Increasing obesity has led to a vast rise in metabolic dysfunction-associated steatotic liver disease (MASLD) in the general population with a significant fraction progressing to metabolic dysfunction-associated steatohepatitis (MASH). Patients with MASH progressively develop inflammation and fibrosis that over time can develop into cirrhosis with an increased risk for hepatocellular carcinoma. Despite the study of human hepatoma lines and development of numerous mouse models to dissect this disease, none of these truly function as a preclinical platform for the human disease. To faithfully model this disease pathogenesis, we identified several families with a genetic predisposition for MASH identified via the clinic, reprogramed their skin fibroblasts into induced pluripotent stem cells (iPSCs) and differentiated these to hepatocytes (iHeps). Focusing on one family, and compared to control iHeps, this MASH family showed increased baseline steatosis. Whole exome sequencing revealed the presence of numerous single nucleotide polymorphisms (SNP) of unclear significance. Interestingly these patients were heterozygous for the transmembrane 6 superfamily member 2 (TM6SF2) E167K SNP. We further analyzed these iHeps for spontaneous steatosis, apoptosis, mitochondrial function, and ER stress. Our findings illustrate the complexity of human genetic MASH patients but also highlights the power of using iHeps to characterize complex human diseases.

Background Cardiac rehabilitation is an established performance measure for adults with ischemic heart disease, but patient participation is remarkably low. Home‐based cardiac rehabilitation (HBCR) may be more practical and feasible, but evidence regarding its efficacy is limited. We sought to compare the effects of HBCR versus facility‐based cardiac rehabilitation (FBCR) on functional status in patients with ischemic heart disease. Methods and Results This was a pragmatic trial of 237 selected patients with a recent ischemic heart disease event, who enrolled in HBCR or FBCR between August 2015 and September 2017. The primary outcome was 3‐month change in distance completed on a 6‐minute walk test. Secondary outcomes included rehospitalization as well as patient‐reported physical activity, quality of life, and self‐efficacy. Characteristics of the 116 patients enrolled in FBCR and 121 enrolled in HBCR were similar, except the mean time from index event to enrollment was shorter for HBCR (25 versus 77 days; P<0.001). As compared with patients undergoing FBCR, those in HBCR achieved greater 3‐month gains in 6‐minute walk test distance (+95 versus +41 m; P<0.001). After adjusting for demographics, comorbid conditions, and indication, the mean change in 6‐minute walk test distance remained significantly greater for patients enrolled in HBCR (+101 versus +40 m; P<0.001). HBCR participants reported greater improvements in quality of life and physical activity but less improvement in exercise self‐efficacy. There were no deaths or cardiovascular hospitalizations. Conclusions Patients enrolled in HBCR achieved greater 3‐month functional gains than those enrolled in FBCR. Our data suggest that HBCR may safely derive equivalent benefits in exercise capacity and overall program efficacy in selected patients. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT02105246.

US deceased donor solid organ transplantation (dd-SOT) depends upon an individual's/family's altruistic willingness to donate organs after death; however, there is a shortage of deceased organ donors in the United States. Informing individuals of their own lifetime risk of needing dd-SOT could reframe the decision-making around organ donation after death. Using United Network for Organ Sharing (UNOS) data (2007-2016), this cross-sectional study identified (1) deceased organ donors, (2) individuals waitlisted for dd-SOT (liver, kidney, pancreas, heart, lung, intestine), and (3) dd-SOT recipients. Using US population projections, life tables, and mortality estimates, we quantified probabilities (Pr) of (1) becoming deceased organ donors, (2) needing dd-SOT, and (3) receiving dd-SOT. Lifetime Pr (per 100 000 US population) for males and females of becoming deceased organ donors were 212 and 146, respectively, and of needing dd-SOT were 1323 and 803, respectively. Lifetime Pr of receiving dd-SOT was 50% for males, 48% for females. Over a lifetime, males were 6.2 and females 5.5 times more likely to need dd-SOT than to become deceased organ donors. Organ donation is traditionally contextualized in terms of charity toward others. Our analyses yield a new tool, in the form of quantifying an individual's own likelihood of needing dd-SOT, which may assist with reframing motivations toward deceased donor organ donation.

A home-based cardiac rehabilitation program improves access and enrollment by using an evidence-based alternative model of care.

 A comprehensive CR program was delivered by a Multidisciplinary team using home exercise equipment.  Home-based CR programs at VA medical centers have the potential of optimizing CR enrollment and adherence. Methods Office of Rural Health funding received in May 2013 to start a homebased CR program . The Healthy Heart Program is a physician directed, nurse-managed, comprehensive CR program consisting of:  Post – PCI and CT surgery automatic referrals  Hospital nurse coordinator/liaison  Phase I CVD risk factor evaluation/education done at the bedside  12 week phase II delivered over the phone  Phase III monthly f/u calls x 9 months

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the United States; however, few data are available about racial and ethnic variation. We investigated relationships between ethnicity, NAFLD severity, metabolic derangements, and sociodemographic characteristics in a well-characterized cohort of adults with biopsy-proven NAFLD. Data were analyzed from 1,026 adults (≥18 years) in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) from 2004 to 2008, for whom liver histology data were available within 6 months of enrollment. Associations between ethnicity (i.e., Latino versus non-Latino white) and NAFLD severity (i.e., NASH versus non-NASH histology and mild versus advanced fibrosis) were explored with multiple logistic regression analysis. We also investigated effect modification of ethnicity on metabolic derangements for NAFLD severity. Within the NASH CRN, 77% (N = 785) were non-Latino white and 12% (N = 118) were Latino. Sixty-one percent (N = 628) had NASH histology and 28% (N = 291) had advanced fibrosis. Latinos with NASH were younger, performed less physical activity, and had higher carbohydrate intake, compared to non-Latino whites with NASH. Gender, diabetes, hypertension, hypertriglyceridemia, aspartate aminotransferase (AST), platelets, and the homeostasis model assessment of insulin resistance (HOMA-IR) were significantly associated with NASH. Age, gender, AST, alanine aminotransferase, alkaline phosphatase, platelets, total cholesterol, hypertension, and HOMA-IR, but not ethnicity, were significantly associated with advanced fibrosis. The effect of HOMA-IR on the risk of NASH was modified by ethnicity: HOMA-IR was not a significant risk factor for NASH among Latinos (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.85-1.02), but was significant among non-Latino whites (OR, 1.06; 95% CI: 1.01-1.11). Conclusion: Metabolic risk factors and sociodemographic characteristics associated with NASH differ by ethnicity. Additional insights into NASH pathogenesis may come from further studies focused on understanding ethnic differences in this disease.

In the absence of surrogate markers, the evaluation of suspected nonalcoholic fatty liver disease (NAFLD) is highly dependent on histological examination. The extent of sampling variability affecting the reliability of a single liver biopsy in patients with suspected NAFLD is poorly characterized. This prospective study aimed to correlate precise histological findings in paired biopsies-right and left lobe-in the diagnosis of NAFLD in morbidly obese subjects undergoing bariatric surgery employing both Brunt and Matteoni classifications and the NAFLD Activity Score (NAS). We also aimed to determine whether the composite histopathological findings of the two biopsies would improve diagnostic accuracy. Consecutive subjects had an intraoperative biopsy from both right and left lobes, evaluated and scored in a blinded manner. Intraobserver agreement was also assessed. Kappa coefficients of agreement were calculated. Forty-one subjects had acceptable biopsies. Agreement for steatosis was excellent and moderate for fibrosis. Concordance was only fair for most features of necroinflammation. Intraobserver agreement was only moderate for lobular inflammation. Excellent agreement was seen for the diagnosis of NASH using Brunt criteria and good agreement when using Matteoni and NAS scoring systems. Composite biopsy data particularly improved identification of hepatocyte ballooning. The diagnostic accuracy also improved substantially when composite features were compared with single-sided biopsy features, especially for the Matteoni and NAS scoring systems. In conclusion, significant sampling variability occurs in NAFLD, particularly for features of necroinflammation. This should be factored into the design of clinical trials and studies of the natural history of the disease.

Nonalcoholic steatohepatitis (NASH) is common in morbidly obese persons. Liver biopsy is diagnostic but technically challenging in such individuals. This study was undertaken to develop a clinically useful scoring system to predict the probability of NASH in morbidly obese persons, thus assisting in the decision to perform liver biopsy. Consecutive subjects undergoing bariatric surgery without evidence of other liver disease underwent intraoperative liver biopsy. The outcome was pathologic diagnosis of NASH. Predictors evaluated were demographic, clinical, and laboratory variables. A clinical scoring system was constructed by rounding the estimated regression coefficients for the independent predictors in a multivariate logistic model for the diagnosis of NASH. Of 200 subjects studied, 64 (32%) had NASH. Median body mass index was 48 kg/m(2) (interquartile range, 43-55). Multivariate analysis identified six predictive factors for NASH: the diagnosis of hypertension (odds ratio [OR], 2.4; 95% confidence interval [CI], 1-5.6), type 2 diabetes (OR, 2.6; 95% CI, 1.1-6.3), sleep apnea (OR, 4.0; 95% CI, 1.3-12.2), AST > 27 IU/L (OR, 2.9; 95% CI, 1.2-7.0), alanine aminotransferase (ALT) > 27 IU/L (OR, 3.3; 95% CI, 1.4-8.0), and non-Black race (OR, 8.4; 95% CI, 1.9-37.1). A NASH Clinical Scoring System for Morbid Obesity was derived to predict the probability of NASH in four categories (low, intermediate, high, and very high). Conclusion: The proposed clinical scoring can predict NASH in morbidly obese persons with sufficient accuracy to be considered for clinical use, identifying a very high-risk group in whom liver biopsy would be very likely to detect NASH, as well as a low-risk group in whom biopsy can be safely delayed or avoided.