Citations

Nonalcoholic fatty liver disease (NAFLD) is considered an independent risk factor for the development of cardiovascular disease. However, the association between changes in NAFLD status and the risk of cardiovascular disease (CVD) remains uncertain. Starting January 1, 2013, participants were followed until the occurrence of CVD event, death, or December 31, 2020. This was a population-based cohort study that included data from adults aged ≥ 20, who underwent 2 consecutive health screenings from 2009 to 2012. NAFLD was defined as a Fatty Liver Index ≥ 60 at each screening. The primary endpoint was a CVD event, which encompassed ischemic heart disease and cerebrovascular disease. The association between changes in NAFLD status and the risk of CVD was determined using multivariable Cox proportional hazards regression. This cohort comprised 4656,305 adults with a median age of 53 years. During 36,396,968 person-years of follow-up, 238,933 (5.1%) CVD events were observed. Compared to patients with no NAFLD at both screenings, patients who developed NAFLD at the second screening exhibited an increased risk of CVD (adjusted hazard ratio, 1.15; 95% confidence interval, 1.13–1.17). In contrast, individuals who recovered from NAFLD at the second screening demonstrated a reduced CVD risk compared to those with persistent NAFLD (adjusted hazard ratio, 0.91; 95% confidence interval, 0.90–0.92). The reversal of NAFLD is associated with a reduced risk of CVD. Therefore, focusing on NAFLD treatment could serve as a clinical target for lowering CVD risk.

Abstract In the general population, physical activity has been associated with a lower risk of several cancers; however, the evidence for ovarian cancer is not clear. It is suggested that early-life physical activity may differentially impact risk. Whether this is true among women at high risk due to a pathogenic variant (mutation) in the BRCA1 or BRCA2 genes has not been evaluated. Thus, we performed a matched case–control study to evaluate the association between adolescent and early-adulthood physical activity and ovarian cancer. BRCA mutation carriers who completed a research questionnaire on various exposures and incident disease and with data available on physical activity were eligible for inclusion. Self-reported activity at ages 12–13, 14–17, 18–22, 23–29, and 30–34 was used to calculate the average metabolic equivalent of task (MET)-hours/week for moderate, vigorous, and total physical activity during adolescence (ages 12–17) and early-adulthood (ages 18–34). Conditional logistic regression was used to estimate the OR and 95% confidence intervals (CI) of invasive ovarian cancer associated with physical activity. This study included 215 matched pairs (mean age = 57.3). There was no association between total physical activity during adolescence (ORhigh vs. low = 0.91; 95% CI: 0.61–1.36; Ptrend = 0.85), early-adulthood (ORhigh vs. low = 0.78; 95% CI: 0.51–1.20; Ptrend = 0.38) and overall (ORhigh vs. low = 0.81; 95% CI: 0.54–1.23; Ptrend = 0.56) and ovarian cancer. Findings were similar for moderate (Ptrend ≥ 0.25) and vigorous (Ptrend ≥ 0.57) activity. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, physical activity should continue to be encouraged to promote overall health. Significance: In this matched case–control study, we observed no association between physical activity during adolescence or early-adulthood and subsequent risk of ovarian cancer. These findings do not provide evidence for an association between early-life physical activity and BRCA-ovarian cancer; however, being active remains important to promote overall health and well-being.

Abstract Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33%–66% of PRS), men with low (0%–33%) and high (66%–100%) PRS had Odds Ratios (ORs) for overall prostate cancer of 2.08 [95% confidence interval (CI) = 0.58–7.49] and 18.06 (95% CI = 4.24–76.84) among P/LP/D carriers and 0.57 (95% CI = 0.46–0.71) and 3.02 (95% CI = 2.53–3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI = 0.24–30.54) and 28.99 (95% CI = 4.39–191.43) among P/LP/D carriers and 0.54 (95% CI = 0.31–0.95) and 3.22 (95% CI = 2.20–4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status. Significance: These findings highlight the importance of considering rare and common variants to comprehensively assess prostate cancer risk in men of African ancestry.

Abstract Background: Ventilator-associated pneumonia (VAP) is one of the leading causes of mortality in patients with critical care illness. Since obesity is highly prevalent, we wanted to study its impact on the outcomes of patients who develop VAP. Methods: Using the National Inpatient Sample (NIS) Database from 2017 to 2020, we conducted a retrospective study of adult patients with a principal diagnosis of VAP with a secondary diagnosis with or without obesity according to ICD-10 codes. Several demographics, including age, race, and gender, were analyzed. The primary endpoint was mortality, while the secondary endpoints included tracheostomy, length of stay in days, and patient charge in dollars. Multivariate logistic regression model analysis was used to adjust for confounders, with a p-value less than 0.05 considered statistically significant. Results: The study included 3832 patients with VAP, 395 of whom had obesity. The mean age in both groups was around 58 years, and 68% of the group with obesity were females compared to 40% in the control group. Statistically significant comorbidities in the obesity group included a Charlson Comorbidity Index score of three and above, Diabetes Mellitus, Hypertension, and chronic kidney disease. Rates and odds of mortality were not significantly higher in the collective obesity group 39 (10%) vs. 336 (8.5%), p-value 0.62, aOR 1.41, p-value 0.39). The rates and odds of tracheostomy were higher in the obesity group but not statistically significant. Obese patients were also found to have a longer and more expensive hospitalization. Conclusions: Obesity was not found to be an independent risk factor for worse outcomes in patients who develop VAP in the intensive care unit.

Background: High-quality lateral radiographs with the wrist in neutral (0°) or near neutral (less than 15° flexion or extension) are felt to be important for diagnosing carpal instability using intracarpal angular measurements, but may be unavailable. In addition, radiolunate (RLA) and capitolunate (CLA) measurement angles for defining carpal instability have poor validation. We sought to establish 95% confidence intervals (CIs) for predicted RLA and CLA throughout the arc of wrist motion in normal cadaveric wrists. Methods: Fresh frozen cadaveric upper extremities were secured in a limb positioner. Scaphopisocapitate lateral radiographs were obtained throughout the arc of motion and RLA and CLA, and wrist flexion or extension angles (WA) were measured by a board-certified hand surgeon. Scatter plots of variables were constructed, and correlation coefficients calculated for areas under the curves. Regression equations for predicted RLA and CLA based on WA were developed. Results: Both RLA and CLA correlated strongly with WA for each measurement in both flexion and extension ( r = 0.7-0.8). Linear regression modeling demonstrated a good relationship between RLA ( R 2 = 84%) and CLA ( R 2 = 80%) with WA. Regression equations were constructed to give predicted values for RLA and CLA based on WA and 95% prediction CI. Conclusions: If RLA and CLA exceed 20° with neutral (0°) wrist alignment, it likely represents pathologic carpal alignment. Presented tables demonstrate 95% CI of RLA and CLA throughout the arc of wrist flexion/extension. Values outside of the 95% CI are also likely to indicate pathologic carpal alignment.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42–4.96]; P <0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93–2.28]; P =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M 1 : 0.86–0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Abstract The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

Background Collection of high-quality videorecorded speech samples is essential for speech outcomes research. Solution Cleft palate team SLPs were trained to collect standard videorecorded speech samples in the clinic setting across 20 sites in North America. Standard training and equipment was provided. What We Did That is New Quality management procedures were developed and utilized to verify video quality and protocol adherence. Over 97% of speech samples collected by trained SLPs met defined quality standards.

AbstractBackgroundPhoton counting detectors (PCDs) for x‐ray computed tomography (CT) face spectral distortion from pulse pileup and charge sharing. The photon counting scheme used by many PCDs is threshold–subtract (TS) with pulse height analysis (PHA), where each counter counts up‐crossing events when pulses exceed an energy threshold. PCD data are not Poisson‐distributed due to charge sharing and pulse pileup, but the counting statistics have never been studied yet.PurposeThe objectives of this study were (1) to propose a modified photon counting scheme, direct energy binning (DB), that is expected to be robust against pulse pileup; (2) to assess the performance of DB compared to TS; and (3) to evaluate its counting statistics.MethodsWith DB scheme, counter k starts a timer upon an up‐crossing event of energy threshold k, and adds a count only if the next higher energy threshold (k+1) was not crossed within a short time window (hence, the pulse peak belongs to the energy bin k). We used Monte Carlo (MC) simulation and assessed count‐rate curves and count‐rate‐dependent spectral imaging task performance for conventional CT imaging as well as water thickness estimation, water–bone material decomposition, and K‐edge imaging with tungsten as the K‐edge material. We also assessed count‐rate‐dependent measurement statistics such as expectation, variance, and covariance of total counts as well as energy bin outputs. The agreement with counting statistics models was also evaluated.ResultsThe DB scheme improved the count‐rate curve, that is, mean measured counts as a function of input count‐rate, and peaked with 59% higher count‐rate capability than the TS scheme (3.5 × 108 counts per second (cps)/mm2 versus 2.3 × 108 cps/mm2). The Cramér–Rao lower bounds (CRLB) of the variance of basis line integrals estimation for DB was better than those for TS by 2% for the conventional CT imaging, 30% for water–bone material decomposition, and 32% for K‐edge imaging at 1000 mA (at 7.3 × 107 cps/sub‐pixel after charge sharing). When count‐rates were lower, PCD data statistics were dominated by charge sharing: the variance of total counts and lower energy bins was larger than the mean counts; the covariance of bin data was positive and non‐zero. When count‐rates were higher, PCD data statistics were dominated by pulse pileup: the variance of data was lower than the mean; the covariance of bin data was negative. The transition between the two regimes occurred smoothly, and pulse pileup dominated the statistics ≥400 mA (when the count‐rate after charge sharing was 2.9 × 107 cps/sub‐pixel and the probability of count‐loss for DB was 37%). Both DB and TS had good agreement with Yu–Fessler's models of total counts; however, DB had a better agreement with Wang's variance and covariance models for energy bin data than TS did.ConclusionsThe proposed DB scheme had several advantages over TS. At low to moderate flux, DB could improve the resilience of PCDs to pulse pileup. Counting statistics deviated from the Poisson distribution due to charge sharing for lower count‐rate conditions and pulse pileup for higher count‐rate conditions.