare longitudinal changes in echocardiographic measures in the premenopausal period to changes in the postmenopausal period.Mean ± SD age (years) at enrollment was 27 ± 3 in those with menopause by Y25, 25 ± 3 in those with menopause between Y25 and Y30, and 21 ± 3 in those premenopausal at Y30. There were no significant differences in race, body mass index, systolic blood pressure, or diabetes between the groups. Postmenopausal women had higher early diastolic mitral inflow (E) to annular (e') velocity ratio than premenopausal after adjusting for demographics and risk factors (P 0.05). Menopause was associated with relative increases in the rates of change in LV mass and left atrial volume, even after adjustment. Change in E/e' ratio was similar before and after menopause.Menopause is associated cross-sectionally with worse diastolic function and longitudinally with adverse LV and left atrial remodeling. This may contribute to the increased HFpEF risk in postmenopausal women.Video Summary:http://links.lww.com/MENO/A787.

OBJECTIVE To examine the relation of knee pain patterns to pain severity and to radiographic osteoarthritis (OA) severity and duration. METHODS The Multicenter Osteoarthritis Study is a longitudinal cohort of older adults with or at risk of knee OA. Participants' Intermittent and Constant Osteoarthritis Pain (ICOAP) scores were characterized as 1) no intermittent or constant pain, 2) intermittent pain only, 3) constant pain only, and 4) a combination of constant and intermittent pain. Knee pain severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and a visual analog scale (VAS). Radiographic knee OA (ROA) severity was defined as Kellgren/Lawrence grade ≥2, and ROA duration was defined according to the clinic visit at which ROA was first noted. We assessed the relation of ICOAP pain patterns to knee pain severity, ROA severity, and ROA duration using regression models with generalized estimating equations. RESULTS There were 2,322 participants (mean age 68.8 years, body mass index 31.0 kg/m2 , 60% female). Higher ICOAP pain patterns, i.e., a mix of constant and intermittent pain, were associated with greater WOMAC pain severity compared with those patients without either pain pattern (odds ratio [OR] 43.2 [95% confidence interval (95% CI) 26.4-61.3]). Results were similar for the VAS (OR 71.2 [95% CI 45.7-110.9]). Those patients with more severe and longer duration of ROA were more likely to have a mix of constant and intermittent pain compared with those without either pain (OR 3.7 [95% CI 3.1-4.6] and OR 2.9 [95% CI 2.5-3.5], respectively). CONCLUSION Knee pain patterns are associated with radiographic disease stage and duration, as well as pain severity, highlighting the fact that pain patterns are important for understanding symptomatic disease progression.

Purpose of review A number of pharmacokinetic and pharmacodynamic factors in critically ill or severely immunosuppressed patients influence the effectiveness of antifungal therapy making dosing less certain. Recent position papers from infectious diseases societies and working groups have proposed methods for dosage individualization of antibiotics in critically ill patients using a combination of population pharmacokinetic models, Monte-Carlo simulation and therapeutic drug monitoring (TDM) to guide dosing. In this review, we examine the current limitations and practical issues of adapting a pharmacometrics-guided dosing approaches to dosing of antifungals in critically ill or severely immunosuppressed populations. Recent findings We review the current status of antifungal susceptibility testing and challenges in incorporating TDM into Bayesian dose prediction models. We also discuss issues facing pharmacometrics dosage adjustment of newer targeted chemotherapies that exhibit severe pharmacokinetic drug-drug interactions with triazole antifungals. Summary Although knowledge of antifungal pharmacokinetic/pharmacodynamic is maturing, the practical application of these concepts towards point-of-care dosage individualization is still limited. User-friendly pharmacometric models are needed to improve the utility of TDM and management of a growing number of severe pharmacokinetic antifungal drug-drug interactions with targeted chemotherapies.

We examined the longitudinal association between blood pressure (BP) and stroke incidence in young and middle-aged adults. BP measured during 9 examinations of the CARDIA study (Coronary Artery Risk Development in Young Adults) from 1985-1986 to 2015-2016 was used to classify participants (n=5079) according to the 2017 Hypertension Clinical Practice Guidelines. We used the highest BP obtained through the third examination (1990–1991) to define baseline BP categories; time-dependent categories (accounting for change in BP over time) were determined incorporating follow-up measurements. BP groups at ages 30 and 40 years were also defined. Stroke events were adjudicated until 2018. Mean age at baseline was 29.8 years. Stroke occurred in 100 participants. Stroke incidence (per 100 000 person-years) was higher ( P

Background The goal of this study is to evaluate germline genetic variants in African American men with metastatic prostate cancer as compared to those in Caucasian men with metastatic prostate cancer in an effort to understand the role of genetic factors in these populations. Methods African American and Caucasian men with metastatic prostate cancer who had germline testing using multigene panels were used to generate comparisons. Germline genetic results, clinical parameters, and family histories between the two populations were analyzed. Results A total of 867 patients were included in this retrospective study, including 188 African American and 669 Caucasian patients. There was no significant difference in the likelihood of a pathogenic or likely‐pathogenic variants (PV/LPVs) between African American and Caucasian patients (p = .09). African American patients were more likely to have a variant of unknown significance than Caucasians (odds ratio [OR] = 1.95; p

Rationale: Patients with malignant/paramalignant pleural effusions (MPE/PMPEs) may have tunneled pleural catheter (TPC) management withheld due to infection concerns from immunosuppression associated with antineoplastic therapy. Objective: To determine the rate of infections related to TPC use and to determine the relationship to antineoplastic therapy, immune system competency and overall survival (OS)? Methods: We performed an international, multi-institutional study of MPE/PMPE patients undergoing TPC management from 2008-2016. Patients were stratified by whether or not they underwent antineoplastic therapy and/or were immunocompromised or not. Cumulative incidence functions and multivariable competing risk regression analyses were performed to identify independent predictors of TPC-related infection. Kaplan-Meier method and multivariable Cox proportional-hazards modeling were performed to examine for independent effects on OS. Results: A total of 1,408 TPCs were placed in 1,318 patients. Patients had a high frequency of overlap between antineoplastic therapy and an immunocompromised state (75-83%). No difference in the overall (6-7%), deep pleural (3-5%) or superficial (3-4%) TPC-related infection rates between subsets of patients stratified by antineoplastic therapy or immune status was observed. The median time to infection was 41 (interquartile range: 19-87) days following TPC insertion. Multivariable competing risk analyses demonstrated longer TPC duration was associated with a higher risk of TPC-related infection [subdistribution hazard ratio (95% CI): 1.03 (1.00-1.06), p=0.028]. Cox proportional-hazards analysis showed antineoplastic therapy was associated with better OS [hazard ratio (95% CI): 0.84 (0.73-0.97), p=0.015]. Conclusion: The risk of TPC-related infection does not appear to be increased by antineoplastic therapy use or an immunocompromised state. The overall rates of infection are low and comparable to immunocompetent patients with no relevant antineoplastic therapy. These results support TPC palliation for MPE/PMPE regardless of plans for antineoplastic therapy.

Objective:To assess the incidence of colonization and infection with carbapenemase-producing Enterobacteriaceae (CPE) and carbapenem-resistant Acinetobacter baumannii (CR-Ab) in the ICUs of our city hospitals before and during the coronavirus disease 2019 (COVID-19) pandemic.Methods:We conducted a multicenter, before-and-after, cross-sectional study to compare the rates of colonization and infection with CPE and/or CR-Ab in 2 study periods, period 1 (January–April 2019) and period 2 (January–April 2020). Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) of weekly colonization and infection rates for each period were compared for the 2 study periods using Poisson regression. Weekly trends in the incidence of colonization or infection for each study period were summarized using local weighted (Loess) regression.Results:We detected no significant change in either IRR and weekly trend in CPE colonization and infection during the 2 study periods. A shift from KPC to other CPE mechanisms (OXA-48 and VIM) was observed during period 2. Compared to period 1, during period 2 the IRR of colonization and infection with CR-Ab increased 7.5- and 5.5-fold, respectively. Genome sequencing showed that all CR-Ab strains belonged to the CC92/IC2 clonal lineage. Clinical strains clustered closely into a single monophyletic group in 1 of the 3 centers, whereas they segregated in 2 different clusters in the other 2 centers, which strongly indicates horizontal transmission.Conclusions:Our findings indicate the need to conduct infection control activities targeted against the spread of antimicrobial resistance between and within hospitals during the COVID-19 pandemic, and if necessary, remodulating them according to the new organizational structures imposed by the pandemic.

Background Little is known about the timing of preclinical heart failure (HF) development, particularly among blacks. The primary aims of this study were to delineate age-related left ventricular (LV) structure and function evolution in a biracial cohort and to test the hypothesis that young-adult LV parameters within normative ranges would be associated with incident stage B–defining LV abnormalities over 25 years, independent of cumulative risk factor burden. Methods Data from the Coronary Artery Risk Development in Young Adults study were analyzed. Participants (n = 2,833) had a mean baseline age of 30.1 years; 45% were black, and 56% were women. Generalized estimating equation logistic regression was used to estimate age-related probabilities of stage B LV abnormalities (remodeling, hypertrophy, or dysfunction) and logistic regression to examine risk factor–adjusted associations between baseline LV parameters and incident abnormalities. Cox regression was used to assess whether baseline LV parameters associated with incident stage B LV abnormalities were also associated with incident clinical (stage C/D) HF events over >25 years’ follow-up. Results Probabilities of stage B LV abnormalities at ages 25 and 60 years were 10.5% (95% CI, 9.4%–11.8%) and 45.0% (95% CI, 42.0%–48.1%), with significant race-sex disparities (e.g., at age 60, black men 52.7% [95% CI, 44.9%–60.3%], black women 59.4% [95% CI, 53.6%–65.0%], white men 39.1% [95% CI, 33.4%–45.0%], and white women 39.1% [95% CI, 33.9%–44.6%]). Over 25 years, baseline LV end-systolic dimension indexed to height was associated with incident systolic dysfunction (adjusted odds ratio per 1 SD higher, 2.56; 95% CI, 1.87–3.52), eccentric hypertrophy (1.34; 95% CI, 1.02–1.75), concentric hypertrophy (0.69; 95% CI, 0.51–0.91), and concentric remodeling (0.68; 95% CI, 0.58–0.79); baseline LV mass indexed to height2.7 was associated with incident eccentric hypertrophy (1.70; 95% CI, 1.25–2.32]), concentric hypertrophy (1.63; 95% CI, 1.19–2.24), and diastolic dysfunction (1.24; 95% CI, 1.01–1.52). Among the entire cohort with baseline echocardiographic data available (n = 4,097; 72 HF events), LV end-systolic dimension indexed to height and LV mass indexed to height2.7 were significantly associated with incident clinical HF (adjusted hazard ratios per 1 SD higher, 1.56 [95% CI, 1.26–1.93] and 1.42 [95% CI, 1.14–1.75], respectively). Conclusions Stage B LV abnormalities and related racial disparities were present in young adulthood, increased with age, and were associated with baseline variation in indexed LV end-systolic dimension and mass. Baseline indexed LV end-systolic dimension and mass were also associated with incident clinical HF. Efforts to prevent the LV abnormalities underlying clinical HF should start from a young age.

BACKGROUND Since 2005, the universal hepatitis B (HepB) birth dose has been recommended for all medically stable infants weighing ≥2,000 g at birth. The timing of the birth dose provides a critical safeguard and prevents infection among infants born to HBsAg-positive mothers not identified prenatally. We assess infant HepB vaccination in the U.S. Department of Defense's Military Health System (MHS) to identify trends in vaccination coverage and sociodemographic factors associated with non-receipt of the birth dose, receiving the first HepB vaccine >3 days of life, and not receiving any HepB vaccine in the first 18 months of life utilizing parental refusal codes. To our knowledge, this is one of the first studies assessing trends in parental refusal of the HepB birth dose utilizing administrative claims parental refusal codes. METHODS We conducted a retrospective cohort analysis of MHS live births from January 1, 2014 through December 31, 2018 utilizing administrative claims data. Data were included from 44 hospitals in 24 unique states, territories, or countries. We analyzed diagnosis codes for vaccine refusal and vaccination and current procedural terminology (CPT) codes to identify vaccination patterns. Generalized linear mixed effects models with a logit link were used to assess factors associated with vaccination patterns. RESULTS HepB birth dose vaccination coverage increased from 79.6% in 2014 to 88.1% in 2018 (p

Objectives:It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults.Methods:Lipids were measured at baseline (1985–1986; age: 18–30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes.Results:There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV.Conclusion:Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.

Background Lactation is associated with lower risks for cardiovascular disease in women. Organ-related adiposity, which plays significant roles in the development of cardiometabolic diseases, could help explain this observation. We evaluated the association of lactation duration with visceral (VAT) and pericardial (PAT) fat volumes in women. Methods Data were obtained from 910 women enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study (1985-1986) without diabetes prior to pregnancy who had ≥1 birth during 25 years of follow-up and had VAT and PAT measured from computed tomographic scans in 2010-2011. Cumulative lactation duration across all births since baseline was calculated from self-reports collected at periodic exams. Results At baseline, the average age of women (48% black, 52% white) was 24 ± 3.7 years. After controlling for baseline age, race, smoking status, body mass index, fasting glucose, family history of diabetes, fat intake, total cholesterol, physical activity, and follow-up covariates (parity, gestational diabetes), the mean fat volumes across categories of lactation [none (n = 221), 1-5 months (n = 306), 6-11 months (n = 210), and ≥12 months (n = 173)] were 122.0, 113.7 105.0, and 110.1 cm3 for VAT and 52.2, 46.7, 44.5, and 43.4 cm3 for PAT, respectively. Changes in body weight from the first post-baseline birth to the end of follow-up mediated 21% and 18% of the associations of lactation with VAT and PAT, respectively. Conclusions In this prospective study, longer cumulative lactation duration was associated with lower VAT and PAT volumes, with weight gain partially mediating these associations.

Steps per day were measured by accelerometer for 7 days among 5,545 women aged 63–97 years between 2012 and 2014. Incident falls were ascertained from daily fall calendars for 13 months. Median steps per day were 3,216. There were 5,473 falls recorded over 61,564 fall calendar-months. The adjusted incidence rate ratio comparing women in the highest versus lowest step quartiles was 0.71 (95% confidence interval [0.54, 0.95]; ptrend across quartiles = .01). After further adjustment for physical function using the Short Physical Performance Battery, the incidence rate ratio was 0.86 ([0.64, 1.16]; ptrend = .27). Mediation analysis estimated that 63.7% of the association may be mediated by physical function (p = .03). In conclusion, higher steps per day were related to lower incident falls primarily through their beneficial association with physical functioning. Interventions that improve physical function, including those that involve stepping, could reduce falls in older adults.

Background Current evidence supports the adoption of healthy diet and physical activity (PA) behaviors in patients with polycystic ovary syndrome (PCOS), given the positive effects of those behaviors on physical well-being. An improved understanding of the associations between diet and PA with PCOS is needed to ascertain whether tailored dietary and PA recommendations are needed for this population. Thus, we investigated the associations of diet and PA with PCOS and its isolated features. Methods Cross-sectional study. Of the 748 women who were included in this study from the Coronary Artery Risk Development in Young Adults (CARDIA) Women’s Study, 40 were classified as having PCOS, 104 had isolated hyperandrogenism (HA) and 75 had isolated oligomenorrhea (OA). Dietary intake was measured using the CARDIA diet history questionnaire and diet quality was scored using the Alternative Healthy Eating Index 2010; a higher score indicated a better quality diet. Self-reported PA was measured using a validated interviewer-administered questionnaire. Polytomous logistic regression analyses examined the associations between diet and PA with PCOS, HA, and OA status (outcomes), adjusting for age, race, total energy intake, education, and/or body mass index. The threshold for statistical significance was set at p Results Mean age of the participants was 25.4 years (SD 3.6) and 46.8% of participants were Black women. There was little to no association of total energy intake, nutrients, diet quality, and PA with PCOS, HA or OA status. Conclusion Energy intake, nutrient composition, diet quality, and PA were not associated with PCOS, supporting recent PCOS guidelines of using national recommendations for the general population to encourage health-promoting behaviors among women with PCOS. However, longitudinal studies evaluating changes in diet and physical activity in relation to the development and/or the progression of PCOS are needed to establish a causal association.

Purpose: Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non–small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes. Experimental Design: We conducted a retrospective analysis of 194 patients with stage I–III NSCLC, including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain. Results: In stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P = 0.0108), and shorter DFS (HR 2.530, P = 0.0029) and OS (HR 2.198, P = 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy. Conclusions: These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over nine years, hazard ratios (aHR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders., A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI+MOST. Walking 0.2 meters/second slower during short- and standard-distance walk tests was associated with 23% (aHR[95%CI]; 1.23[1.10, 1.39]) and 25% (1.25[1.09, 1.43]) higher mortality risk, respectively. Walking

BACKGROUND Blood pressure (BP) measured in the office setting increases from early through later adulthood. However, it is unknown to what extent out-of-office BP derived via ambulatory BP monitoring (ABPM) increases over time, and which participant characteristics and risk factors might contribute to these increases. METHODS We assessed 25-year change in office- and ABPM-derived BP across sex, race, diabetes mellitus (DM), and body mass index (BMI) subgroups in the Coronary Artery Risk Development in Young Adults study using multivariable-adjusted linear mixed effects models. RESULTS We included 288 participants who underwent ABPM at the Year 5 Exam (mean [SD] age, 25.1 [3.7]; 45.8% men) and 455 participants who underwent ABPM at the Year 30 Exam (mean [SD] age, 49.5 [3.7]; 42.0% men). Office, daytime, and nighttime systolic BP (SBP) increased 12.8 (95% confidence interval [CI], 7.6–17.9), 14.7 (95% CI, 9.7–19.8), and 16.6 (95% CI, 11.4–21.8) mm Hg, respectively, over 25 years. Office SBP increased 6.5 (95% CI, 2.3–10.6) mm Hg more among black compared with white participants. Daytime SBP increased 6.3 (95% CI, 0.2–12.4) mm Hg more among participants with a BMI ≥25 vs. CONCLUSIONS Office- and ABPM-derived BP increased more from early through middle adulthood among black adults and participants with DM and BMI ≥25 kg/m2.

INTRODUCTION Mock oral examinations (MOE) are used to prepare residents and assess their readiness for the American Board of Surgery Certifying Exam (ABSCE). Delivery of MOEs varies by institution and previous studies have demonstrated significant implementation barriers such as availability of faculty examiners and exam scenarios. OBJECTIVE To assess the value and participant satisfaction of a standardized multi-institutional MOE for general surgery residents. PARTICIPANTS Thirty-three general surgery residents and 37 faculty members from 3 institutions participated in a regional MOE. Residents were examined in three 20-minute sessions. Faculty examiners were given a wide selection of prescripted exam scenarios and instructed to use standardized grading rubrics during a brief orientation on the day of the exam. All participants were surveyed on their overall experience. RESULTS Of 33 participating residents, 26 (79%) passed the MOE (92% of R5, 91% R4, and 50% of R3). Response rates were 91% for residents, and 57% for faculty members respectively. Most respondents were satisfied with the overall exam experience (88%), standardized question quality (86%) and question variety (82%). A total of 92% of respondents agreed that the time, effort, and cost of the MOE was justified by its educational value to residents. Higher medical knowledge ratings assigned by faculty examiners correlated with stronger trainee performance (β = 0.48; 95% confidence interval [CI] 0.29-0.66), while patient care and interpersonal communication skill ratings were not associated with trainee performance. The standardized grading rubric achieved moderate inter-rater reliability among examiner pairs with 70.6% agreement (Kappa 0.47). CONCLUSIONS General Surgery residents and faculty perceived the standardized multi-institutional MOE to be a highly satisfactory educational experience and valuable assessment tool. Developing a repertoire of scripted exam scenarios made it feasible to recruit sufficient faculty participants, and standardizing grading rubrics allowed for a consistent exam experience with moderate inter-rater reliability.

Summary Background Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. Methods SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov , NCT01206062 . Findings From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7–5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of −0·005 (95% CI −0·010 to 0·001) in the intensive treatment group and −0·001 (–0·006 to 0·005) in the standard treatment group (between-group difference −0·004, 95% CI −0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference −0·010, 95% CI −0·017 to −0·002; p=0·02), with an annual decline of −0·025 (–0·030 to −0·019) for the intensive treatment group and −0·015 (–0·021 to 0·009) for the standard treatment group. Interpretation Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. Funding National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association.

Alcohol use disorder is a chronic disease, and the consumption of alcohol after treatment is an integral part of the disease process. However, drinking alcohol itself is not a disorder; persistent problematic drinking is. This paper assesses the stability of the yearly drinking patterns of individuals with alcohol use disorder after discharge from psychiatric hospitalization for Alcohol Use Disorder (AUD).

The major component of non-traumatic thoracic aortic emergencies is the acute aortic syndromes. These include acute aortic dissection, intramural haematoma and penetrating atherosclerotic ulcer, grouped together because they are indistinguishable clinically and highly fatal. All three entities involve disruption to the tunica intima and media and may be complicated by rupture, end-organ ischaemia or aneurysmal transformation. Early diagnosis is vital to allow timely and appropriate management. Paired unenhanced and electrocardiogram-gated computed tomography angiography of the chest, extending more distally if required, is recommended for diagnosis. Specific computed tomography features of all three entities are reviewed, with a focus on morphological features associated with complications. Those with type A pathology are usually managed with open surgery because this has a high risk of complication. Patients with uncomplicated type B pathology are usually managed with best medical therapy whereas those with complicated type B pathology are usually offered either surgery or thoracic endovascular aortic repair. The limited evidence regarding the use of thoracic endovascular aortic repair in patients with subacute uncomplicated type B pathology is briefly discussed.

As the population ages, there is a growing burden owing to musculoskeletal diseases, such as knee osteoarthritis, and subsequent functional decline. In the absence of a cure, there is a need to identify factors amenable to intervention to prevent or slow this process. The Multicenter Osteoarthritis Study cohort was developed for this purpose. In this study, associations between variability in peak knee flexor and extensor torque at baseline and worsening of pain and physical function over the subsequent 60 mos were assessed in a cohort of 2680 participants. The highest quartile of baseline knee flexor torque variability was found to be associated longitudinally with worsening pain (fourth quartile s estimate, mean ± SE, 0.49 ± 0.19; P = 0.0115; with R2 = 0.28 and P for trend across quartiles = 0.0370) and physical function scores (fourth quartile s estimate, mean ± SE, 1.39 ± 0.64; P = 0.0296; with R2 = 0.25 and P for trend across quartiles = 0.0371), after adjusting for baseline knee osteoarthritis and maximum knee flexor torque. There were no associations between baseline knee extensor torque and worsening pain or physical function by 60 mos. The presence of greater variability in maximum knee flexor strength may identify patients who may benefit from therapies aimed at preventing worsening knee pain and physical function.

Objective This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality. Methods Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer. Results After a median follow-up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity-related cancers were 6.1 and 7.3 per 1,000 person-years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95% CI: 0.68-1.04). There was no significant difference between the two groups in total cancer incidence (HR, 0.93; 95% CI: 0.80-1.08), incidence of nonobesity-related cancers (HR, 1.02; 95% CI: 0.83-1.27), or total cancer mortality (HR, 0.92; 95% CI: 0.68-1.25). Conclusions An ILI aimed at weight loss lowered incidence of obesity-related cancers by 16% in adults with overweight or obesity and type 2 diabetes. The study sample size likely lacked power to determine effect sizes of this magnitude and smaller.

Aims The long‐term impact of coffee or tea consumption on subclinical left ventricular (LV) systolic or diastolic function has not been previously studied. We examined the association between coffee or tea consumption beginning in early adulthood and cardiac function in midlife. Methods and results We investigated 2735 Coronary Artery Risk Development in Young Adults (CARDIA) study participants with long‐term total caffeine intake, coffee, and tea consumption data from three visits over a 20 year interval and available echocardiography indices at the CARDIA Year‐25 exam (2010–2011). Linear regression models were used to assess the association between caffeine intake, tea, and coffee consumption (independent variables) and echocardiography outcomes [LV mass, left atrial volume, and global longitudinal strain (GLS), LV ejection fraction (LVEF), and transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/e´)]. Models were adjusted for standard cardiovascular risk factors, socioeconomic status, physical activity, alcohol use, and dietary factors (calorie intake, whole and refined grain intake, and fruit and vegetable consumption). Mean (standard deviation) age was 25.2 (3.5) years at the CARDIA Year‐0 exam (1985–1986), 57.4% were women, and 41.9% were African‐American. In adjusted multivariable linear regression models assessing the relationship between coffee consumption and GLS, beta coefficients when comparing coffee drinkers of 4 cups/day with non‐coffee drinkers were β = −0.30%, P 0.05; respectively (more negative values implies better systolic function). In adjusted multivariable linear regression models assessing the relationship between coffee consumption and E/e´, beta coefficients when comparing coffee drinkers of 4 cups/day with non‐coffee drinkers were β = −0.29, P .05; and β = −0.37, P > 0.05, respectively (more negative values implies better diastolic function). High daily coffee consumption (>4 cups/day) was associated with worse LVEF (β = −1.69, P 0.05 for all). Conclusions Low‐to‐moderate daily coffee consumption from early adulthood to middle age was associated with better LV systolic and diastolic function in midlife. High daily coffee consumption (>4cups/day) was associated with worse LV function. There was no association between caffeine or tea intake and cardiac function.

OBJECTIVE This study hypothesized that both preconception and postchildbearing patterns of cardiometabolic risk factors may be different for women with gestational diabetes mellitus (GDM) compared with women without GDM. METHODS Among 1,302 (51% black) women in the Coronary Artery Risk Development in Young Adults (CARDIA) study with births and followed for 30 years, this study evaluated changes in cardiometabolic factors (BMI, waist circumference [WC], lipids, blood pressure) during prechildbearing (prior to the first postbaseline birth) and postchildbearing periods (after the last birth) by GDM status using piecewise linear mixed models adjusted for sociodemographics, parity, and time-varying covariates. RESULTS Compared with women who did not develop GDM, weight and WC increases in women who developed GDM (n = 152, 12%) were faster (BMI difference: +0.12 kg/m2 /y, P = 0.04; WC difference: +0.28 cm/y, P = 0.04) during the prechildbearing period, accounting for covariates. This translated to an average of 1.3 kg of excess weight gain across 4 years among women with subsequent GDM versus non-GDM births. In contrast, slopes after childbearing did not differ by GDM status, nor were there other cardiometabolic differences. CONCLUSIONS Women with GDM exhibited an increasing prepregnancy pattern of weight gain and central adiposity. Absolute postchildbearing weight was also higher in GDM-affected women, but the slope of gain after GDM was not.

The association between dietary sodium and potassium intake with the development of kidney disease remains unclear, particularly among younger individuals. Here, we determined whether dietary sodium and potassium intake are associated with incident chronic kidney disease (CKD) using data from 1,030 adults (age 23–35 in 1990–1991) from the Coronary Artery Risk Development In Young Adults study, based on repeated measurements of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (ACR) from 1995 through 2015. Urinary sodium and potassium excretion (mg/day), calculated from three 24-hour urine collections in 1990–1991, were averaged to measure sodium and potassium intake. Serum creatinine was used to calculate eGFR using the CKD EPI equation; spot urine albumin and creatinine were used to calculate ACR, each at five visits from 1995–1996 through 2015–2016. CKD was defined as decreased eGFR (under 60 ml/min/1.73m(2)) or the development of albuminuria (ACR over 30 mg/g). We used log binomial regression models adjusted for socio-demographic, behavioral, and clinical factors to determine whether sodium and potassium intake were associated with incident CKD (decreased eGFR or developed albuminuria) among those free of CKD in 1995. Dietary sodium intake was not significantly associated with incident CKD. However, every 1,000 mg/day increment of potassium intake in 1990 was significantly associated with a 29% lower risk of incident albuminuria (relative risk 0.71, 95% confidence interval 0.53, 0.95), but not eGFR. Thus, higher dietary potassium intake may protect against the development of kidney damage, particularly albuminuria.

Purpose The primary purpose of this study was to explore the efficacy of using virtual reality (VR) technology in hearing research with children by comparing speech perception abilities in a typical laboratory environment and a simulated VR classroom environment. Method The study included 48 final participants (40 children and eight young adults). The study design utilized a speech perception task in conjunction with a localization demand in auditory-only (AO) and auditory–visual (AV) conditions. Tasks were completed in simulated classroom acoustics in both a typical laboratory environment and in a virtual classroom environment accessed using an Oculus Rift head-mounted display. Results Speech perception scores were higher for AV conditions over AO conditions across age groups. In addition, interaction effects of environment (i.e., laboratory environment and VR classroom environment) and visual accessibility (i.e., AV vs. AO) indicated that children's performance on the speech perception task in the VR classroom was more similar to their performance in the laboratory environment for AV tasks than it was for AO tasks. AO tasks showed improvement in speech perception scores from the laboratory to the VR classroom environment, whereas AV conditions showed little significant change. Conclusion These results suggest that VR head-mounted displays are a viable research tool in AV tasks for children, increasing flexibility for audiovisual testing in a typical laboratory environment.

It remains uncertain whether intensive control of blood pressure (BP) results in a lower risk of atrial fibrillation (AF) in patients with hypertension. Using data from SPRINT (Systolic Blood Pressure Intervention Trial), which enrolled participants with hypertension at increased risk of cardiovascular disease, we examined whether intensive BP lowering (target systolic BP [SBP] P =0.037). This effect was consistent among prespecified subgroups of SPRINT participants stratified by age, sex, race, SBP tertiles, prior cardiovascular disease, and prior chronic kidney disease when interactions between treatment effect and these subgroups were assessed using Hommel adjusted P values. In conclusion, intensive treatment to a target of SBP Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

Evidence has established obesity as a risk factor for total knee replacement (TKR) due to osteoarthritis. Obesity is a risk factor for TKR. Randomized trials such as Look AHEAD (Action for Health in Diabetes) have shown long-term successful weight loss with an intensive lifestyle intervention (ILI). It is unknown, however, if intentional weight loss can reduce the risk of TKR.Look AHEAD randomized persons aged 45-76 with type 2 diabetes who had overweight or obesity to either an ILI to achieve/maintain 7% weight loss or to standard diabetes support and education (DSE). Reported knee pain was assessed using the Visual Analog Scale and Western Ontario McMaster University Osteoarthritis Index questionnaire in 5125 participants without previous TKR. Cox proportional hazard regression was used to model differences in risk of TKR in relation to randomization group assignment (ILI vs DSE) along with baseline body mass index category and baseline knee pain as potential confounders from baseline through Look AHEAD-Extension.Baseline mean ± SD Western Ontario McMaster University Osteoarthritis Index knee pain scores did not differ by treatment assignment (ILI: 3.6 ± 2.9, DSE: 3.9 ± 3.0, P = .08); as expected due to randomization. During follow up, the 631 (12%) participants who reported having a TKR were more likely to have been heavier (P.001) and older (P.001) at enrollment, but risk of TKR did not differ by treatment group assignment (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.91-1.25, P = .43). Heterogeneity of treatment effect was observed according to baseline knee pain (interaction P = .02). In persons without knee pain at baseline, there was a 29% reduced risk of TKR in ILI compared to DSE (HR 0.71, 95% CI 0.52-0.96). However, in persons with knee pain at baseline, there was no statistically significant association of treatment assignment with respect to subsequent TKR incidence (HR 1.11, 95% CI 0.92-1.33).Findings suggest that intensive lifestyle change including physical activity, dietary restriction and behavioral changes to achieve weight loss for prevention of TKR may be most effective in preventing TKR prior to the development of knee pain.

Objective Osteoarthritis (OA) and pain are both made more severe by low-grade inflammation. This study was undertaken to examine whether visceral fat, a major source of inflammatory cytokines and adipokines, is associated with an increased risk of knee OA or musculoskeletal pain. Methods Subjects in the Multicenter Osteoarthritis Study cohort, who were age 50-79 years and had or were at high risk of knee OA, underwent whole-body dual x-ray absorptiometry (DXA) at baseline. At baseline, 30 months, and 60 months radiographs and magnetic resonance images (MRIs) of the knees were obtained, and patients were asked to score the severity of their knee pain and to identify sites of joint pain using a body homunculus. Baseline DXA scans were used to measure total body fat and visceral and subcutaneous fat in the torso. The association of fat depot size with structural outcomes (incident radiographic OA and cartilage loss and synovitis on MRI) and with pain outcomes (worsening knee pain, number of painful joints, and widespread pain) was assessed. Regression analyses were adjusted for age, sex, race, education level, smoking status, physical activity, body mass index (BMI), and depressive symptoms. Results Of the 2,961 participants at baseline, 60.7% were women. The mean age was 62.5 years and mean BMI was 30.5 kg/m2 . After adjustment for covariates, no fat measures were associated with any structural outcomes. However, total and visceral, but not subcutaneous, fat were positively associated with worsening knee pain (P = 0.0005 for total fat and P = 0.007 for visceral fat) and widespread pain (P = 0.001 for total fat and P = 0.02 for visceral fat), and the amount of visceral fat was associated with the number of painful joints (P = 0.07). Conclusion Our findings indicate that visceral fat is associated with an increased risk of musculoskeletal and widespread pain.

Salivary duct carcinoma (SDC) commonly expresses androgen receptor (AR) and HER2, giving rise to treatment implications. SDC may also express programmed-death-ligand-1 (PD-L1), a predictive marker of response to checkpoint inhibitors. PD-L1 can be associated with genomic instability and high density of tumor infiltrating lymphocytes (TILs). Evaluation of HER2 immunohistochemistry (IHC) in SDC is not standardized, and relationships between ERBB2 copy numbers, PD-L1 expression and TILs in SDC are unknown. We evaluated 32 SDCs for HER2, AR and PD-L1 expression (IHC), ERBB2 status (FISH) and TILs (slide review). HER2 was scored with three different systems (breast, gastric, proposed salivary gland). PD-L1 was evaluated with the combined positive score. Most patients were older men, presenting at advanced clinical stage with nodal or distant metastases. During follow-up (mean 5 years, range 6 months to 21 years), 25 of the 32 patients (78%) died of SDC. We propose a HER2 IHC scoring system which accurately predicts underlying ERBB2 amplification or increased copy numbers in SDC. Most tumors had increased ERBB2 copy numbers (19/32 amplification, 6/32 aneusomy), a finding associated with higher TIL densities (p = 0.045) and PD-L1 expression (p = 0.025). Patients with TILs ≥ 40% had better prognoses (Log-Rank p = 0.013), with TILs being favorable prognosticators in univariate analysis (Hazard ratio: 0.18, p = 0.024). A subset of SDCs with increased ERBB2 copy numbers have higher TILs and PD-L1 expression. TILs ≥ 40% are associated with better prognosis. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-020-01163-x) contains supplementary material, which is available to authorized users.

Aims Cumulative blood pressure (BP) is a measure that incorporates the severity and duration of BP exposure. The prognostic significance of cumulative BP in young adults for cardiovascular diseases (CVDs) in comparison to BP severity alone is, however, unclear. Methods and results We investigated 3667 Coronary Artery Risk Development in Young Adults participants who attended six visits over 15 years (year-0 (1985–1986), year-2, year-5, year-7, year-l0, and year-15 exams). Cumulative BP was calculated as the area under the curve (mmHg × years) from year 0 through year 15. Cox models assessed the association between cumulative BP (year 0 through year 15), current BP (year 15), and BP change (year 0 and year 15) and CVD outcomes. Mean (standard deviation) age at year 15 was 40.2 (3.6) years, 44.1% were men, and 44.1% were African-American. Over a median follow-up of 16 years, there were 47 heart failure (HF), 103 coronary heart disease (CHD), 71 stroke, and 191 CVD events. Cumulative systolic BP (SBP) was associated with HF (hazard ratio (HR) = 2.14 (1.58–2.90)), CHD (HR = 1.49 (1.19–1.87)), stroke (HR = 1.81 (1.38–2.37)), and CVD (HR = 1.73 (1.47–2.05)). For CVD, the C-statistic for SBP (year 15) was 0.69 (0.65–0.73) and change in C-statistic with the inclusion of SBP change and cumulative SBP was 0.60 (0.56–0.65) and 0.72 (0.69–0.76), respectively. For CVD, using year-15 SBP as a reference, the net reclassification index (NRI) for cumulative SBP was 0.40 (p Conclusions Cumulative BP in young adults was associated with the subsequent risk of HF, CHD, stroke, and CVD. Cumulative BP provided incremental prognostic value and improved risk reclassification for CVD, when compared to single BP assessments or changes in BP.

The primary objective of the study was to evaluate the effect of a hydrolyzed polysaccharide, Rice Bran Arabinoxylan Compound (RBAC), on biomarkers in adults with nonalcoholic fatty liver disease (NAFLD). A 90-day randomized double-blind placebo-controlled trial examined the effect of RBAC on complete blood count, liver enzymes, lipids, oxidative stress markers, cytokines, and growth factors. Twenty-three adults with NAFLD were enrolled and randomly assigned to one of the two study conditions (n = 12 RBAC and n = 11 placebo) and consumed 1 gram/day of either compound for 90 days. Subjects were assessed at baseline and 45 and 90 days. No adverse effects were reported. Alkaline phosphatase significantly decreased (−3.1%; SD = 19.9; F[1, 19] = 5.1, p=0.03) in the RBAC group compared to placebo. Percent monocytes (17.9%; SD = 18.3; F[1, 19] = 5.9, p=0.02) and percent eosinophils (30.6%; SD = 30.5; F[1, 19] = 12.3, p<0.01) increased in the RBAC group. IFN-γ (156%; SD = 131.8; F[1, 19] = 4.2, p=0.06) and IL-18 (29.1%; SD = 64; F[1, 19] = 5.3, p=0.03) increased in the RBAC group compared to placebo. Other improvements were noted for platelets, neutrophils, neutrophil-lymphocyte ratio, γ-glutamyl transferase, and 4-hydroxynonenal. RBAC had beneficial effects on several biomarkers that add to the known immunomodulatory activities of RBAC, which may be promising for people with NAFLD. This trial is registered with NCT02568787.

// Marcus Moses 1 , Ulkuhan Koksal 1 , Elisa Ledet 1 , Charlotte Manogue 1 , Patrick Cotogno 1 , Brian Lewis 1 , Jodi Layton 1 , A. Oliver Sartor 1 and Pedro Barata 1 1 Tulane Cancer Center, School of Medicine, Tulane University, New Orleans, LA, USA Correspondence to: Pedro Barata, email: pbarata@tulane.edu A. Oliver Sartor, email: osartor@tulane.edu Keywords: castration-resistant prostate cancer; high-dose testosterone; next-generation sequencing; androgen receptor Received: October 29, 2019 Accepted: December 16, 2019 Published: January 07, 2020 ABSTRACT Introduction: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA). Methods: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2–4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety. Results: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6–5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone ( n = 2) or enzalutamide ( n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT ( n = 9), yet no association between clinical outcomes and ctDNA findings was observed. Conclusions: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed.

Objective To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). Methods This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. Results Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. Conclusions Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

OBJECTIVES: To evaluate the associations of high awake blood pressure (BP), high asleep BP, and non-dipping BP, determined by ambulatory BP monitoring (ABPM), with left ventricular (LV) hypertrophy (LVH) and geometry. METHODS: Black and white participants (n=687) in the Coronary Artery Risk Development in Young Adults (CARDIA) study underwent 24-hour ABPM and echocardiography at the Year 30 Exam in 2015–2016. The prevalence and prevalence ratios (PR) of LVH were calculated for high awake systolic BP (≥ 130 mmHg), high asleep systolic BP (≥ 110 mmHg), the cross-classification of high awake and asleep systolic BP, and non-dipping systolic BP (percentage decline in awake-to-asleep systolic BP < 10%). Odds ratios (ORs) for abnormal LV geometry associated with these phenotypes were calculated. RESULTS: Overall, 46.0% and 49.1% of study participants had high awake and asleep systolic BP, respectively, and 31.1% had non-dipping systolic BP. After adjustment for demographics and clinical characteristics, high awake systolic BP was associated with a PR for LVH of 2.79, (95% confidence interval [95% CI] 1.63–4.79). High asleep systolic BP was also associated with a PR for LVH of 2.19 (95% CI 1.25–3.83). There was no evidence of an association between non-dipping systolic BP and LVH (PR 0.70, 95% CI 0.44–1.12). High awake systolic BP with or without high asleep systolic BP was associated with a higher OR of concentric remodeling and hypertrophy. CONCLUSION: Awake and asleep systolic BP, but not the decline in awake-to-asleep systolic BP, were associated with increased prevalence of cardiac end-organ damage.