Nasobiliary Drain Diverted through a Percutaneous Endoscopic Gastrostomy Tube: A Novel Approach to Nasobiliary Drainage.

Intractable pruritus is a common, debilitating symptom and a well-defined entity occurring in chronic cholestatic disorders. Treatment options include cholestyramine, rifampicin, naltrexone, gabapentin, and sertraline, as well as more interventional measures, such as plasmapheresis, extracorporeal albumin dialysis, nasobiliary drains (NBDs), and UVB phototherapy in patients who fail to respond to medical therapy. Despite the limited data, NBD seems to be a highly effective treatment in the relief of refractory cholestatic pruritus. In this article, we present the case of a 73-year-old woman with primary biliary cholangitis and intractable pruritus, refractory to medical treatment. The patient had a complete resolution of her symptoms following an NBD placement, in which, with a novel approach, the nasal end was redirected and exited through a percutaneous endoscopic gastrostomy port, significantly improving her quality of life.

Integrative omics provide biological and clinical insights into acute respiratory distress syndrome.

PURPOSE: Acute respiratory distress syndrome (ARDS) is accompanied by a dysfunctional immune-inflammatory response following lung injury, including during coronavirus disease 2019 (COVID-19). Limited causal biomarkers exist for ARDS development. We sought to identify novel genetic susceptibility targets for ARDS to focus further investigation on their biological mechanism and therapeutic potential. METHODS: Meta-analyses of ARDS genome-wide association studies were performed with 1250 cases and 1583 controls in Europeans, and 387 cases and 387 controls in African Americans. The functionality of novel loci was determined in silico using multiple omics approaches. The causality of 114 factors potentially involved in ARDS development was assessed using Mendelian Randomization analysis. RESULTS: There was distinct genetic heterogeneity in ARDS between Europeans and African Americans. rs7967111 at 12p13.2 was functionally associated with ARDS susceptibility in Europeans (odds ratio = 1.38; P = 2.15 × 10-8). Expression of two genes annotated at this locus, BORCS5 and DUSP16, was dynamic but ultimately decreased during ARDS development, as well as downregulated in immune cells alongside COVID-19 severity. Causal inference implied that comorbidity of inflammatory bowel disease and elevated levels of C-reactive protein and interleukin-10 causally increased ARDS risk, while vitamin D supplementation and vasodilator use ameliorated risk. CONCLUSION: Our findings suggest a novel susceptibility locus in ARDS pathophysiology that implicates BORCS5 and DUSP16 as potentially acting in immune-inflammatory processes. This locus warrants further investigation to inform the development of therapeutic targets and clinical care strategies for ARDS, including those induced by COVID-19.

Adult liver transplantation: UK clinical guideline - part 2: surgery and post-operation.

Survival rates for patients following liver transplantation exceed 90% at 12 months and approach 70% at 10 years. Part 1 of this guideline has dealt with all aspects of liver transplantation up to the point of placement on the waiting list. Part 2 explains the organ allocation process, organ donation and organ type and how this influences the choice of recipient. After organ allocation, the transplant surgery and the critical early post-operative period are, of necessity, confined to the liver transplant unit. However, patients will eventually return to their referring secondary care centre with a requirement for ongoing supervision. Part 2 of this guideline concerns three key areas of post liver transplantation care for the non-transplant specialist: (1) overseeing immunosuppression, including interactions and adherence; (2) the transplanted organ and how to initiate investigation of organ dysfunction; and (3) careful oversight of other organ systems, including optimising renal function, cardiovascular health and the psychosocial impact. The crucial significance of this holistic approach becomes more obvious as time passes from the transplant, when patients should expect the responsibility for managing the increasing number of non-liver consequences to lie with primary and secondary care.

The relative resistance of children to sepsis mortality: from pathways to drug candidates.

Attempts to develop drugs that address sepsis based on leads developed in animal models have failed. We sought to identify leads based on human data by exploiting a natural experiment: the relative resistance of children to mortality from severe infections and sepsis. Using public datasets, we identified key differences in pathway activity (Pathprint) in blood transcriptome profiles of septic adults and children. To find drugs that could promote beneficial (child) pathways or inhibit harmful (adult) ones, we built an in silico pathway drug network (PDN) using expression correlation between drug, disease, and pathway gene signatures across 58,475 microarrays. Specific pathway clusters from children or adults were assessed for correlation with drug-based signatures. Validation by literature curation and by direct testing in an endotoxemia model of murine sepsis of the most correlated drug candidates demonstrated that the Pathprint-PDN methodology is more effective at generating positive drug leads than gene-level methods (e.g., CMap). Pathway-centric Pathprint-PDN is a powerful new way to identify drug candidates for intervention against sepsis and provides direct insight into pathways that may determine survival.

What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases.

Leukotrienes have physiological roles in innate immune responses and pathological roles in inflammatory diseases, such as asthma, allergic rhinitis and atherosclerosis. Anti-leukotriene therapy has proven benefits in the treatment of respiratory disease, either through the inhibition of leukotriene synthesis or the selective antagonism of leukotriene receptors. The first committed step in the synthesis of leukotrienes is the oxidation of arachidonic acid (AA) by 5-lipoxygenase (5-LO), and the integral membrane protein 5-lipoxygenase-activating protein (FLAP) is an essential partner of 5-LO for this process. FLAP was molecularly identified via a photoaffinity probe and an affinity gel based on MK-886, a selective leukotriene inhibitor that has no activity against broken-cell preparations of 5-LO. Several FLAP inhibitors showed efficacy in early clinical trials in asthma but were not developed commercially for unpublished reasons. Recently, the FLAP (ALOX5AP) gene has been linked to risk for myocardial infarction, stroke and restenosis, reigniting pharmaceutical interest in this target. In addition, the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design.

Nonpeptide alphavbeta3 antagonists. Part 11: discovery and preclinical evaluation of potent alphavbeta3 antagonists for the prevention and treatment of osteoporosis.

3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.

Nonpeptide alpha V beta 3 antagonists. Part 10: In vitro and in vivo evaluation of a potent 7-methyl substituted tetrahydro-[1,8]naphthyridine derivative.

Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.

Non-peptide alpha(v)beta(3) antagonists. Part 5: identification of potent RGD mimetics incorporating 2-aryl beta-amino acids as aspartic acid replacements.

A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements.

Non-peptide alpha(v)beta(3) antagonists. Part 3: identification of potent RGD mimetics incorporating novel beta-amino acids as aspartic acid replacements.

Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.