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Diverticulosis is an anatomic change in the colon that is characterized by outpouching of the mucosa and submucosa through the muscularis. Its prevalence increases with age so most of the elderly patients have this condition. Although diverticulosis is common, diverticular disease, in which there are clinical sequelae, is rare. This collective term includes diverticulitis, diverticular hemorrhage and less well-defined entities such as segmental colitis associated with diverticulosis, and symptomatic uncomplicated diverticular disease. Diverticulitis presents as acute lower abdominal pain, and initial management traditionally includes antibiotics, with surgery reserved for complicated disease, although newer evidence questions the optimal role and timing of both interventions.

Alcohol-associated liver disease encompasses all forms of liver injury related to the consumption of alcohol, one of the most common hepatotoxic agents in the world. The spectrum of this disease ranges from steatosis, which is present in everyone who drinks alcohol in excess, to cirrhosis, which occurs in approximately 10 to 15% of individuals with alcohol abuse and conveys an annual risk of 1 to 2% for the development of hepatocellular carcinoma. Despite the prevalence of alcohol-associated liver disease and its profound impact on health, questions remain surrounding its pathogenesis and management. This review of alcohol-associated liver disease addresses the epidemiology, etiology and genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis and comorbidities, treatment, complications, measures of quality of care, and prognosis and outcome measurements. This review contains 6 highly rendered figures, 6 tables, and 50 references. Keywords: Alcohol-associated Liver Disease (ALD), alcohol, cirrhosis, liver injury, Alcohol Use Disorder (AUD), alcohol-associated hepatitis, substance abuse

Introduction Although current literature has addressed gastrointestinal presentations including nausea, vomiting, diarrhea, abnormal liver chemistries, and hyperlipasemia as possible coronavirus disease 2019 (COVID-19) manifestations, the risk and type of gastrointestinal bleeding (GIB) in this population is not well characterized. Methods This is a matched case-control (1:2) study with 41 cases of GIB (31 upper and 10 lower) in patients with COVID-19 and 82 matched controls of patients with COVID-19 without GIB. The primary objective was to characterize bleeding etiologies, and our secondary aim was to discuss outcomes and therapeutic approaches. Results There was no difference in the presenting symptoms of the cases and controls, and no difference in severity of COVID-19 manifestations (P > 0.05) was observed. Ten (32%) patients with upper GIB underwent esophagogastroduodenoscopy and 5 (50%) patients with lower GIBs underwent flexible sigmoidoscopy or colonoscopy. The most common upper and lower GIB etiologies were gastric or duodenal ulcers (80%) and rectal ulcers related to rectal tubes (60%), respectively. Four of the esophagogastroduodenoscopies resulted in therapeutic interventions, and the 3 patients with rectal ulcers were referred to colorectal surgery for rectal packing. Successful hemostasis was achieved in all 7 cases that required interventions. Transfusion requirements between patients who underwent endoscopic therapy and those who were conservatively managed were not significantly different. Anticoagulation and rectal tube usage trended toward being a risk factor for GIB, although it did not reach statistical significance. Discussion In COVID-19 patients with GIB, compared with matched controls of COVID-19 patients without GIB, there seemed to be no difference in initial presenting symptoms. Of those with upper and lower GIB, the most common etiology was peptic ulcer disease and rectal ulcers from rectal tubes, respectively. Conservative management seems to be a reasonable initial approach in managing these complex cases, but larger studies are needed to guide management.

Objective The 2019 novel coronavirus disease (COVID-19) has triggered a rapidly expanding global pandemic in which patients exhibit a wide spectrum of disease severity. Given the high prevalence of obesity in the United States, we hypothesized that the presence of obesity may play a role in the clinical course of patients with COVID-19. Methods This is a retrospective review of adult patients admitted with confirmed severe acute respiratory syndrome coronavirus 2. Demographics, clinical characteristics, laboratory data, and clinical outcomes were abstracted. BMI (kilograms per meter squared) was analyzed with regard to a composite outcome of intensive care unit (ICU) admission or death and intubation rate. Results About 770 patients were included (61% male, mean age 63.5 years). Patients with obesity were more likely to present with fever, cough, and shortness of breath. Obesity was also associated with a significantly higher rate of ICU admission or death (RR = 1.58, P = 0.002) even after adjusting for age, race, and troponin level. Conclusions Patients with obesity had an increased risk for critical illness leading to ICU admission or death compared with normal weight individuals. This study confirms that obesity is a major risk factor for COVID-19 disease severity, significantly impacting disease presentation and critical care requirements.

In brown adipose tissue, thermogenesis is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase. Them1 is highly upregulated by cold ambient temperature, where it reduces fatty acid availability and limits thermogenesis. Here, we show that Them1 regulates metabolism by undergoing conformational changes in response to β-adrenergic stimulation that alter Them1 intracellular distribution. Them1 forms metabolically active puncta near lipid droplets and mitochondria. Upon stimulation, Them1 is phosphorylated at the N-terminus, inhibiting puncta formation and activity and resulting in a diffuse intracellular localization. We show by correlative light and electron microscopy that Them1 puncta are biomolecular condensates that are inhibited by phosphorylation. Thus, Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 provides fine-tuning of thermogenesis and energy expenditure., Cold exposure activates thermogenesis and fatty acid oxidation in brown fat, a process suppressed by Them1. Here, the authors show that cold induces Them1 phosphorylation and loss of puncta that suppress fatty acid use, leading to a diffuse localization and increased energy expenditure in mice.

In brown adipose tissue, cold exposure promotes thermogenesis, in large part by increasing mitochondrial β-oxidation of lipid droplet-derived fatty acids. This process is suppressed by thioesterase superfamily member 1 (Them1), a long chain fatty acyl-CoA thioesterase that is highly upregulated by cold ambient temperatures. Them1 reduces fatty acid availability for β-oxidation in mitochondria and limits thermogenesis by cellular mechanisms that are not well defined. We show that Them1 regulates metabolism by undergoing marked intracellular conformational changes that occur in response to β-adrenergic stimulation. Mechanistically, Them1 formed puncta that were localized near LD and mitochondria in an immortalized brown adipose cell line. In response to stimulation by norepinephrine, Them1 was phosphorylated by PKCβ at S15, which specifically inhibited puncta formation and resulted in a diffuse intracellular localization. This change in Them1 localization also occurred after stimulation in vivo. Puncta formation activated Them1 metabolic activity in vitro, as evidenced by suppression of oxygen consumption following β-adrenergic stimulation. We show by correlative light and electron microscopy that puncta are biomolecular condensates (also known as membraneless organelles) that typically form by phase separation. Them1 contains one intrinsically disordered region at the N-terminus with multiple interacting motifs that is frequently observed in phase-separating proteins. Phosphorylation, which is known to disrupt phase separation and aggregation, results in a diffuse Them1 localization. Our data thus establish that Them1 forms intracellular biomolecular condensates that limit fatty acid oxidation and suppress thermogenesis. During a period of energy demand, the condensates are disrupted by phosphorylation to allow for maximal thermogenesis. The stimulus-coupled reorganization of Them1 thus provides fine-tuning of thermogenesis and energy expenditure.

BackgroundThe 2019 novel coronavirus disease (COVID-19) has created unprecedented medical challenges. There remains a need for validated risk prediction models to assess short-term mortality risk among hospitalized patients with COVID-19. The objective of this study was to develop and validate a 7-day and 14-day mortality risk prediction model for patients hospitalized with COVID-19.MethodsWe performed a multicenter retrospective cohort study with a separate multicenter cohort for external validation using two hospitals in New York, NY, and 9 hospitals in Massachusetts, respectively. A total of 664 patients in NY and 265 patients with COVID-19 in Massachusetts, hospitalized from March to April 2020.ResultsWe developed a risk model consisting of patient age, hypoxia severity, mean arterial pressure and presence of kidney dysfunction at hospital presentation. Multivariable regression model was based on risk factors selected from univariable and Chi-squared automatic interaction detection analyses. Validation was by receiver operating characteristic curve (discrimination) and Hosmer-Lemeshow goodness of fit (GOF) test (calibration). In internal cross-validation, prediction of 7-day mortality had an AUC of 0.86 (95%CI 0.74-0.98; GOF p = 0.744); while 14-day had an AUC of 0.83 (95%CI 0.69-0.97; GOF p = 0.588). External validation was achieved using 265 patients from an outside cohort and confirmed 7- and 14-day mortality prediction performance with an AUC of 0.85 (95%CI 0.78-0.92; GOF p = 0.340) and 0.83 (95%CI 0.76-0.89; GOF p = 0.471) respectively, along with excellent calibration. Retrospective data collection, short follow-up time, and development in COVID-19 epicenter may limit model generalizability.ConclusionsThe COVID-AID risk tool is a well-calibrated model that demonstrates accuracy in the prediction of both 7-day and 14-day mortality risk among patients hospitalized with COVID-19. This prediction score could assist with resource utilization, patient and caregiver education, and provide a risk stratification instrument for future research trials.

Summary Recent studies suggest that a key mechanism whereby the gut microbiome influences energy balance and glucose homeostasis is through the recruitment of brown and beige adipocytes, primary mediators of the adaptive thermogenic response. To test this, we assessed energy expenditure and glucose metabolism in two complementary mouse models of gut microbial deficiency, which were exposed to a broad range of thermal and dietary stresses. Neither ablation of the gut microbiome, nor the substantial microbial perturbations induced by cold ambient temperatures, influenced energy expenditure during cold exposure or high-fat feeding. Nevertheless, we demonstrated a critical role for gut microbial metabolism in maintaining euglycemia through the production of amino acid metabolites that optimized hepatic TCA (tricarboxylic acid) cycle fluxes in support of gluconeogenesis. These results distinguish the dispensability of the gut microbiome for the regulation of energy expenditure from its critical contribution to the maintenance of glucose homeostasis.