Carmen Ching

HNF4A and HNF1A encode transcription factors that are important for the development and function of the pancreas and liver. Mutations in both genes have been directly linked to Maturity Onset Diabetes of the Young (MODY) and type 2 diabetes (T2D) risk. To better define the pleiotropic gene regulatory roles of HNF4A and HNF1A, we generated a comprehensive genome-wide map of their binding targets in pancreatic and hepatic cells using ChIP-Seq. HNF4A was found to bind and regulate known (ACY3, HAAO, HNF1A, MAP3K11) and previously unidentified (ABCD3, CDKN2AIP, USH1C, VIL1) loci in a tissue-dependent manner. Functional follow-up highlighted a potential role for HAAO and USH1C as regulators of beta cell function. Unlike the loss-of-function HNF4A/MODY1 variant I271fs, the T2D-associated HNF4A variant (rs1800961) was found to activate AKAP1, GAD2 and HOPX gene expression, potentially due to changes in DNA-binding affinity. We also found HNF1A to bind to and regulate GPR39 expression in beta cells. Overall, our studies provide a rich resource for uncovering downstream molecular targets of HNF4A and HNF1A that may contribute to beta cell or hepatic cell (dys)function, and set up a framework for gene discovery and functional validation.

BACKGROUND AND AIMS: Oral probiotic supplementation may be a beneficial adjunctive therapy for patients with symptomatic COVID-19. However, its safety and efficacy are unclear. We aimed to investigate how probiotic supplementation impacts COVID-19 symptom trajectory and patient outcomes by conducting a systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: RCTs randomizing patients with COVID-19 to probiotics were searched in PubMed Central, Embase, CINAHL, and Cochrane Library from inception to July 31, 2022. We performed a random-effects pairwise meta-analysis for all outcomes using the restricted maximum likelihood (REML) estimator. We used the GRADE approach to assess the certainty of the evidence. RESULTS: A total of 1027 participants from eight RCT studies were included in the meta-analysis. Probiotic supplements probably reduce the incidence of diarrhea (RR 0.61 [0.43 to 0.87]; moderate certainty) and probably reduce cough or dyspnea compared to placebo/standard care (RR 0.37 [0.19 to 0.73]; moderate certainty). Probiotic supplements may improve composite endpoint measured by clinical escalation or mortality compared to placebo (RR 0.41 [0.18 to 0.93]; low certainty evidence); however, they may not significantly reduce the need for clinical escalation (RR 0.57 [0.31 to 1.07]; low certainty evidence) or mortality (RR 0.50 [0.20 to 1.29]; low certainty evidence). In addition, the probiotic supplement is associated with reduced adverse events (RR 0.62 [0.46 to 0.83]; moderate certainty). CONCLUSION: Early probiotic supplement is a safe and effective adjunctive therapy that reduces the risk of symptoms and health care burden related to COVID-19 across all severity types.

Background: Cirrhosis is a major cause of morbidity and mortality. Caregivers of cirrhotic patients provide significant support related to disease manifestations and complications. This scoping review aims to identify the prevalence of caregiver burden among patients with cirrhosis and to identify patient and caregiver factors that predict caregiver burden in patients with cirrhosis. Methods: A literature search was conducted using MEDLINE, EMBASE, CINAHL, and Web of Science to identify studies for inclusion. Screening and data extraction were performed using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia). Results: 604 articles were identified, and 15 were included in the review. Caregivers were predominantly female and spouses of the patient. The average age of patients varied between 41.2 and 57.2 (SD 10.3 to 12.5). The most common cirrhotic aetiologies were alcohol-related, viral hepatitis-related, and metabolic-related aetiologies. The most used survey tools to assess burden were the Zarit Burden Interview (ZBI) score, Short Form-36 Health Survey (SF-36), and Beck Depression/Anxiety Inventory (BDI or BAI). Patient factors contributing toward caregiver burden included prior hepatic encephalopathy (HE), alcohol use, and high Model for End-Stage Liver Disease (MELD) scores. Caregiver factors that contribute toward caregiver burden included poor perceived social supports, low and disrupted income, and being the spouse of the patient. Conclusions: Several patient and caregiver factors contribute to caregiver burden, and greater levels of burden may affect multiple aspects of a caregiver's life, potentially worsening patient outcomes. A multidisciplinary approach is critical to alleviate caregiver burnout and optimize the overall care for a patient with cirrhosis.

We describe reconstruction of a sternal cleft in a neonate using acellular dermal matrix, full-thickness calvarial bone graft and myocutaneous pectoralis flaps.