"PROTAC" modified dihydroquinolizinones (DHQs) that cause degradation of PAPD-5 and inhibition of hepatitis A virus and hepatitis B virus, in vitro.

Dihydroquinolizinones (DHQs) that inhibit cellular polyadenylating polymerases 5 and 7 (PAPD5 & 7), such as RG7834, have been shown to inhibit both hepatitis A (HAV) and hepatitis B virus (HBV) in vitro and in vivo. In this report, we describe RG7834-based proteolysis-targeting chimeras (PROTACs), such as compound 12b, (6S)-9-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-21-oxo-3,6,9,12,15,18-hexaoxa-22-azapentacosan-25-yl)oxy)-6-isopropyl-10-methoxy-2-oxo-6,7-dihydro-2H-pyrido[2,1-a]isoquinoline-3-carboxylic acid. The PROTAC DHQs described here inhibited an HAV reporter virus in vitro with an IC of 277 nM.

Racial and ethnic minorities in lower income brackets are associated with late-stage diagnosis of non-ocular melanoma.

Introduction: Despite advances in oncologic care, racial and socio-economic outcome disparities persist in non-ocular melanoma patients. However, the unmet need is understanding the population at risk for late tumor stage at diagnosis. We sought to analyze the groups with an increased risk of unfavorable tumor stage at diagnosis.

Interactome Profiling of DNA Damage Response (DDR) Mediators with Immunoprecipitation-Mass Spectrometry.

Immunoprecipitation-mass spectrometry (IP-MS) is a versatile tool to probe for global protein-protein interactions (PPIs) in biological samples. Such interactions coordinate complex biological processes, such as the DNA damage response (DDR). Induction of DNA damage activates signaling networks where posttranslational modifications cause PPI that facilitate DNA repair and cell cycle coordination.

Colonic oxygen microbubbles augment systemic oxygenation and CO removal in a porcine smoke inhalation model of severe hypoxia.

Inhalation injury can lead to pulmonary complications resulting in the development of respiratory distress and severe hypoxia. Respiratory distress is one of the major causes of death in critically ill patients with a reported mortality rate of up to 45%. The present study focuses on the effect of oxygen microbubble (OMB) infusion via the colon in a porcine model of smoke inhalation-induced lung injury.

Bacteria commonly associated with central nervous system catheter infections elicit distinct CSF proteome signatures.

Background: Cerebrospinal fluid (CSF) shunt infection is a common and devastating complication of the treatment of hydrocephalus. Timely and accurate diagnosis is essential as these infections can lead to long-term neurologic consequences including seizures, decreased intelligence quotient (IQ) and impaired school performance in children. Currently the diagnosis of shunt infection relies on bacterial culture; however, culture is not always accurate since these infections are frequently caused by bacteria capable of forming biofilms, such as , and resulting in few planktonic bacteria detectable in the CSF.

Matched comparison between external aortic root support and valve-sparing root replacement.

Objectives: Differences in indication and technique make a randomised comparison between valve-sparing root replacement (VSRR) and personalised external aortic root support (PEARS) challenging. We performed a propensity score (PS)-matched comparison of PEARS and VSRR for syndromic root aneurysm.

Methods: Patients in the PEARS 200 Database and Aortic Valve Insufficiency and ascending aorta Aneurysm InternATiOnal Registry (undergoing VSRR) with connective tissue disease operated electively for root aneurysm <60 mm with aortic regurgitation (AR) <1/4 were included.

Arteriovenous Fistulae in Chronic Kidney Disease and the Heart: Physiological, Histological, and Transcriptomic Characterization of a Novel Rat Model.

Background Arteriovenous fistulae (AVFs) are the gold standard for vascular access in those requiring hemodialysis but may put an extra hemodynamic stress on the cardiovascular system. The complex interactions between the heart, kidney, and AVFs remain incompletely understood. Methods and Results We characterized a novel rat model of five-sixths partial nephrectomy (NX) and AVFs.

Current and Emerging Trends in Diabetes Care and Education: 2021 National Practice and Workforce Survey.

Purpose: The purpose of the National Practice Survey is to understand current trends related to the diabetes care and education specialist's integration into the full care team beyond formal diabetes self-management education and support services.

Methods: The 2021 National Practice Survey (NPS2021) contained 61 questions for all respondents with an additional 56 questions pertaining to specific diabetes care and education segments. An anonymous survey was administered online to respondents who are diabetes care and education specialists or a part of the diabetes care team.

Primary Sjögren syndrome and development of another autoimmune rheumatic disease during the follow-up.

Background: Primary Sjögren syndrome (pSS) is a chronic autoimmune disease with its main target being exocrine glands, and is the connective tissue disease more frequently associated with other autoimmune diseases. The aim of this study was to assess the frequency of another autoimmune rheumatic disease (ARD) developed in primary Sjögren syndrome (pSS) patients and to describe it's clinical, serological and histologic characteristics.

Materials And Methods: This is a retrospective cohort study.

Combined Alcohol Exposure and KRAS Mutation in Human Pancreatic Ductal Epithelial Cells Induces Proliferation and Alters Subtype Signatures Determined by Multi-Omics Analysis.

Pancreatic Ductal adenocarcinoma (PDAC) is an aggressive cancer commonly exhibiting KRAS-activating mutations. Alcohol contributes to the risk of developing PDAC in humans, and murine models have shown alcohol consumption in the context of KRAS mutation in the pancreas promotes the development of PDAC. The molecular signatures in pancreas cells altered by alcohol exposure in the context of mutant KRAS could identify pathways related to the etiology of PDAC.

Nutritional assessment in idiopathic pulmonary fibrosis: a prospective multicentre study.

Background: Nutritional status impacts quality of life and prognosis of patients with respiratory diseases, including idiopathic pulmonary fibrosis (IPF). However, there is a lack of studies performing an extensive nutritional assessment of IPF patients. This study aimed to investigate the nutritional status and to identify nutritional phenotypes in a cohort of IPF patients at diagnosis.

Revascularization strategies in patients with multivessel coronary artery disease: a Bayesian network meta-analysis.

Treatment modalities for multivessel disease have rapidly evolved, yet the preferred strategy remains controversial. This meta-analysis compared outcomes after on-pump (ONCAB), off-pump coronary artery bypass grafting (OPCAB), percutaneous coronary intervention (PCI) or hybrid coronary revascularization. A comprehensive search for observational studies and randomized controlled trials published by August 2020 was performed.

Time course of the Bioelectrical Impedance Vector Analysis and muscular ultrasound in critically ill patients.

Purpose: Several different tools have been developed to integrate the clinical and biochemical nutritional evaluations in critical care patients. Aims of this study were to evaluate the changes in the Bioelectrical Impedance Vector Analysis (BIVA) and ultrasonographic features of the diaphragm (DTee) and rectus femoris (RFCSA) during the first week of ICU stay.

Materials And Methods: Ninety-six adult mechanically ventilated patients enrolled within 24 h after the admission to the ICU (T1).

Ketogenic diets in the management of type 1 diabetes: Safe or safety concern?

The jury is still out on whether a low-carbohydrate, ketosis-inducing diet is an effective and safe adjunctive therapy to insulin in type 1 diabetes. The limited published literature reports an association with weight loss and improved glycemic control and may, over the long-term, lead to reduced macrovascular and microvascular harm. However, the attendant increased risk of dyslipidemia, diabetic ketoacidosis, and hypoglycemia warrant caution, close monitoring of patients who embark on the diet, and further research.

Hepatoselective Dihydroquinolizinone Bis-acids for HBsAg mRNA Degradation.

Chronic hepatitis B (CHB) is characterized by high levels of hepatitis B virus (HBV) surface antigen (HBsAg) in blood circulation. A major goal of CHB interventions is reducing or eliminating this antigenemia; however, there are currently no approved methods that can do this. A novel family of compounds with a dihydroquinolizinone (DHQ) scaffold has been shown to reduce circulating levels of HBsAg in animals, representing a first for a small molecule.

Parameter Estimation and Reporting in Noncompartmental Analysis of Clinical Pharmacokinetic Data.

The noncompartmental analysis (NCA) of pharmacokinetic (PK) data is important throughout all phases of clinical drug development. Although there are numerous regulatory guidances and articles in the literature concerned with best practices for the modeling of PK data, there are relatively few sources of information on how to conduct a high-quality NCA. This article provides a systematic review of issues related to the estimation of plasma and urine PK parameters with the intent of encouraging rigor in the performance of NCAs so as to provide reliable and informative analysis results.

Criteria for reporting noncompartmental estimates of half-life and area under the curve extrapolated to infinity.

Various criteria have been proposed for determining the reliability of noncompartmental pharmacokinetic estimates of the terminal disposition phase half-life (t ) and the extrapolated area under the curve (AUC ). This simulation study assessed the performance of two frequently used reportability rules: the terminal disposition phase regression adjusted-r classification rule and the regression data point time span classification rule. Using simulated data, these rules were assessed in relation to the magnitude of the variability in the terminal disposition phase slope, the length of the terminal disposition phase captured in the concentration-time profile (data span), the number of data points present in the terminal disposition phase, and the type and level of variability in concentration measurement.

Performance characteristics of the adjusted r algorithm for determining the start of the terminal disposition phase and comparison with a simple r algorithm and a visual inspection method.

The adjusted r algorithm is a popular automated method for selecting the start time of the terminal disposition phase (t ) when conducting a noncompartmental pharmacokinetic data analysis. Using simulated data, the performance of the algorithm was assessed in relation to the ratio of the slopes of the preterminal and terminal disposition phases, the point of intercept of the terminal disposition phase with the preterminal disposition phase, the length of the terminal disposition phase captured in the concentration-time profile, the number of data points present in the terminal disposition phase, and the level of variability in concentration measurement. The adjusted r algorithm was unable to identify t accurately when there were more than three data points present in a profile's terminal disposition phase.

Undernutrition, risk of malnutrition and obesity in gastroenterological patients: A multicenter study.

Aim: To investigate the prevalence of undernutrition, risk of malnutrition and obesity in the Italian gastroenterological population.

Methods: The Italian Hospital Gastroenterology Association conducted an observational, cross-sectional multicenter study. Weight, weight loss, and body mass index were evaluated.

Postpartum bonding: the impact of maternal depression and adult attachment style.

Maternal depression poses a risk for the developing mother-infant relationship. Similarly, maternal insecure attachment styles may limit the ability to adequately connect with the newborn during the postpartum period. The aim of this study was to investigate the effect of maternal depression and insecure attachment (insecure and dual/disorganized) on maternal bonding in a sample of n = 34 women with depression according to DSM-IV and n = 59 healthy women.

Influence of dyadic matching of affect on infant self-regulation.

Background/aims: Affective behavioural matching during face-to-face interaction fosters the transition from mutual regulation to infant self-regulation. Optimum midrange models of mother-infant interaction hold that moderate degrees of dyadic matching facilitate infant socio-emotional development. The aim of this study was to examine which degree of dyadic matching is most beneficial for infant self-regulation.

Mild training program in metabolic syndrome improves the efficiency of the oxygen pathway.

In sedentary patients suffering of metabolic syndrome, we evaluated the effects of mild exercise program (EP) on the efficiency of the oxygen delivery system. The prescription of exercise (40 min/session, 3 times/week) was tailored at workload corresponding to ∼90% individual anaerobic threshold (AT). EP improved significantly by ∼10% peak values of oxygen consumption (VO2) and heart rate (HR).