Search

Summary: Background: Dietary interventions and increased physical activity are the cornerstones for management of the paediatric non‐alcoholic fatty liver disease (NAFLD). Though, no specific diet has been proven superior, Indo‐Mediterranean diet (IMD) has shown promise in adult literature. Thus, we aimed to compare the effect of IMD and a standard calorie‐restricted diet (CRD) in Indian overweight children and adolescents with biopsy‐proven NAFLD. Methods: Thirty‐nine consecutive biopsy‐proven NAFLD children between the ages of 8 and 18 years were randomized into either IMD or CRD for 180 days, and various parameters were evaluated at baseline and then after 180 days (NCT05073588). Results: A total of 34 subjects (18 in IMD and 16 in CRD group) completed the study. There was a significantly higher decrease in controlled attenuation parameter (CAP) values (as a marker of hepatic steatosis; on transient elastography) (95% CI: 4.2–73.4, p = 0.042), weight (95% CI: 0.75–5.5, p = 0.046) and body mass index (BMI) (95% CI: 0.21–2.05, p = 0.014) (but not in Pediatric NAFLD Fibrosis Index or PNFI; as a marker of hepatic fibrosis) in IMD group compared to the CRD group. Liver stiffness measurement, serum cholesterol and low‐density lipoprotein levels and HOMA‐IR decreased only in the IMD group (p < 0.001). Our statistical model showed that delta‐Weight was the only independent variable associated with delta‐CAP. Conclusion: Both IMD and CRD can improve the various anthropometric, clinical, imaging and biochemical parameters but IMD was superior to CRD in terms of reducing CAP values and weight/BMI over 180 days in overweight/obese NAFLD children. [ABSTRACT FROM AUTHOR]

Background and Aims: Nonselective beta‐blockers (NSBB) are the mainstay for treatment of portal hypertension (PH), but require caution in decompensated cirrhosis (DC) or acute‐on‐chronic liver failure (ACLF) with hypotension, hyponatremia, acute kidney injury (AKI) or type 2 hepatorenal syndrome (HRS). Midodrine is oral, rapidly acting, α1‐adrenergic agonist. We evaluated acute effects of midodrine on hepatic venous pressure gradient (HVPG) in DC and ACLF with contraindications to NSBB. Methods: Patients of DC (n = 30) with grade III ascites and serum sodium (Na) <130/systolic blood pressure (SBP) <90/type II HRS (group I) and ACLF patients (n = 30) with Na <130/SBP <90/AKI (group II) were included. HVPG was done at baseline and repeated 3 h after 10 mg midodrine. Primary outcome was HVPG response (reduction by >20% or to <12 mmHg). Results: In group I, midodrine significantly reduced HVPG (19.2 ± 4.6 to 17.8 ± 4.2, p =.02) and heart rate (HR) (86.3 ± 11.6 to 77.9 ± 13.1, p <.01) and increased mean arterial pressure (MAP) (74.1 ± 6.9 to 81.9 ± 6.6 mmHg, p <.01). In group II also, midodrine reduced HVPG (19.1 ± 4.1 to 17.0 ± 4.2) and HR (92.4 ± 13.7 to 84.6 ± 14.1) and increased MAP (85.4 ± 7.3 to 91.2 ± 7.6 mmHg), p <.01 for all. HVPG response was achieved in 3/30 (10%) in group I and 8/30 (26.7%) in group II. On logistic regression analysis, prerenal AKI (OR 11.04, 95% CI 1.83–66.18, p <.01) and increase in MAP (OR 1.22, 95% CI 1.03–1.43, p =.02) were independent predictors of response. Increase in MAP by 8.5 mmHg with midodrine had best cut‐off with AUROC of.76 for response. Conclusion: In decompensated cirrhosis and ACLF patients with contraindications to NSBB, midodrine is useful in decreasing HVPG. Dose of midodrine should be titrated to increase MAP atleast by 8.5 mmHg. [ABSTRACT FROM AUTHOR]

Crisis cartel refers to the collaboration between organisations during unprecedented conditions to counter the effect of disruption during an economic crisis. Despite its prevalence, scholarly attention to this phenomenon remains scant. Employing a dual‐channel framework involving manufacturers, online retailers (ORs) and traditional brick‐and‐mortar retailers (BMRs), the authors scrutinised the efficacy of crisis cartels in mitigating the impact of negative demand disruptions. Three distinct game theoretic frameworks were applied to model the interactive dynamics between the supply chain partners, namely, the horizontal Nash game, the Stackelberg game and the collusion game. It was observed that, during disruption under crisis cartels, the optimal price and profit of both the downstream channel partners increased, whereas the optimal order quantity decreased. Manufacturers and consumers are worse off in terms of profit and consumer surplus, respectively, during the crisis cartel engagement between BMR and OR. Nonetheless, a crisis cartel emerged as a potential solution to address negative demand disruptions. In evaluating post‐disruption cartels, the study finds the necessity of regulating crisis cartels. The findings offer valuable insights for policymakers, market regulators and practitioners, suggesting the need for strategic regulatory adjustments to effectively manage disruptions through the prudent utilisation of crisis cartel as a proactive management tool. The study expands existing theory by providing novel insights into the strategic interactions and dynamics within collaborative responses to demand disruptions, thus offering a pioneering approach to crisis management research. [ABSTRACT FROM AUTHOR]

Contextualizing the void of research on inhalant abuse among adolescents as epistemic neglect, in this study, we use mixed‐methods action research to understand inhalant abuse in a specific context in the Global South. Focusing on a large metropolitan city in Western India, we surveyed 158 street‐involved children and adolescents (110 boys and 48 girls, age range from 5 to 17 years) in a group setting along with follow‐up group interviews. Despite finding a high prevalence rate of inhalant abuse, our work suggests an absence of supporting structures and emphasizes the need to revisit our understanding and interpretation of substance‐using behavior of street‐involved youth. Instead of explaining inhalant‐abusing behavior as emerging from pathological deficiencies in individuals or households, we stress the need to critically examine the exploitative environment they are embedded in. In doing so, we join efforts to decolonize conventional ways of understanding "deviant" behavior. [ABSTRACT FROM AUTHOR]

Background and Aims: Acute‐on‐chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. Methods: We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post‐HA and TPE sessions on days 7 and 14 using high‐resolution mass spectrometry. Results: The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p <.05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine‐proline metabolism (6 metabolites) and microbial metabolism respectively (p <.05). Metabolites linked to taurine‐hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post‐TPE therapy (p <.05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post‐HA therapy compared to TPE and SMT (p <.05). Higher baseline plasma level of 11‐deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r2 > 0.5, p <.05) and mortality (log‐rank‐p <.05). Notably, 51 of the 64 metabolite signatures (ACLF non‐survivor) were reversed post‐HA treatment compared to TPE and SMT(p <.05). Conclusion: HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11‐deoxycorticosterone level correlates with early mortality in ACLF patients. [ABSTRACT FROM AUTHOR]

Preliminary studies have shown BRCA1 (170–1600) residues to be intrinsically disordered with unknown structural details. However, thousands of clinically reported variants have been identified in this central region of BRCA1. Therefore, we aimed to characterize h‐BRCA1(260–553) to assess the structural basis for pathogenicity of two rare missense variants Ser282Leu, Gln356Arg identified from the Indian and Russian populations respectively. Small‐angle X‐ray scattering analysis revealed WT scores Rg−32 Å, Dmax−93 Å, and Rflex‐51% which are partially disordered, whereas Ser282Leu variant displayed a higher degree of disorderedness and Gln356Arg was observed to be aggregated. WT protein also possesses an inherent propensity to undergo a disorder‐to‐order transition in the presence of cruciform DNA and 2,2,2‐Trifluoroethanol (TFE). An increased alpha‐helical pattern was observed with increasing concentration of TFE for the Gln356Arg mutant whereas Ser282Leu mutant showed significant differences only at the highest TFE concentration. Furthermore, higher thermal shift was observed for WT‐DNA complex compared to the Gln356Arg and Ser282Leu protein‐DNA complex. Moreover, mature amyloid‐like fibrils were observed with 30 μM thioflavin T (ThT) at 37°C for Ser282Leu and Gln356Arg proteins while the WT protein exists in a protofibril state as observed by TEM. Gln356Arg formed higher‐order aggregates with amyloidogenesis over time as monitored by ThT fluorescence. In addition, computational analyses confirmed larger conformational fluctuations for Ser282Leu and Gln356Arg mutants than for the WT. The global structural alterations caused by these variants provide a mechanistic approach for further classification of the variants of uncertain clinical significance in BRCA1 into amyloidogenic variants which may have a significant role in disease pathogenesis. [ABSTRACT FROM AUTHOR]

Summary: Background: Metabolic associated fatty liver disease (MAFLD) is a relatively new term with limited studies done in South Asian population. Aim: To determine prevalence and clinico‐epidemiological characteristics of MAFLD in general population. Methods: A cross‐sectional study was conducted in randomly selected regions across Delhi, India. Data were collected on socio‐demographic particulars, health status and lifestyle factors. Anthropometric measurements, transient elastography, and laboratory investigations were carried out. Results: Altogether 6146 participants (mean age: 43.1 ± 13.9 years, 48.1% males) were included. The prevalence of MAFLD was 56.4% (n = 3468), of which lean MAFLD constituted 11.3%. Higher age (OR: 2.47; 95% CI: 2.21–2.76), low education level (OR: 1.23; 95% CI: 1.09–1.39), upper socio‐economic class (OR: 1.32; 95% CI: 1.17–1.49), and low physical activity (OR: 1.15; 95% CI: 1.03–1.28) were more common in MAFLD. The association of female sex with MAFLD differed in age groups <40 years (OR: 0.64 and 95% CI: 0.55–0.75) and >40 years (OR: 1.40 and 95% CI: 1.22–1.62) in both magnitude and direction (p < 0.001). Liver fibrosis was present in 23% of the study population (32.2% among MAFLD group). Advanced liver fibrosis was three times more common in MAFLD group (6.2% vs 1.8%, p < 0.001). Obesity and fibrosis had a statistically significant relationship and 75.8% of the individuals with advanced stages of fibrosis had obesity. Conclusion: Nearly half of study population was found to have MAFLD. Advanced hepatic fibrosis was three times more common in these subjects. Aggressive public health measures are urgently required to raise awareness and introduce interventional strategies. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis B virus X protein (HBx) play a key role in pathogenesis of HBV-induced hepatocellular carcinoma (HCC) by promoting epithelial to mesenchymal transition (EMT). In this study, we hypothesized that inhibition of HBx is an effective strategy to combat HCC. Methodology and Results: We designed and synthesized novel HBx gene specific single guide RNA (sgRNA) with CRISPR/Cas9 system and studied its in vitro effects on tumour properties of HepG2-2.15. Full length HBx gene was excised using HBx-CRISPR that resulted in significant knockdown of HBx expression in hepatoma cells. HBx-CRISPR also decreased levels of HBsAg and HBV cccDNA expression. A decreased expression of mesenchymal markers, proliferation and tumorigenic properties was observed in HBx-CRISPR treated cells as compared to controls in both twoand three- dimensional (2D and 3D) tumour models. Transcriptomics data showed that out of 1159 differentially expressed genes in HBx-CRISPR transfected cells as compared to controls, 70 genes were upregulated while 1089 genes associated with cell proliferation and EMT pathways were downregulated. Conclusion: Thus, targeting of HBx by CRISPR/Cas9 gene editing system reduces covalently closed circular DNA (cccDNA) levels, HBsAg production and mesenchymal characteristics of HBV-HCC cells. We envision inhibition of HBx by CRISPR as a novel therapeutic approach for HBV-induced HCC. [ABSTRACT FROM AUTHOR]

Low energy availability (LEA) is a health concern for athletes, although it may paradoxically lead to improved cardiometabolic health in the general population. We investigated the associations between LEA, body composition, and serum cardiometabolic profile in 23 physique athletes (DIET) and 21 controls (CONT) during a 5‐month pre‐competition diet (MID), followed by 1 week of increased energy availability (COMP) and a 5‐month weight regain period (POST). Quantification of 250 serum metabolome variables was conducted by NMR spectroscopy, body composition by dual‐energy x‐ray absorptiometry, dietary intake by food diaries, and exercise levels by training logs. Body fat percentage decreased from 19.5 ± 7.0% to 8.3 ± 5.3% (p < 0.001) in DIET through increased exercise levels and decreased energy intake, while CONT maintained those constant. In MID, DIET had increased (FDR < 0.01) HDL cholesterol, HDL particle size and number, and decreased (FDR < 0.05) VLDL lipids, serum triglycerides, and low‐grade inflammation (glycoprotein acetyls) compared to baseline and CONT. The changes were associated with reduced android fat mass (‐78 ± 13%) and energy intake (‐28 ± 10%). In COMP, most of the metabolic changes found in MID persisted, except for altered triglycerides in all lipoprotein classes. After weight regain in POST, serum metabolome, body composition, energy intake, and exercise levels had reverted to baseline levels. In conclusion, fat loss and LEA may have beneficial yet transient effects on the serum cardiometabolic profile of lean individuals. Especially the HDL lipidome and lipoprotein triglycerides offer potential novel biomarkers for detecting LEA in athletes. [ABSTRACT FROM AUTHOR]

Pregnancy being an immune compromised state, coronavirus disease of 2019 (COVID‐19) disease poses high risk of premature delivery and threat to fetus. Plasma metabolome regulates immune cellular responses, therefore we aimed to analyze the change in plasma secretome, metabolome, and immune cells with disease severity in COVID‐19 positive pregnant females and their cord blood. COVID‐19 reverse transcriptase‐polymerase chain reaction positive pregnant females (n = 112) with asymptomatic (Asy) (n = 82), mild (n = 21), or moderate (n = 9) disease, healthy pregnant (n = 18), COVID‐19 positive nonpregnant females (n = 7) were included. Eighty‐two cord blood from COVID‐19 positive and seven healthy cord blood were also analyzed. Mother's peripheral blood and cord blood were analyzed for untargeted metabolome profiling and cytokines by using high‐resolution mass spectrometry and cytokine bead array. Immune scan was performed only in mothers' blood by flow cytometry. In Asy severe acute respiratory syndrome coronavirus 2 infection, the amino acid metabolic pathways such as glycine, serine, l‐lactate, and threonine metabolism were upregulated with downregulation of riboflavin and tyrosine metabolism. However, with mild‐to‐moderate disease, the pyruvate and nicotinamide adenine dinucleotide (NAD+) metabolism were mostly altered. Cord blood mimicked the mother's metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in Asy and NAD+, riboflavin metabolism in mild and moderate. Additionally, with disease severity tumor necrosis factor‐α, interferon (IFN)‐α, IFN‐γ, interleukin (IL)‐6 cytokine storm, IL‐9 was raised in both mothers and neonates. Pyruvate, NAD metabolism and increase in IL‐9 and IFN‐γ had an impact on nonclassical monocytes, exhausted T and B cells. Our results demonstrated that immune‐metabolic interplay in mother and fetus is influenced with increase in IL‐9 and IFN‐γ regulated pyruvate, lactate tricarboxylic acid, and riboflavin metabolism with context to disease severity. [ABSTRACT FROM AUTHOR]

Aim: Shifts in diversification rates of Australian flora and fauna have been associated with aridification, but the relationship between diversification rates and aridity has never been quantified. We employed multiple approaches to reconstruct paleoenvironments of Australia for the first time. We used this information, and phylogenetic‐based analyses, to explore how changes in temperature and increasing aridity during the Neogene influenced the diversification of the Australian blindsnakes. We tested whether diversification rates differ between arid‐adapted and mesic‐adapted lineages. Taxon: Typhlopidae, Anilios blindsnakes. Location: Australia. Materials and Methods: We estimated the historical biogeography of blindsnakes using BioGeoBEARS. We synthesised multiple approaches to reconstruct paleotemperature and paleoaridity of Australia during the Neogene. We fitted several birth‐death models and estimated diversification rates under paleoenvironmental conditions using RPANDA. We further compared diversification rates between arid‐adapted lineages versus mesic‐adapted lineages using ClaDS and GeoHiSSE. Results: Ancestral area estimation indicated Australian blindsnakes have tropical grassland origins. We found that Australia‐specific regional paleotemperature and paleoaridity provided a better explanation for diversification rate variation than global paleotemperature. Specifically, our best‐fitting model indicated that speciation rates of blindsnakes decreased with increasing aridity. We found no difference in diversification rates between arid‐ and mesic‐adapted lineages. Main Conclusions: Soon after dispersing to Australia, the common ancestors of Australian blindsnakes diversified rapidly in mesic habitats during the early Miocene. However, as the continent became increasingly arid, diversification rates decreased. We found that shifts in the environment led to the emergence of two major clades: one remaining in primarily mesic habitats and the other adapting to the expanding arid biome. Our results emphasise the importance of both arid and tropical biomes as sources and sinks of diversification. [ABSTRACT FROM AUTHOR]

This article discusses the use of the da Vinci SP (dVSP) robot in transanal excision of rectal lesions. The dVSP platform allows surgeons to control three instruments and an endoscope through a single port, providing greater precision and flexibility. The article describes two cases where rectal lesions were successfully excised using the dVSP platform. The authors believe that the dVSP platform has the potential to enhance the resection of rectal lesions, but further research is needed to understand the risks and benefits of this technique. [Extracted from the article]

Objective: The type 1 interferon (IFN) pathway is up‐regulated in dermatomyositis (DM). We sought to define how organ‐specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. Methods: RNA sequencing was performed on 355 whole blood samples collected from 202 well‐phenotyped DM patients followed up during the course of their clinical care. A previously defined 13‐gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross‐sectional and longitudinal data. Results: The pattern of type I IFN–driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti–melanoma differentiation–associated protein 5 (anti–MDA‐5) or anti–Mi‐2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti–MDA‐5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84–0.95). Conclusion: The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti–MDA‐5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM. [ABSTRACT FROM AUTHOR]

Summary: Background: Renal tubular epithelial cells (RTECs) cause maladaptive repair and perpetuate renal fibrosis. Aim: To evaluate urinary neutrophil gelatinase‐associated lipocalin (NGAL) and RTEC as risk factors for non‐resolution of acute kidney injury (AKI–NR) at day seven and chronic kidney disease (CKD) in critically ill patients with cirrhosis. Methods: We performed urinary NGAL and microscopy at enrolment and day 7 in all patients. We assessed 17 renal injury, endothelial injury and repair markers, genes for mitochondrial biogenesis by qRT–PCR in RTEC, and post‐mortem renal biopsies for understanding mechanisms of AKI non‐resolution (n = 30). Results: We enrolled 310 patients, aged 48.1 ± 11.6 years, 87% male, 90% alcoholic. Of these, 36% had RTEC at enrolment, and 53% had AKI–NR on day 7. On mean follow‐up of 136 days (range 43–365), 150 (48.3%) developed CKD. The presence of RTEC or granular casts, NGAL and AKI–NR were independent predictors of CKD development on competing risk analysis. Higher MCP‐1, renal endothelial injury, decrease in tubular repair markers and failure of mitochondrial biogenesis in RTEC were seen in patients with AKI–NR compared with AKI–R (p < 0.05). Renal biopsies showed infiltration with monocyte–macrophage, increased α‐SMA, and tubulointerstitial fibrosis. Conclusion: Almost two‐thirds of critically ill patients with cirrhosis have AKI, which resolves in only one‐half at day seven and predicts the development of CKD. Higher NGAL, RTEC, or granular casts were independent predictors of AKI–NR and CKD development. Enhanced tubular and endothelial injury, decreased repair, monocyte–macrophage infiltration and mitochondrial dysfunction in RTEC are associated with AKI non‐resolution and risk of renal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Alcohol relapse after liver transplantation has a negative impact on outcomes. There is limited data on its burden, the predictors, and impact following live donor liver transplantation (LDLT). Methods: A single‐center observational study was carried out between July 2011 and March 2021 for patients undergoing LDLT for alcohol associated liver disease (ALD). The incidence, predictors of alcohol relapse, and post‐transplant outcomes were assessed. Results: Altogether 720 LDLT were performed during the study period, 203 (28.19%) for ALD. The overall relapse rate was 9.85% (n = 20) with a median follow‐up of 52 months (range, 12–140 months). Sustained harmful alcohol use was seen in 4 (1.97%). On multivariate analysis, pre‐LT relapse (P =.001), duration of abstinence period (P =.007), daily intake of alcohol (P =.001), absence of life partner (P =.021), concurrent tobacco abuse before transplant (P =.001), the donation from second‐degree relative (P =.003) and poor compliance with medications (P =.001) were identified as predictors for relapse. Alcohol relapse was associated with the risk of graft rejection (HR 4.54, 95% CI: 1.751–11.80, P =.002). Conclusion: Our results show that the overall incidence of relapse and rate of harmful drinking following LDLT is low. Donation from spouse and first degree relative was protective. History of daily intake, prior relapse, shorter pretransplant abstinence duration and lack of family support significantly predicted relapse. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the associations between obstructive sleep apnea (OSA) and sensorineural hearing loss (SNHL) and the effects of continuous positive airway pressure (CPAP) therapy on SNHL. Data Sources: Ovid Medline, Embase, and Scopus databases. Review Methods: A systematic search was done for studies investigating relationships between OSA and SNHL in adults, with manual searches for additional references. The final update was done on December 22, 2021. The Risk of Bias Assessment Tool for Nonrandomized Studies was applied for quality assessments. Results: The 20 included studies had a total of 34,442 participants (66% male; mean age, 46.6 years). The OSA group had a significantly worse mean hearing threshold level (HTL) than the control group for midfrequency ranges (500, 1000, 2000 Hz; mean difference, 4.00 dB; 95% CI, 2.40‐5.61) and high‐frequency ranges (4000, 8000 Hz; mean difference, 6.24 dB; 95% CI, 2.99‐9.49). An association between OSA and SNHL was found. When compared with controls, patients with OSA had an odds ratio of 1.52 (95% CI, 1.12‐2.06) for midfrequency hearing impairment and 1.19 (95% CI, 1.05‐1.34) for high‐frequency hearing impairment. However, we did not find significant improvements in midfrequency HTL after CPAP therapy. Conclusions: HTL was significantly poorer among participants with OSA (especially in severe cases) than non‐OSA controls. Studies on patients with OSA with SNHL treated with CPAP did not show significant improvements in midfrequency HTL. Further studies are warranted on these issues. [ABSTRACT FROM AUTHOR]

Background: Patients with cirrhosis and treatment non‐responsive spontaneous bacterial peritonitis (SBP) have high mortality. We aimed to investigate whether GM‐CSF can improve SBP response rates. Patients and Methods: In this open‐label RCT, 131 cirrhosis patients with difficult‐to‐treat SBP (DTT SBP) were randomized to receive meropenem alone (1 g IV thrice daily for 5 days) (MERO Group, n = 66) or in combination with GM‐CSF (1.5 mcg/Kg daily IV till resolution or till 5d) (MEROGM Group, n = 65). The primary end‐point was SBP early‐response (reduction in absolute neutrophil count (ANC) by >25% after 48 h). Secondary end‐points included SBP resolution at day 5. Results: Patients in MEROGM group in comparison to MERO group had higher SBP early‐response (60% vs. 31.8%; p =.001) and SBP resolution rates (55.4% vs. 24.2%; p =.0003). Patients in the combination arm also had better resolution of pneumonia {8/17 (47.05%) vs. 2/19 (10.5%), p =.02} and lower incidence of new‐onset AKI (15.4% vs. 31.8%, p =.02), HE (18.5% vs. 34.8%, p =.04) and infections (21.5% vs. 37.9%, p =.05). In comparison to MERO group, 7‐day survival was higher in MEROGM group (89.2% vs. 78.7%, p =.03), though the 28‐day survival was comparable (78.4% vs. 71.2%; p =.66). None of the patients developed treatment‐related severe adverse effects requiring discontinuation of therapy. Conclusions: The addition of GM‐CSF to meropenem significantly improves response rates in DTT SBP patients within 48 h. Early use of GMCSF modulates host immune response, and enhances antibiotic response with higher SBP resolution. The use of GMCSF needs to be considered in combating difficult SBP in cirrhosis patients. [ABSTRACT FROM AUTHOR]

Summary: Background: Hepatitis B surface antigen (HBsAg) seroconversion is sometimes observed in hepatitis B reactivation (rHBV), probably due to immune resetting and differentiation. Aims: To investigate sequential immune differentiation and abrogation of tolerance in patients with rHBV who achieved HBsAg seroconversion. Methods: We included 19 patients with chronic hepatitis B (CHBV; HBV DNA log103‐8), 67 with rHBV (raised ALT [>5XULN], HBV DNAlog104‐8) and 10 healthy controls. Immune differentiation, tolerance and functional status of CD4, CD8, T regulatory cells (Tregs), B cells and follicular T helper (Tfh) cells were assessed at baseline and 24 weeks. Results: At 24 weeks, 81% rHBV (n = 67) lost HBV DNA and HBeAg (41%), and 12 (19%) lost HBsAg and made anti‐HBs titers >10 IU/ml. rHBV patients had higher Th1/17, TEM, Tfh, Tfh1/17, plasma and ATM B cells, and lower Tregs, Th2, Th17 and TEMRA expression. rHBV showed lower PD1, TIM3, LAG3, SLAM and TOX compared to CHBV. There was a significant increase in CD8, CD8EM, Tfh, Tfh1/17 and plasma B cells in seroconverters than non‐seroconverters. At 24 weeks, we also observed increased plasma B cell frequency in seroconverters. While non‐seroconverters showed higher expression of PD1, TIM3, LAG3, SLAM and TOX on CD4/CD8 T cells, blockade of PD1, TIM3, LAG3 and CTLA4 significantly enhanced IFN‐γ, TNF‐α, IL‐4 and IL‐21 expression on CD4/CD8 and Tfh cells in non‐seroconverters. Conclusions: Non‐seroconverters have increased inhibitory markers on CD4/CD8 T cells. There is a critical play of CD8, Tfh and B cells and subsets in seroclearance, along with checkpoint molecules as a potential therapy for non‐seroconverters in HBV infection. [ABSTRACT FROM AUTHOR]

Background and aims: India has a significant burden of hepatitis C virus (HCV) infection and has committed to achieving national elimination by 2030. This will require a substantial scale‐up in testing and treatment. The "HEAD‐Start Project Delhi" aimed to enhance HCV diagnosis and treatment pathways among the general population. Methods: A prospective study was conducted at 5 district hospitals (Arm 1: one‐stop shop), 15 polyclinics (Arm 2: referral for viral load (VL) testing and treatment) and 62 screening camps (Arm 3: referral for treatment). HCV prevalence, retention in the HCV care cascade, and turn‐around time were measured. Results: Between January and September 2019, 37 425 participants were screened for HCV. The median (IQR) age of participants was 35 (26‐48) years, with 50.4% male and 49.6% female. A significantly higher proportion of participants in Arm 1 (93.7%) and Arm 3 (90.3%) received a VL test compared with Arm 2 (52.5%, P <.001). Of those confirmed positive, treatment was initiated at significantly higher rates for participants in both Arms 1 (85.6%) and 2 (73.7%) compared to Arm 3 (41.8%, P <.001). Arm 1 was found to be a cost‐saving strategy compared to Arm 2, Arm 3, and no action. Conclusions: Delivery of all services at a single site (district hospitals) resulted in a higher yield of HCV seropositive cases and retention compared with sites where participants were referred elsewhere for VL testing and/or treatment. The highest level of retention in the care cascade was also associated with the shortest turn‐around times. [ABSTRACT FROM AUTHOR]

Slack exists when entities hold resources in excess of those required to support current operations. "Sticky" spending is a specific type of slack spending that occurs when a firm reduces spending by less when sales fall than it increases spending when sales rise by an equivalent amount. Changes in a firm's environment affect its propensity to engage in sticky spending. We examine how competition influences sticky spending, positing two hypotheses. First, we hypothesize that competition will be positively associated with firms' investment in sticky spending both for cost of goods manufactured (COGM) and selling, general, and administrative (SG&A). Second, we hypothesize that competition moderates the relation between sticky spending and firm performance. Utilizing variations of tariff rates as exogenous shocks to reflect competition, we measure sticky spending in the firm's COGM and SG&A spending. To empirically verify our hypotheses, we draw data from three different sources, industry‐level tariff data, Compustat, and the Hoberg–Phillips data library, for firms in the manufacturing sector from 1974 through 2017. Our regression analyses confirm that managers maintain more stickiness in spending as competition increases. The market's assessment of firm performance (as measured by Tobin's Q) is largely positively associated with sticky spending as competition increases. This expectation of higher performance is evidenced by immediate improvements in the firm's return on assets (ROA) when we consider COGM spending, but not when we consider SG&A spending. Highlights: As competition increases, both COGM and SG&A spending exhibit stickiness; that is, firms decrease their spending less when sales decrease than they increase this spending when sales increase.Sticky spending is largely associated with higher Tobin's Q ratios for both COGM and SG&A as competition increases.Sticky COGM spending results in immediate performance benefits, as measured by return on assets (ROA) in the period immediately following the window over which sticky spending is measured, while the benefits of sticky SG&A spending take longer to manifest. [ABSTRACT FROM AUTHOR]

Background and Aim: There is limited data on natural course and interventions in stage‐3 acute kidney injury (AKI‐3) in patients with acute‐on‐chronic liver failure (ACLF). We studied the factors of AKI‐3 reversal and outcomes of dialysis in ACLF patients. Methods: Consecutive patients with ACLF were prospectively enrolled (n = 1022) and variables determining AKI and its outcomes were analysed. Results: At 1 month, 337 (33%) patients had AKI‐3, of which, 131 had AKI‐3 at enrolment and 206 developed AKI‐3 during hospital stay. Of patients with AKI‐3 at enrolment, 18% showed terlipressin response, 21% had AKI resolution and 59% required dialysis. High MELD (≥35) (model 1), serum bilirubin (≥23 mg/dL) (model 2) and AARC score (≥11) (model 3) were independent risk factors for dialysis. Dialysis was associated with worse survival in all AKI patients but improved outcomes in patients with AKI‐3 (p =.022, HR 0.69 [0.50–0.95]). Post‐mortem kidney biopsies (n = 61) revealed cholemic nephropathy (CN) in 54%, acute tubular necrosis (ATN) in 31%, and a combination (CN and ATN) in 15%. Serum bilirubin was significantly higher in patients with CN, CN and ATN compared with ATN respectively ([30.8 ± 12.2] vs. [26.7 ± 12.0] vs. [18.5 ± 9.8]; p =.002). Conclusion: AKI‐3 rapidly increases from 13% to 33% within 30 days in ACLF patients. Histopathological data suggested cholemic nephropathy as the predominant cause which correlated with high bilirubin levels. AKI‐3 resolves in only one in five patients. Patients with AARC grade 3 and MELD >35 demand need for early dialysis in AKI‐3 for improved outcomes. [ABSTRACT FROM AUTHOR]

Objective: To understand experiences of patients with genitourinary cancer who experienced delayed cancer care due to the COVID‐19 pandemic. Methods: We conducted a mixed methods study with an explanatory sequential design. Qualitative findings are reported here. Patients with muscle invasive bladder, advanced prostate or kidney cancer were eligible. Participants were selected for interviews if they self‐reported low (0–3/10) or high (6–10/10) levels of distress on a previous survey. Participants were interviewed about their experiences. Interviews were transcribed, coded and categorised using thematic data analysis methodology. Results: Eighteen patients were interviewed. Seven had prostate cancer, six bladder cancer and five kidney cancer. Six themes were derived from the interviews: (1) arriving at cancer diagnosis was hard enough, (2) response to treatment delay, (3) labelling cancer surgery as elective, (4) fear of COVID‐19 infection, (5) quality of patient‐provider relationship and communication and (6) what could have been done differently. Conclusion: These findings offer insight into the concerns of patients with genitourinary cancers who experienced treatment delays due to COVID‐19. This information can be applied to support patients with cancers more broadly, should treatment delays occur in the future. [ABSTRACT FROM AUTHOR]

Modulation of endothelial cell behavior and phenotype by hemodynamic forces involves many signaling components, including cell surface receptors, intracellular signaling intermediaries, transcription factors, and epigenetic elements. Many of the signaling mechanisms that underlie mechanotransduction by endothelial cells are inadequately defined. Here we sought to better understand how β-arrestins, intracellular proteins that regulate agonistmediated desensitization and integration of signaling by transmembrane receptors, may be involved in the endothelial cell response to shear stress. We performed both in vitro studies with primary endothelial cells subjected to β-arrestin knockdown, and in vivo studies using mice with endothelial specific deletion of β-arrestin 1 and β-arrestin 2. We found that β-arrestins are localized to primary cilia in endothelial cells, which are present in subpopulations of endothelial cells in relatively low shear states. Recruitment of β-arrestins to cilia involved its interaction with IFT81, a component of the flagellar transport protein complex in the cilia. β-arrestin knockdown led to marked reduction in shear stress response, including induction of NOS3 expression. Within the cilia, β-arrestins were found to associate with the type II bone morphogenetic protein receptor (BMPR-II), whose disruption similarly led to an impaired endothelial shear response. β-arrestins also regulated Smad transcription factor phosphorylation by BMPR-II. Mice with endothelial specific deletion of β-arrestin 1 and β-arrestin 2 were found to have impaired retinal angiogenesis. In conclusion, we have identified a novel role for endothelial β-arrestins as key transducers of ciliary mechanotransduction that play a central role in shear signaling by BMPR-II and contribute to vascular development. [ABSTRACT FROM AUTHOR]

The global burden of deaths caused by liver failure is substantial. The Asia-Pacific region is home to more than half of the global population and accounted for 62.6% of global deaths because of liver diseases in 2015. The aetiology of liver failure varies in different countries at different times. Viruses (Hepatitis A, B and E), drugs (herbs and anti-tuberculous drugs), toxins (alcohol use) and autoimmune flares are mainly responsible of majority of liver failure in individuals with normal liver (acute liver failure; ALF); else these may precipitate liver failure in those with chronic liver disease (acute-on-chronic liver failure; ACLF). Concomitant increases in alcohol misuse and metabolic syndrome in recent years are concerning. Ongoing efforts to address liver failure-related morbidity and mortality require accurate contemporary estimates of epidemiology and outcomes. In light of the ever-changing nature of liver disease epidemiology, accurate estimates for the burden of liver failure across the countries are vital for setting clinical, research and policy priorities. In this review, we aimed to describe the current as well as changing epidemiological trends of common liver failure syndromes, ALF and ACLF in the Asia-Pacific region. [ABSTRACT FROM AUTHOR]

The prime purpose of the article is to revisit past studies related to the link between export instability, export diversification, and economic growth. In this regard, an extensive literature survey has been made across academic journals that provided structured, comprehensive, and chronological findings and results. The authors have examined and reviewed the full text of eighty‐eight important and relevant research articles published in various scholarly journals. Most of the articles provided robust evidence about positive impact of export diversification on economic growth and mixed results regarding the impact of export instability on economic growth. The paper also attempts to find the areas where the existing literature is silent or throws light that needs to be further examined with future research in this area. Since literature gives little evidence on various aspects of export diversification and economic growth from the perspective of a group of emerging economies identified by UNCTAD and IMF, therefore, the article recommends future research in this context to explore this less unexplored area. [ABSTRACT FROM AUTHOR]

Background: The relationship between alcohol and pain is complex. Associations between pain and alcohol use disorder (AUD) vary by race, but the underlying biological basis is not understood. We examined the association of the kappa opioid receptor (KOR) with responses to the cold‐pressor test (CPT), before and after treatment with the opioid antagonist naltrexone, among individuals with AUD who self‐identified as Black or White. Methods: Thirty‐seven individuals (12 Black, 24 White, and 1 Multiracial) with AUD participated in two CPTs, separated by 1 week during which they received naltrexone 100 mg daily. During each CPT, pain reporting threshold (PRT), average pain increase rate (APIR), relative pain recovery (RPR), and alcohol craving were recorded. KOR availability was measured using [11C]‐LY2795050 positron emission tomography (PET) prior to treatment with naltrexone. Results: Black participants reported higher PRT and APIR than White participants during the CPT before, but not after, naltrexone treatment. Among Black participants, KOR availability was positively associated with PRT and APIR before, but not after naltrexone. Greater KOR availability was associated with faster RPR for White, but not Black, participants. The CPT induced more alcohol craving in Black than White participants, particularly in individuals with low KOR availability, an effect that was not attenuated by naltrexone. Conclusions: KOR involvement and naltrexone effects on responses to the CPT were different between Black and White participants. These preliminary findings suggest that further exploration of the differences in the opioid system and pain among Black and White individuals with AUD and their relationship with naltrexone's effects is warranted. [ABSTRACT FROM AUTHOR]

Summary: There is growing evidence that post‐transcriptional RNA modifications are highly dynamic and can be used to improve crop production. Although more than 172 unique types of RNA modifications have been identified throughout the kingdom of life, we are yet to leverage upon the understanding to optimize RNA modifications in crops to improve productivity. The contributions of internal mRNA modifications such as N6‐methyladenosine (m6A) and 5‐methylcytosine (m5C) methylations to embryonic development, root development, leaf morphogenesis, flowering, fruit ripening and stress response are sufficiently known, but the roles of the two most abundant RNA modifications, pseudouridine (Ψ) and 2′‐O‐methylation (Nm), in the cell remain unclear due to insufficient advances in high‐throughput technologies in plant development. Therefore, in this review, we discuss the latest methods and insights gained in mapping internal Ψ and Nm and their unique properties in plants and other organisms. In addition, we discuss the limitations that remain in high‐throughput technologies for qualitative and quantitative mapping of these RNA modifications and highlight future challenges in regulating the plant epitranscriptome. [ABSTRACT FROM AUTHOR]

Confirm and authentic identification of species is required for the implementation of wildlife laws in cases of illegal trafficking of snake venoms. Illegally trafficked snake venom might be misidentified with other drugs of abuse, and sometimes, the species of venom-yielding snake cannot be verified. Snake venoms from medically important snake species, Naja naja and Daboia russelii, were procured from Irula Snake Catcher's Society, Tamil Nadu, India. Comparative analyses of both venoms were carried out using SDS-PAGE, LC-MS/MS, ICP-MS, and mtDNA analysis. The protein concentration of Naja naja and Daboia russelii venoms was 76.1% and 83.9%, respectively. SDS analysis showed a distinct banding pattern of both venoms. LC-MS/MS results showed proteins and toxins from 12 to 14 protein families in Naja naja and Daboia russelii venoms. Elemental analysis using ICP-MS showed a different profile of some elements in both venoms. mtDNA analysis of venoms using universal primers against Cyt b gene showed homology with sequence of Naja naja and Daboia russelii genes. The study proposed a template of various conventional and advanced molecular and instrumental techniques with their pros and cons. The template can be used by forensic science laboratories for detection, screening, and confirmatory analysis of suspected venoms of snakes. Clubbing of various techniques can be used to confirm the identification of species of snake from which the alleged venom was milked. The results can be helpful in framing charge-sheets against accused of illegal venom trafficking and can also be used to verify the purity and quality of commercially available snake venoms. [ABSTRACT FROM AUTHOR]

To prevent the progression of posttraumatic osteoarthritis, assessment of cartilage composition is critical for effective treatment planning. Posttraumatic changes include proteoglycan (PG) loss and elevated water content. Quantitative dual‐energy computed tomography (QDECT) provides a means to diagnose these changes. Here, we determine the potential of QDECT to evaluate tissue quality surrounding cartilage lesions in an equine model, hypothesizing that QDECT allows detection of posttraumatic degeneration by providing quantitative information on PG and water contents based on the partitions of cationic and nonionic agents in a contrast mixture. Posttraumatic osteoarthritic samples were obtained from a cartilage repair study in which full‐thickness chondral defects were created surgically in both stifles of seven Shetland ponies. Control samples were collected from three nonoperated ponies. The experimental (n = 14) and control samples (n = 6) were immersed in the contrast agent mixture and the distributions of the agents were determined at various diffusion time points. As a reference, equilibrium moduli, dynamic moduli, and PG content were measured. Significant differences (p < 0.05) in partitions between the experimental and control samples were demonstrated with cationic contrast agent at 30 min, 60 min, and 20 h, and with non‐ionic agent at 60 and 120 min. Significant Spearman's rank correlations were obtained at 20 and 24 h (ρ = 0.482–0.693) between the partition of cationic contrast agent, cartilage biomechanical properties, and PG content. QDECT enables evaluation of posttraumatic changes surrounding a lesion and quantification of PG content, thus advancing the diagnostics of the extent and severity of cartilage injuries. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Prabhakar et al papers. To view these articles, visit https://doi.org/10.1111/apt.17892 and https://doi.org/10.1111/apt.17903 [ABSTRACT FROM AUTHOR]

This article discusses the use of transanal minimally invasive surgery (TAMIS) for the repair of colorectal anastomotic leaks, a complication that can occur after rectal cancer surgery. The video vignette demonstrates a novel technique called robotic TAMIS (r-TAMIS), which combines the benefits of a transluminal approach with the dexterity of robotic instrumentation. The procedure involves inserting a single-incision port into the anal canal and using robotic instruments to repair the anastomotic defect. This minimally invasive approach reduces the risks associated with major abdominal surgery. The authors suggest that surgeons with experience in this technique should consider r-TAMIS for the management of anastomotic leaks. [Extracted from the article]

We previously generated Brassica juncea lines overexpressing either glyoxalase I (gly I) or γ-tocopherol methyltransferase (γ-TMT) involved in the glyoxalase system and tocopherol biosynthesis, respectively. These transgenic plants showed tolerance to multiple abiotic stresses. As tolerance is a complex trait that can be improved by pyramiding of several characteristics in a single genotype, we generated in this study B. juncea plants coexpressing gly I and γ-TMT by crossing the previously generated stable transgenic lines. The performance of the newly generated B. juncea lines coexpressing gly I and γ-TMT was compared with that of wild-type and the single transgenic lines under non-stressed and NaCl and mannitol stress conditions. Our results show a more robust antioxidant response of B. juncea plants coexpressing gly I and γ-TMT compared to the other lines in terms of higher chlorophyll retention, relative water content, antioxidant enzyme and proline levels, and photosynthetic efficiency and lower oxidative damage. The differences in response to the stress of the different lines were reflected in their yield parameters. Overall, we demonstrate that the pyramiding of multiple genes involved in antioxidant pathways could be a viable and useful approach for achieving higher abiotic stress tolerance in crop plants. [ABSTRACT FROM AUTHOR]

Background: Numerous studies and guidelines suggest an outcome detriment from radiation treatment breaks (rTBs) and the need for compensatory dosing in patients with head and neck cancer. Methods: In a consecutive cohort of 521 patients with oropharyngeal squamous cell carcinoma (OPSCC), we investigated the impact of rTBs and prolongation of overall treatment time (OTT) on OS, DFS, LRC, and cancer recurrence using competing risk and multivariate analyses. Results: Neither OTT prolongation by ≤2 days nor rTBs of ≤3 days were associated with detriments to clinical outcomes. Consecutive breaks of ≥3 days were also not significantly associated with detriment to clinical outcomes. There was significantly increased competing mortality in those with longer breaks. Conclusions: In OPSCC patients treated with definitive concurrent chemoradiotherapy, there is no significant association between disease failure and total rTBs of ≤3 consecutive or scattered days. Further investigation is needed for longer breaks. [ABSTRACT FROM AUTHOR]

Introduction: Intense monocyte activation and infiltration into the target tissues are the main mechanisms of lung injury in severe acute respiratory syndrome coronavirus 2 infection. A reduction in the degree and nature of such cellular responses is expected following recovery. We aimed to investigate the immune responses in moderate coronavirus disease 2019 (COVID-19) patients and recovered patients. Methods: Moderate COVID-19 patients (n = 34) at Lok Nayak Hospital, New Delhi, and COVID-19 recovered patients (n = 15) from the mild disease who were considered for convalescent plasma (COPLA) donation at the Institute of Liver and Biliary Sciences, New Delhi and healthy individuals (n = 10), were recruited. We have assessed 21 plasma cytokines using cytokine bead array, performed proteomics on serum proteins, and analyzed immune cells using a detailed multicolor flow cytometry. Results: A significant increase in inflammatory markers such as macrophage inflammatory protein (MIP)1-α, monocyte chemotactic protein-1, macrophage migration inhibitory factor, vascular endothelial growth factor-A, and Leptin was observed in the moderate patients. Nonsurvivors additionally showed increased interleukin (IL)-6 levels. Consistently, the proteomics analysis showed the signatures of cytokine production and interferon-γ response, and increased level of acute-phase protein SAA1 in the serum of COVID-19 patients. Despite the sustained expression of MIPs, the recovered COPLA donors showed a surge in MCSF and IL-18 levels. Both the groups had increased CCR2, CX3CR1 positive monocytes, low CD8+ T cells, A proliferationinducing ligand, and B-cell activating factor receptor+ B cells compared with healthy subjects. Conclusions: Patients who have recovered and considered for COPLA donations still have compromised immunity with sustained expression of inflammatory monocytes and activated T cells. [ABSTRACT FROM AUTHOR]

Background and Aim: Risk stratification beyond the endoscopic classification of esophageal varices (EVs) to predict first episode of variceal bleeding (VB) is currently limited in patients with compensated advanced chronic liver disease (cACLD). We aimed to assess if machine learning (ML) could be used for predicting future VB more accurately. Methods: In this retrospective analysis, data from patients of cACLD with EVs, laboratory parameters and liver stiffness measurement (LSM) were used to generate an extreme‐gradient boosting (XGBoost) algorithm to predict the risk of VB. The performance characteristics of ML and endoscopic classification were compared in internal and external validation cohorts. Bleeding rates were estimated in subgroups identified upon risk stratification with combination of model and endoscopic classification. Results: Eight hundred twenty‐eight patients of cACLD with EVs, predominantly related to non‐alcoholic fatty liver disease (28.6%), alcohol (23.7%) and hepatitis B (23.1%) were included, with 455 (55%) having the high‐risk varices. Over a median follow‐up of 24 (12–43) months, 163 patients developed VB. The accuracy of machine learning (ML) based model to predict future VB was 98.7 (97.4–99.5)%, 93.7 (88.8–97.2)%, and 85.7 (82.1–90.5)% in derivation (n = 497), internal validation (n = 149), and external validation (n = 182) cohorts, respectively, which was better than endoscopic classification [58.9 (55.5–62.3)%] alone. Patients stratified high risk on both endoscopy and model had 1‐year and 3‐year bleeding rates of 31–43% and 64–85%, respectively, whereas those stratified as low risk on both had 1‐year and 3‐year bleeding rates of 0–1.6% and 0–3.4%, respectively. Endoscopic classification and LSM were the major determinants of model's performance. Conclusion: Application of ML model improved the performance of endoscopic stratification to predict VB in patients with cACLD with EVs. [ABSTRACT FROM AUTHOR]

Introduction: The role of HLA compatibility in kidney, heart, and stem cell transplantation is well known, but with regard to living donor liver transplantation (LDLT), there is a different scenario. In the present study, we aim to examine the effects of donor‐recipient HLA mismatches at A, B, and DR loci on various outcomes of LDLT‐like graft survival, early allograft dysfunction (EAD), acute rejection, length of hospital (LOH) stay, sepsis, and cytomegalovirus (CMV) reactivation. Methods: This is a retrospective single center study of a cohort of adult patients who underwent first time ABO‐compatible (ABOc) LDLT between January 2010 and December 2018. Transplants with incomplete records or without HLA typing data were excluded. Donor‐recipient HLA‐A, B, and DR mismatches were assessed in the host versus graft (HVG) direction and were correlated with various post‐transplant outcomes. Results: Among 140 transplants being evaluated, approximately two third had total HLA mismatches between 2 and 3. HLA mismatches at each locus as well as cumulative HLA mismatches did not show any association with overall graft survival, EAD, acute rejection episodes, and LOH stay. However, the presence of minimum one mismatch at HLA‐A and DR loci was associated with the development of CMV reactivation (P =.03) and sepsis (P =.02) post‐LDLT respectively. Conclusion: HLA mismatch is not associated with acute rejection, early graft dysfunction, and overall survival in LDLT. Its impact on CMV reactivation and sepsis needs further evaluation. [ABSTRACT FROM AUTHOR]

Background and Aim: Sepsis is an important determinant of the outcome of acute‐on‐chronic liver failure (ACLF) patients. Omega‐3 fatty acids (FAs) are known to suppress inflammation, reduce morbidity, and mortality in postoperative and critically ill patients. We aimed to evaluate the effect of intravenous omega‐6 and omega‐3 FA lipid emulsions in ACLF patients. Methods: Ninety ACLF patients were randomly allocated to three groups: Gr. A received no lipid emulsions, Gr. B received omega‐6 FAs, and Gr. C received omega‐3 FAs. The primary and secondary aims were to compare the effects of lipid emulsions on immune modulation, the incidence of bacterial sepsis, and mortality at day 28. Results: The baseline characteristics of the patients were comparable. Serum endotoxin levels remained suppressed by 22% in Gr. C compared with a 4% and 12% rise in Gr. B and A (P < 0.001). Omega‐3 FAs also suppressed C‐reactive protein levels and neutrophil‐to‐lymphocyte ratio in Gr. C. Compared with Gr. A, omega‐3 FAs reduced sepsis by 86% (HR, 0.14; 95% CI 0.04–0.43; P < 0.001). Omega‐3 FAs significantly increased the expression of TLR2 and TLR4 on both CD14+ and CD16+ monocytes, and TLR4, on macrophages and neutrophils. There were no serious adverse events, except transient flushing in 20% and 16.6% of patients receiving omega‐6 FAs and omega‐3 FAs, respectively. Conclusion: Omega‐3 FAs are safe and effective in reducing systemic inflammation, endotoxemia, and sepsis in patients with ACLF. These lipid emulsions could also be considered as effective sources of immunonutrition in such sick patients. [ABSTRACT FROM AUTHOR]

Background: Sepsis is common in cirrhosis and is often a result of immune dysregulation. Specific stimuli and pathways of inter‐cellular communications between immune cells in cirrhosis and sepsis are incompletely understood. Immune cell‐derived extracellular vesicles (EV) were studied to understand mechanisms of sepsis in cirrhosis. Methods: Immune cell‐derived EV were measured in cirrhosis patients [Child‐Turcotte‐Pugh (Child) score A, n = 15; B n = 16; C n = 43 and Child‐C with sepsis (n = 38)], and healthy controls (HC, n = 11). In vitro and in vivo functional relevance of EV in cirrhosis and associated sepsis was investigated. Results: Monocyte, neutrophil and hematopoietic stem cells associated EV progressively increased with higher Child score (P <.001)and correlated with liver disease severity indices (r2 > 0.3, P <.001), which further increased in Child C sepsis than without sepsis(P <.001); monocyte EV showing the highest association with disease stage [P =.013; Odds ratio‐4.14(1.34‐12.42)]. A threshold level of monocyte EV of 53/µl predicted mortality in patients of Child C with sepsis [Odds ratio‐6.2 (2.4‐15.9), AUROC = 0.76, P <.01]. In vitro EV from cirrhotic with sepsis compared without sepsis, induced mobilization arrest in healthy monocytes within 4 hours (P =.004), reduced basal oxygen consumption rate (P <.001) and induced pro‐inflammatory genes (P <.05). The septic‐EV on adoptive transfer to C57/BL6J mice, induced sepsis‐like condition within 24 h with leukocytopenia (P =.005), intrahepatic inflammation with increased CD11b + cells (P =.03) and bone marrow hyperplasia (P <.01). Conclusion: Extracellular vesicles induce functional impairment in circulating monocytes and contribute to the development and perpetuation of sepsis. High levels of monocyte EV correlate with mortality and can help early stratification of sicker patients. [ABSTRACT FROM AUTHOR]