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Backgrounds/Aims Hepatocellular carcinoma (HCC) is generally diagnosed at an advanced stage, which limits curative treatment options for these patients. Locoregional therapy (LRT) is the standard approach to bridge and downstage unresectable HCC for liver transplantation (LT). Atezolizumab-bevacizumab (atezo-bev) can induce objective responses in nearly one-third of patients; however, the role and outcomes of downstaging using atezo-bev remains unknown. Methods In this retrospective single-center study, we included consecutive patients between November 2020 and August 2023, who received atezo-bev with or without LRT and were subsequently considered for resection/LT after downstaging. Results Of the 115 patients who received atezo-bev, 12 patients (10.4%) achieved complete or partial response and were willing to undergo LT; they (age, 58.5 years; women, 17%; Barcelona Clinic Liver Cancer stage system B/C, 5/7) had received 3-12 cycles of atezo- bev, and four of them had received prior LRT. Three patients died before LT, while three were awaiting LT. Six patients underwent curative therapies: four underwent living donor LT after a median of 79.5 days (range, 54-114) following the last atezo-bev dose, one underwent deceased donor LT 38 days after the last dose, and one underwent resection. All but one patient had complete pathologic response with no viable HCC. Three patients experienced wound healing complications, and one required re-exploration and succumbed to sepsis. After a median follow-up of 10 months (range, 4-30), none of the alive patients developed HCC recurrence or graft rejection. Conclusions Surgical therapy, including LT, is possible after atezo-bev therapy in well-selected patients after downstaging.

Background : Steatotic liver disease (SLD) encompasses metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (AALD) at extremes as well as an overlap group termed MASLD with increased alcohol intake (MetALD). The Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease Index (ANI) was proposed to differentiate ALD from nonalcoholic fatty liver disease (NAFLD). We analysed the performance of the ANI in differentiating within the SLD spectrum. Methods : In a cross-sectional study at a tertiary care center, 202 adults (>18 years) who were prospectively diagnosed with SLD defined by magnetic resonance imaging-proton density fat fraction >6.4% were enrolled. Alcohol consumption (AC) was recorded according to thresholds for significant AC: 140-350 g/week (or 20-50 g/day) for females and 210-420 g/week (or 30-60 g/day) for males. The ANI was calculated, and area under the receiver operating characteristic curve (AUROC) was generated. Results : Of 202 patients (47 years [interquartile range, IQR, 38 to 55], 23.75% females, 77% obese, 42.1% with diabetes, 38.1% hypertensive, 28.7% statin use), 40.5% were ever-alcohol consumers; 120 (59%), 50 (24.7%), and 32 (15.8%) were MASLD (ANI, -3.7 [IQR, -7 to -1.6]; MetALD, - 1.45 [IQR, -2.4 to 0.28]; and AALD, 0.71 [IQR, -1.3 to 4.8], respectively; P-1.49), respectively. The ANI outperformed aspartate transaminase/alanine transaminase (AST/ALT) ratio (AUROC=0.75 [IQR, 0.69 to 0.81]) and gamma glutamyl transpeptidase (GGT) (AUROC=0.74 [IQR, 0.67 to 0.80]). Addition of GGT did not improve model performance (AUCdiff=0.004; P=0.33). Conclusion : AC is common in MASLD. The ANI distinguishes MASLD and AALD, with individual cut-offs within the intermediate zone indicating MetALD. ANI also outperforms AST/ALT ratio or GGT.

Abstract It has proved challenging to quantitatively relate the proteome to the transcriptome on a per-gene basis. Recent advances in data analytics have enabled a biologically meaningful modularization of the bacterial transcriptome. We thus investigate whether matched datasets of transcriptomes and proteomes from bacteria under diverse conditions can be modularized in the same way to reveal novel relationships between their compositions. We find that; (1) the modules of the proteome and the transcriptome are comprised of a similar list of gene products, (2) the modules in the proteome often represent combinations of modules from the transcriptome, (3) known transcriptional and post-translational regulation is reflected in differences between two sets of modules, allowing for knowledge-mapping when interpreting module functions, and (4) through statistical modeling, absolute proteome allocation can be inferred from the transcriptome alone. Quantitative and knowledge-based relationships can thus be found at the genome-scale between the proteome and transcriptome in bacteria.

Aim: This study aims to evaluate the GP dissolving property of ethanolic extract of sweet lime peel (Citrus limetta), peppermint oil, cedarwood oil, and an emulsion (equal volumes of ethanolic extract of sweet lime peel, peppermint, and cedarwood oils) compared to xylene and chloroform (CHCl3). Methods: Equal weight of GP were divided into 7 groups and immersed for 5 min and 10 min in the test and control groups. Distilled water was used as a negative control. Absolute weight loss (WL) was calculated. Results: Data were analyzed using Kruskal–Wallis test followed by Dunn's pairwise comparison with a significance value of P ≤ 0.05. The median WL of GP in the solvents shows a significant difference at 5 min (P = 0.001) and 10 min (P = 0.000). After 5 min, the order of WL was highest in sweet lime peel extract, CHCl3, and emulsion followed by xylene and peppermint oil. After 10 min, the highest WL was seen in emulsion, CHCl3 followed by sweet lime peel and peppermint oil. Cedarwood oil had no GP solvent effect at both time intervals. Conclusion: Sweet lime peel extract, emulsion, and peppermint oil showed a significant GP dissolving effect at 5 and 10 min and were comparable to CHCl3. Cedarwood oil showed no GP dissolving effect.

Recent advances in the field of hepatology include new and effective treatments for viral hepatitis. Further effort is now being directed to other disease entities, such as non-alcoholic fatty liver disease, with an increased need for assessment of liver function and histology. In fact, with the evolving nomenclature of fat-associated liver disease and the emergence of the term “metabolic-associated fatty liver disease” (MAFLD), new diagnostic challenges have emerged as patients with histologic absence of steatosis can still be classified under the umbrella of MAFLD. Currently, there is a growing number of endoscopic procedures that are pertinent to patients with liver disease. Indeed, interventional radiologists mostly perform interventional procedures such as percutaneous and intravascular procedures, whereas endoscopists focus on screening for and treatment of esophageal and gastric varices. EUS has proven to be of value in many areas within the realm of hepatology, including liver biopsy, assessment of liver fibrosis, measurement of portal pressure, managing variceal bleeding, and EUS-guided paracentesis. In this review article, we will address the endoscopic applications that are used to manage patients with chronic liver disease.

Abstract Background Pancreatic cancer is a devastating disease with less than 5% 5-year survival. Inoperable patients often present with pain. Randomized controlled trial have shown that endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) improves pain control. It is usually performed by injecting bupivacaine followed by absolute alcohol around the celiac axis. Study design Single center, randomized, double blind controlled trial of EUS-CPN with and without bupivacaine in patients with inoperable malignancy (pancreatic or other) involving the celiac plexus. The study was approved by research ethics board with approval number of 2022-9969, 21.151 and registered on ClinicalTrials.gov (NCT04951804). Discussion We hypothesize that bupivacaine is superfluous and may actually reduce pain control by diluting the neurolytic effect of alcohol. Bupivacaine is also potentially dangerous in that it may produce serious adverse events such as arrythmias and cardiac arrest if inadvertently injected intravascularly. Conclusion This randomized trial is designed to assess whether bupivacaine is of any value during EUS-CPN.

ABSTRACTAcinetobacter baumannii causes severe infections in humans, resists multiple antibiotics, and survives in stressful environmental conditions due to modulations of its complex transcriptional regulatory network (TRN). Unfortunately, our global understanding of the TRN in this emerging opportunistic pathogen is limited. Here, we apply independent component analysis, an unsupervised machine learning method, to a compendium of 139 RNA-seq data sets of three multidrug-resistant A. baumannii international clonal complex I strains (AB5075, AYE, and AB0057). This analysis allows us to define 49 independently modulated gene sets, which we call iModulons. Analysis of the identified A. baumannii iModulons reveals validating parallels to previously defined biological operons/regulons and provides a framework for defining unknown regulons. By utilizing the iModulons, we uncover potential mechanisms for a RpoS-independent general stress response, define global stress-virulence trade-offs, and identify conditions that may induce plasmid-borne multidrug resistance. The iModulons provide a model of the TRN that emphasizes the importance of transcriptional regulation of virulence phenotypes in A. baumannii. Furthermore, they suggest the possibility of future interventions to guide gene expression toward diminished pathogenic potential.IMPORTANCEThe rise in hospital outbreaks of multidrug-resistant Acinetobacter baumannii infections underscores the urgent need for alternatives to traditional broad-spectrum antibiotic therapies. The success of A. baumannii as a significant nosocomial pathogen is largely attributed to its ability to resist antibiotics and survive environmental stressors. However, there is limited literature available on the global, complex regulatory circuitry that shapes these phenotypes. Computational tools that can assist in the elucidation of A. baumannii’s transcriptional regulatory network architecture can provide much-needed context for a comprehensive understanding of pathogenesis and virulence, as well as for the development of targeted therapies that modulate these pathways.

The presence of hazardous metals, such as nickel and copper, has been identified in the effluents of the textile industries. Due to such hazardous components, this waste water exhibits a significant chemical oxygen demand (COD). Various methods are used to reduce the COD presence in the effluents. This investigation employs hydrodynamic cavitation, to decrease COD levels potentially. This reduction is achieved by implementing different orifice plate designs, including 3-star pattern, 3-circular hole pattern, 5-star pattern, and 5-circular hole pattern, as part of an innovative strategy. According to current investigations, implementing the 5-circular hole layout significantly reduced of COD by 49.14%. In contrast, using the 5-star design yielded a low drop of 34.15% COD. These experimental findings indicated that the most effective orifice plate for removing COD from textile wastewater was a circular design with 5- holes.

ABSTRACT The transcriptional regulatory network (TRN) of the phytopathogen Pseudomonas syringae pv. tomato DC3000 regulates its response to environmental stimuli, including interactions with hosts and neighboring bacteria. Despite the importance of transcriptional regulation during these agriculturally significant interactions, a comprehensive understanding of the TRN of P. syringae is yet to be achieved. Here, we collected and decomposed a compendium of public RNA-seq data from P. syringae to obtain 45 independently modulated gene sets (iModulons) that quantitatively describe the TRN and its activity state across diverse conditions. Through iModulon analysis, we (i) untangle the complex interspecies interactions between P. syringae and other terrestrial bacteria in cocultures, (ii) expand the current understanding of the Arabidopsis thaliana-P. syringae interaction, and (iii) elucidate the AlgU-dependent regulation of flagellar gene expression. The modularized TRN yields a unique understanding of interaction-specific transcriptional regulation in P. syringae. IMPORTANCE Pseudomonas syringae pv. tomato DC3000 is a model plant pathogen that infects tomatoes and Arabidopsis thaliana. The current understanding of global transcriptional regulation in the pathogen is limited. Here, we applied iModulon analysis to a compendium of RNA-seq data to unravel its transcriptional regulatory network. We characterize each co-regulated gene set, revealing the activity of major regulators across diverse conditions. We provide new insights on the transcriptional dynamics in interactions with the plant immune system and with other bacterial species, such as AlgU-dependent regulation of flagellar genes during plant infection and downregulation of siderophore production in the presence of a siderophore cheater. This study demonstrates the novel application of iModulons in studying temporal dynamics during host-pathogen and microbe-microbe interactions, and reveals specific insights of interest.

Abstract The development of cost‐effective and durable electrocatalysts possesses a broad spectrum of applications in sustainable energy systems. Herein, a hierarchical composite of Co‐based bi‐ligand zeolite imidazole framework (ZIF‐67) with highly conducting 2D MXene as highly efficient noble metal free electrocatalyst for electrochemical oxygen reduction reaction (ORR), complete water splitting, along with zinc‐air battery (ZAB) has been studied. ZIF‐67 is reported as an efficient electrocatalyst due to its porous structures, high surface area and atomically dispersed active metal centres while low conductivity and structural instability have been addressed by pyrolysis. In this work, structural disintegration due to temperature effect has been handled by using bi‐ligand linkers in ZIF (b‐ZIF‐67) which controls its sharp morphology and uniform mesoporous structure. This b‐ZIF‐67 has been supported on highly conducting 2D MXene material which exposes ample accessible active sites to accelerate the electroactivity of the synthesized catalyst. The resultant b‐CZIF‐67/MXene catalyst exhibits superior onset of 0.91 and 0.93 V in acidic and alkaline medium respectively for ORR. At the current density of 10 mA/cm2 catalyst shows a very low overpotential of 0.170 mV and 1.47 V for HER and OER, respectively. The excellent specific charge storage of 550.6 mAh/g was displayed by the homemade ZAB pouch.

Summary: Relationships between the genome, transcriptome, and metabolome underlie all evolved phenotypes. However, it has proved difficult to elucidate these relationships because of the high number of variables measured. A recently developed data analytic method for characterizing the transcriptome can simplify interpretation by grouping genes into independently modulated sets (iModulons). Here, we demonstrate how iModulons reveal deep understanding of the effects of causal mutations and metabolic rewiring. We use adaptive laboratory evolution to generate E. coli strains that tolerate high levels of the redox cycling compound paraquat, which produces reactive oxygen species (ROS). We combine resequencing, iModulons, and metabolic models to elucidate six interacting stress-tolerance mechanisms: (1) modification of transport, (2) activation of ROS stress responses, (3) use of ROS-sensitive iron regulation, (4) motility, (5) broad transcriptional reallocation toward growth, and (6) metabolic rewiring to decrease NADH production. This work thus demonstrates the power of iModulon knowledge mapping for evolution analysis.

Summary: Background: Atezolizumab-bevacizumab (atezo-bev) is recommended as first-line therapy for patients with unresectable hepatocellular carcinoma (uHCC). However, its effectiveness and safety in other populations, including those with Child-Turcotte-Pugh (CTP) class B cirrhosis, is unclear. Methods: For this systematic review and meta-analysis, electronic databases, including PubMed, Embase, and Scopus, were searched from 1st May, 2020 till 5th October, 2022; the last date of access was January 31, 2023. Pooled progression-free survival (PFS), overall survival (OS), and radiological response rate among patients receiving atezo-bev were compared between patients with CTP-A and CTP-B cirrhosis, with tyrosine kinase inhibitors (TKIs) and among those receiving the drug as first-line and later line therapy. The protocol was registered in Prospero (CRD42022364430). Findings: Among 47 studies (n = 5400 patients), pooled PFS and OS were 6.86 (95% CI, 6.31–7.41) and 13.8 months (95% CI, 11.81–15.8), respectively. Objective response rate (ORR) and disease control rate were 26.7% (24.6–29.1) and 75.3% (73.1–77.4) using RECIST criteria, and 34% (30.3–37.8) and 73.6% (68.8–78) using mRECIST criteria, respectively. Among those receiving atezo-bev, patients with CTP-B cirrhosis had similar ORRs by RECIST (odds ratio [OR], 1.42 [0.77–2.6]; P = 0.25) and mRECIST criteria (OR, 1.33 [0.52–3.39]; P = 0.53) but shorter PFS (mean difference [MD]:3.83 months [1.81–5.84]) than those with CTP-A cirrhosis. Compared to patients receiving TKIs, those receiving atezo-bev had longer PFS (MD: 2.27 months [0.94–3.5]) and higher ORR (RECIST: OR, 1.44 [1.01–2.04] and mRECIST: OR, 1.33 [1.01–1.75]). Compared to first-line therapy, later-line therapy had lower ORR (RECIST: OR, 1.82 [1.3–2.53]; P

Aim: The purpose of this survey is to gain insight into the choice of endodontic posts and failure mode of different types of posts and their management by the dentist. Material and Methods: Dentists have a wide range of options for the use of endodontic posts, so they should know the preferred post, the failure mode for a different type of post, and its management in case of failure, so questionnaire was prepared based on this. Survey was done among general dentists, endodontists and prosthodontists, through Google Sheets, SurveyMonkey, and manually. 230 dentists (156-general; 45-endodontists; 29-Prosthodontists) participated in this survey. Results: FRC post is preferred post in anteriors among general dentists, endodontists and prosthodontists. The most preferred post in posteriors among endodontists is FRC(49%), prosthodontists is cast post, among general dentists it is cast post and metal posts(36% each). Selection criteria among all the groups are requirement for esthetic crown. Managing endodontic failure among 54% of general dentists, 56% of endodontists and 66% of prosthodontists is post retrieval using ultrasonics followed by retreatment. Fracture of teeth is the predominant reason among all the groups for failure of post retained crown. The management of FRC post failure among endodontists and prosthodontists were ultrasonic retrieval. Commonest failure for FRC post among general dentists and endodontists is post dislodgement wheras among prosthodontists is tooth fracture. Conclusion: Prosthetic rehabilitation of root canal-treated teeth is the ultimate goal of endodontics. Correct knowledge ensures the right attitude in selecting the best post for core retention in endodontically treated teeth.

Aims: To evaluate a customised enriched formulation of coconut (CEC) oil with Arimedadi Tailam (AT) and 0.2% chlorhexidine mouth rinse (CHX) for their plaque control and potential anticaries effects using the oratest in healthy volunteers. Settings and Design: Parallel, double-blinded (outcome assessor and statistician), randomised controlled institution-based pilot study. Methods and Materials: 60 adults (18-22 years) having DMFT score of 2-11, gingival and plaque index as zero, no history of antibiotics for one month or fluoride application in 2 weeks were randomly divided (computer-generated list) and allocated into 3 groups (A-CHX, B-CEC, C-AT) of 20 subjects each based on the intervention. Oratest at baseline, days 15 and 30 were recorded. Statistical Analysis Used: Due to 5 dropouts on day 30, data were analysed based on the intention-to-treat (ITT) approach. The difference in oratest scores (baseline vs. day 15 and 30) were found to be normally distributed (Shapiro-Wilk test and Levene's test). One way ANOVA followed by Tukey's post hoc test was used to determine the statistically significant difference (P < 0.05) between groups. Results: Plaque and gingival index was zero throughout the study period. Difference in oratest scores was highest with CEC oil, followed by CHX and AT though there was no statistically significant differences between groups at baseline vs day 15 (P = 0.203) and baseline vs day 30 (P = 0.085) and between oils from baseline vs day 30 (P = 0.068). Conclusions: Within the limitations of the pilot study, both oils are comparable to CHX for their antiplaque and anticaries potential. Clinically, CEC was better than AT though statistical difference was not there.

Aim: Thyme has got good anti-inflammatory, antimicrobial, and antifungal properties and is reported to be very effective against oral microflora. The aim of the present study was to compare the antimicrobial activity of zinc oxide and thyme oil to zinc oxide and eugenol. Methods: Anti-bacterial efficacy of zinc oxide + eugenol and zinc oxide + thyme oil paste was evaluated against mature Enterococcus faecalis (E. faecalis) dentinal biofilm evaluated by the zone of inhibition (ZOI), biofilm disruption evaluated by colony-forming unit (CFU) reduction, and confocal laser scanning microscopy (CLSM). The red and green fluorescence thresholds were manually set according to their respective intensity and kept consistent for each sample. The ratios of live/dead cells were automatically calculated by the software. Results: The results of the present study showed that there was a statistically significant difference in antimicrobial efficacy for thyme oil compared to eugenol as evaluated by ZOI (P = 0.032). Thyme oil was significantly better than eugenol in antimicrobial efficacy according to the percentage of CFU reduction (P = 0.0422) in E. faecalis biofilm. Based on CLSM evaluation, there was no statistically significant difference (P = 0.172) between the two groups. Conclusion: Zinc oxide + Thyme oil paste, used in this study has shown promising antibacterial activity against E. faecalis and hence can be used as an alternative sealer.

We have described a patient with a history of type A-11 dissection repair, who subsequently underwent thoracic endovascular aortic repair with distal bare metal dissection stents (provisional extension to induce complete attachment) and renal artery stenting for malperfusion. During the next 3 years, the thoracoabdominal aorta had continued to enlarge to 6.9 cm, despite false lumen embolization and thoracic endovascular aortic repair extension. Given the continued aortic enlargement, physician-modified fenestrated endovascular aortic repair was performed within the prior aortic and renal stents with successful aneurysm sealing. The results from the present case have illustrated that continued aneurysmal degeneration can occur after provisional extension to induce complete attachment and that subsequent physician-modified fenestrated endovascular aortic repair is feasible.

In this experimental work, evaporation, degree of hydration, capillary porosity, total porosity and gel/space ratio of hardened state of Ordinary Portland Cement (OPC) of 53 grade, incorporated with Polyethylene Glycol 400 (PEG 400) have been investigated. Curing periods considered were 3, 7 and 28 days. As the Self-Curing concretes of M20 grade with 0.55 water -cement ratio and M50 grade with 0.34 water-cement ratio were being produced in the laboratory, the water-cement ratios considered for this laboratory work were also 0.34 and 0.55. Average molecular mass of Self-Curing chemical was 400. Its dosages were 1%, 1.5% and 2% by mass of dry cement. The conventional cement paste cubes were cured by placing under water. However, cubes with PEG 400 were kept in an open air in the laboratory to self-cure. Experimental work showed that PEG 400 proved to be an effective Self-Curing chemical by retaining water, thereby reducing the evaporation, maintaining the adequate degree of hydration, exhibiting capillary porosity, total porosity and gel/space ratio values on par with the water-cured cement paste at both the water-cement ratios.

Background & Aims: Model for End-Stage Liver Disease (MELD) score better predicts mortality in alcohol-associated hepatitis (AH) but could underestimate severity in women and malnourished patients. Using a global cohort, we assessed the ability of the MELD 3.0 score to predict short-term mortality in AH. Methods: This was a retrospective cohort study of patients admitted to hospital with AH from 2009 to 2019. The main outcome was all-cause 30-day mortality. We compared the AUC using DeLong's method and also performed a time-dependent AUC with competing risks analysis. Results: A total of 2,124 patients were included from 28 centres from 10 countries on three continents (median age 47.2 ± 11.2 years, 29.9% women, 71.3% with underlying cirrhosis). The median MELD 3.0 score at admission was 25 (20–33), with an estimated survival of 73.7% at 30 days. The MELD 3.0 score had a better performance in predicting 30-day mortality (AUC:0.761, 95%CI:0.732–0.791) compared with MELD sodium (MELD-Na; AUC: 0.744, 95% CI: 0.713–0.775; p = 0.042) and Maddrey’s discriminant function (mDF) (AUC: 0.724, 95% CI: 0.691–0.757; p = 0.013). However, MELD 3.0 did not perform better than traditional MELD (AUC: 0.753, 95% CI: 0.723–0.783; p = 0.300) and Age-Bilirubin-International Normalised Ratio-Creatinine (ABIC) (AUC:0.757, 95% CI: 0.727–0.788; p = 0.765). These results were consistent in competing-risk analysis, where MELD 3.0 (AUC: 0.757, 95% CI: 0.724–0.790) predicted better 30-day mortality compared with MELD-Na (AUC: 0.739, 95% CI: 0.708–0.770; p = 0.028) and mDF (AUC:0.717, 95% CI: 0.687–0.748; p = 0.042). The MELD 3.0 score was significantly better in predicting renal replacement therapy requirements during admission compared with the other scores (AUC: 0.844, 95% CI: 0.805–0.883). Conclusions: MELD 3.0 demonstrated better performance compared with MELD-Na and mDF in predicting 30-day and 90-day mortality, and was the best predictor of renal replacement therapy requirements during admission for AH. However, further prospective studies are needed to validate its extensive use in AH. Impact and implications: Severe AH has high short-term mortality. The establishment of treatments and liver transplantation depends on mortality prediction. We evaluated the performance of the new MELD 3.0 score to predict short-term mortality in AH in a large global cohort. MELD 3.0 performed better in predicting 30- and 90-day mortality compared with MELD-Na and mDF, but was similar to MELD and ABIC scores. MELD 3.0 was the best predictor of renal replacement therapy requirements. Thus, further prospective studies are needed to support the wide use of MELD 3.0 in AH.

Introduction and Objectives: Lately, there has been a steady increase in early liver transplantation for alcohol-associated hepatitis (AAH). Although several studies have reported favorable outcomes with cadaveric early liver transplantation, the experiences with early living donor liver transplantation (eLDLT) are limited. The primary objective was to assess one-year survival in patients with AAH who underwent eLDLT. The secondary objectives were to describe the donor characteristics, assess the complications following eLDLT, and the rate of alcohol relapse. Materials and Methods: This single-center retrospective study was conducted at AIG Hospitals, Hyderabad, India, between April 1, 2020, and December 31, 2021. Results: Twenty-five patients underwent eLDLT. The mean time from abstinence to eLDLT was 92.4 ± 42.94 days. The mean model for end-stage liver disease and discriminant function score at eLDLT were 28.16 ± 2.89 and 104 ± 34.56, respectively. The mean graft-to-recipient weight ratio was 0.85 ± 0.12. Survival was 72% (95%CI, 50.61–88) after a median follow-up of 551 (23-932) days post-LT. Of the 18 women donors,11 were the wives of the recipient. Six of the nine infected recipients died: three of fungal sepsis, two of bacterial sepsis, and one of COVID-19. One patient developed hepatic artery thrombosis and died of early graft dysfunction. Twenty percent had alcohol relapse. Conclusions: eLDLT is a reasonable treatment option for patients with AAH, with a survival of 72% in our experience. Infections early on post-LT accounted for mortality, and thus a high index of suspicion of infections and vigorous surveillance, in a condition prone to infections, are needed to improve outcomes.

ABSTRACT Streptococcus pyogenes can cause a wide variety of acute infections throughout the body of its human host. An underlying transcriptional regulatory network (TRN) is responsible for altering the physiological state of the bacterium to adapt to each unique host environment. Consequently, an in-depth understanding of the comprehensive dynamics of the S. pyogenes TRN could inform new therapeutic strategies. Here, we compiled 116 existing high-quality RNA sequencing data sets of invasive S. pyogenes serotype M1 and estimated the TRN structure in a top-down fashion by performing independent component analysis (ICA). The algorithm computed 42 independently modulated sets of genes (iModulons). Four iModulons contained the nga-ifs-slo virulence-related operon, which allowed us to identify carbon sources that control its expression. In particular, dextrin utilization upregulated the nga-ifs-slo operon by activation of two-component regulatory system CovRS-related iModulons, altering bacterial hemolytic activity compared to glucose or maltose utilization. Finally, we show that the iModulon-based TRN structure can be used to simplify the interpretation of noisy bacterial transcriptome data at the infection site. IMPORTANCE S. pyogenes is a pre-eminent human bacterial pathogen that causes a wide variety of acute infections throughout the body of its host. Understanding the comprehensive dynamics of its TRN could inform new therapeutic strategies. Since at least 43 S. pyogenes transcriptional regulators are known, it is often difficult to interpret transcriptomic data from regulon annotations. This study shows the novel ICA-based framework to elucidate the underlying regulatory structure of S. pyogenes allows us to interpret the transcriptome profile using data-driven regulons (iModulons). Additionally, the observations of the iModulon architecture lead us to identify the multiple regulatory inputs governing the expression of a virulence-related operon. The iModulons identified in this study serve as a powerful guidepost to further our understanding of S. pyogenes TRN structure and dynamics.

Cirrhosis transcends various progressive stages from compensation to decompensation driven by the severity of portal hypertension. The downstream effect of increasing portal hypertension severity leads to various pathophysiological pathways, which result in the cardinal complications of cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. Additionally, the severity of portal hypertension is the central driver for further advanced complications of hyperdynamic circulation, hepatorenal syndrome, and cirrhotic cardiomyopathy. The management of these individual complications has specific nuances which have undergone significant developments. In contrast to the classical natural history of cirrhosis and its complications which follows an insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill course with high short-term mortality unless intervened at the early stages. The management of ACLF involves specific interventions, which have quickly evolved in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF.

Nonalcoholic fatty liver disease (NAFLD), once considered a benign condition, has been associated with several cardiometabolic complications over the past two decades. The worldwide prevalence of NAFLD is as high as 30%. NAFLD requires the absence of a “significant alcohol intake.” Conflicting reports have suggested that moderate alcohol consumption may be protective; therefore, the diagnosis of NAFLD previously relied on negative criteria. However, there has been a significant increase in alcohol consumption globally. Apart from the rise in alcohol-related liver disease (ARLD), alcohol, a major toxin, is associated with an increased risk of several cancers, including hepatocellular carcinoma. Alcohol misuse is a significant contributor to disability-adjusted life years. Recently, the term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed instead of NAFLD to include the metabolic dysfunction responsible for the major adverse outcomes in patients with fatty liver disease. MAFLD, dependent on the “positive diagnostic criteria” rather than previous exclusion criteria, may identify individuals with poor metabolic health and aid in managing patients at increased risk of all-cause and cardiovascular mortality. Although MAFLD is less stigmatizing than NAFLD, excluding alcohol intake may increase the risk of already existing underreported alcohol consumption in this subgroup of patients. Therefore, alcohol consumption may increase the prevalence of fatty liver disease and its associated complications in patients with MAFLD. This review discusses the effects of alcohol intake and MAFLD on fatty liver disease.

Abstract Aim Nonselective beta‐blockers (NSBBs) can reduce the incidence of complications in patients with cirrhosis and prolong survival. The safety and efficacy of NSBBs in real‐world settings in patients with acute‐on‐chronic liver failure (ACLF) identified by the Asian Pacific Association for the Study of Liver criteria are unknown. This study aimed to assess the safety and efficacy of NSBBs in patients with Asian Pacific Association for the Study of Liver (APASL)‐defined ACLF Methods In this retrospective, multicenter study, patients with ACLF with complete 30 days follow‐up from January 2019 to December 2021 were included. The primary objective was to compare 30‐day mortality among standard of care (SOC) and NSBB (+SOC) groups. The secondary objectives were to compare the incidence of infection, variceal bleed, and recompensation among both the groups. Results A total of 346 patients were included. Only 26% (n = 89) of them received NSBBs, while 74% (n = 257) received only SOC. On Kaplan–Meier analysis, the incidence of mortality was 21% (95% confidence interval [CI]: 16.20–26.50) in SOC group compared to only 8% (95% CI: 3.22–15.53) in NSBB group at Day 30 (p = 0.005). Similarly, mortality in SOC group was 63% (95% CI: 56.81–69.00) compared to 46% (95% CI: 35.44–57.00) in NSBB group at 1 year (p = 0.001). NSBB therapy could not reduce the incidence of infections or variceal bleed. Forty‐seven percent of patients in the SOC group and 73% of patients in the NSBB group (p

Tinospora cordifolia (Giloy) is an herbal supplement commonly used in the Indian alternative medicine system Ayurveda. This herb has been promoted to the public in India as an immune booster to prevent novel coronavirus disease 2019. However, small reports have recently shown an association between Giloy use and the development of herb‐induced liver injury (HILI) with autoimmune features in some patients. This large retrospective Indian multicenter study spanning 13 centers at nine locations was designed to identify features and outcomes of HILI temporally associated with Giloy use. Chemical and toxicological analyses of retrieved Giloy samples using state‐of‐the‐art methods were also performed. We report 43 patients, of whom more than half were female, with a median time from initial Giloy consumption to symptom onset of 46 days. Patients presented with acute hepatitis, acute worsening of chronic liver disease (CLD, the most common clinical presentation), or acute liver failure. Causality assessment revealed probable liver injury in 67.4%. The most common autoantibody detected was anti‐nuclear antibody. Liver biopsy in a subset revealed HILI associated with autoimmune features and hepatocyte and canalicular cholestasis and neutrophilic and eosinophilic infiltration. Conclusion: Giloy is associated with acute hepatitis with autoimmune features and can unmask autoimmune hepatitis (AIH) in people with silent AIH‐related CLD. Further studies on the safety (and efficacy) of untested but heavily promoted herbals in alternative systems of medicine are an unmet need in the interests of public health and are especially important during this global health emergency.

Introduction and Objectives: The long-term impact of alcohol-related public health policies (PHP) on the burden of liver disease is unclear. This study aimed to assess the association between alcohol-related PHP and alcohol-related health consequences; 2. To develop an instrument to quantify the establishment of alcohol-related PHP in each country. Materials and Methods: We performed an ecological multi-national study including 169 countries. We recorded socio-demographic data and the presence of alcohol-related PHP in each country from the WHO Global Information System of Alcohol and Health (GISAH) in 2010. Data on alcohol-related health consequences was collected from the Global Burden of Disease database (between 2010-2019). We classified the WHO categories into five domains to design an instrument with criteria for a low, moderate, and strong establishment of PHP. We estimated an incidence rate ratio (IRR) using multilevel generalized linear models with a Poisson family distribution. The models were adjusted by population size, age structure, and gross domestic product. We also estimated a preparedness index using multiple correspondence analysis. Results: The table summarizes the final instrument. We included 169 countries; the median preparedness index was 54 [34.9-76.8]. The preparedness index was associated with lower alcohol-associated liver disease (ALD) mortality (IRR:0.25, 95%CI: 0.06-1.09, p=0.064), cancer mortality (IRR:0.22, 95%CI: 0.05-0.97, p=0.046), hepatocellular carcinoma (HCC) mortality (IRR:0.20, 95%CI: 0.04-0.95, p=0.043), and cardiovascular mortality (IRR:0.15, 95%CI: 0.04-0.61, p=0.008). There was also a trend to lower alcohol use disorder prevalence (IRR:0.25, 95%CI: 0.06-1.09, p=0.064). The highest linear associations were observed in the Americas and Africa, while Europe exhibits a nonlinear association. Conclusions: The preparedness index on alcohol policies is a valuable instrument to assess the establishment and strength of PHP. Those countries with a higher number of PHP had lower mortality due to ALD, cancer, HCC, and cardiovascular diseases. Our results strongly encourage the development and implementation of PHP on alcohol consumption worldwide.

Abstract Terlipressin with albumin, the recommended treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI), is associated with adverse events. Furthermore, the course of AKI in patients with acute-on-chronic liver failure (ACLF) is unknown. We aimed to analyze the safety and efficacy of terlipressin infusion and AKI course in patients with ACLF. We prospectively enrolled consecutive adult patients with ACLF with HRS-AKI (satisfying EASL criteria) treated with terlipressin infusion between 14 October 2019 and 24 July 2020. The objectives were to assess the incidence of adverse events, response to terlipressin, course of HRS-AKI and predictors of mortality. A total of 116 patients were included. Twenty-one percent of patients developed adverse effects. Only 1/3rd of patients who developed adverse events were alive at day 90. Sixty-five percent of the patients responded to terlipressin. Nearly 22% developed recurrence of HRS, and 5.2% progressed to HRS-chronic kidney disease. TFS was 70.4% at day 30 and 57.8% at day 90. On multivariate stepwise Cox regression analysis terlipressin non-response (hazard ratio [HR], 3.49 [1.85–6.57]; P

Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID‐19) complications and deaths. We aimed to describe cases of SARS‐CoV‐2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID‐19 vaccine dose. The SECURE‐Liver and COVID‐Hep international reporting registries were used to identify laboratory‐confirmed COVID‐19 in CLD and LT patients who received a COVID‐19 vaccination. Of the 342 cases of lab‐confirmed SARS‐CoV‐2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID‐19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID‐19 occurred in patients who had a single vaccine dose within the last 1‐2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID‐19 infections among patients with CLD and LT recipients who had received the COVID‐19 vaccination. Vaccination against SARS‐CoV‐2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.

Abstract Background Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. Silencing macrophages by reducing foamy macrophages showed significant improvement of age-related degenerative changes in peripheral nerves of aged mice. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist, GW3965, alleviates pain in a diet-induced obesity model. We sought to test whether LXR activation may improve neuropathy in aged mice. Methods 21-month-old mice were treated with GW3965 (25 mg/Kg body weight) for 3 months while testing for mechanical allodynia and thermal hyperalgesia. At termination, flow cytometry was used to profile dorsal root ganglia and sciatic nerve cells. Immune cells were sorted and analyzed for cholesterol and gene expression. Nerve fibers of the skin from the paws were analyzed. Some human sural nerves were also evaluated. Comparisons were made using either t test or one-way ANOVA. Results Treatment with GW3965 prevented the development of mechanical hypersensitivity and thermal hyperalgesia over time in aged mice. We also observed change in polarization and cholesterol content of sciatic nerve macrophages accompanied by a significant increase in nerve fibers of the skin. Conclusions These results suggest that activation of the LXR may delay the PNS aging by modifying nerve-immune cell lipid content. Our study provides new potential targets to treat or delay neuropathy during aging.

Background Tumor intracellular programmed cell death ligand-1 (PDL1) mediates pathologic signals that regulate clinical treatment responses distinctly from surface-expressed PDL1 targeted by αPDL1 immune checkpoint blockade antibodies.Methods We performed a drug screen for tumor cell PDL1 depleting drugs that identified Food and Drug Administration (FDA)-approved chlorambucil and also 9-[2-(phosphonomethoxy)ethyl] guanine. We used in vitro and in vivo assays to evaluate treatment and signaling effects of pharmacological tumor PDL1 depletion focused on chlorambucil as FDA approved, alone or plus αPDL1.Results PDL1-expressing mouse and human ovarian cancer lines and mouse melanoma were more sensitive to chlorambucil-mediated proliferation inhibition in vitro versus corresponding genetically PDL1-depleted lines. Orthotopic peritoneal PDL1-expressing ID8agg ovarian cancer and subcutaneous B16 melanoma tumors were more chlorambucil-sensitive in vivo versus corresponding genetically PDL1-depleted tumors. Chlorambucil enhanced αPDL1 efficacy in tumors otherwise αPDL1-refractory, and improved antitumor immunity and treatment efficacy in a natural killer cell-dependent manner alone and plus αPDL1. Chlorambucil-mediated PDL1 depletion was relatively tumor-cell selective in vivo, and treatment efficacy was preserved in PDL1KO hosts, demonstrating tumor PDL1-specific treatment effects. Chlorambucil induced PDL1-dependent immunogenic tumor cell death which could help explain immune contributions. Chlorambucil-mediated PDL1 reduction mechanisms were tumor cell-type-specific and involved transcriptional or post-translational mechanisms, including promoting PDL1 ubiquitination through the GSK3β/β-TRCP pathway. Chlorambucil-mediated tumor cell PDL1 depletion also phenocopied genetic PDL1 depletion in reducing tumor cell mTORC1 activation and tumor initiating cell content, and in augmenting autophagy, suggesting additional treatment potential.Conclusions Pharmacological tumor PDL1 depletion with chlorambucil targets tumor-intrinsic PDL1 signaling that mediates treatment resistance, especially in αPDL1-resistant tumors, generates PDL1-dependent tumor immunogenicity and inhibits tumor growth in immune-dependent and independent manners. It could improve treatment efficacy of selected agents in otherwise treatment-refractory, including αPDL1-refractory cancers, and is rapidly clinically translatable.

Abstract Background Independent component analysis is an unsupervised machine learning algorithm that separates a set of mixed signals into a set of statistically independent source signals. Applied to high-quality gene expression datasets, independent component analysis effectively reveals both the source signals of the transcriptome as co-regulated gene sets, and the activity levels of the underlying regulators across diverse experimental conditions. Two major variables that affect the final gene sets are the diversity of the expression profiles contained in the underlying data, and the user-defined number of independent components, or dimensionality, to compute. Availability of high-quality transcriptomic datasets has grown exponentially as high-throughput technologies have advanced; however, optimal dimensionality selection remains an open question. Methods We computed independent components across a range of dimensionalities for four gene expression datasets with varying dimensions (both in terms of number of genes and number of samples). We computed the correlation between independent components across different dimensionalities to understand how the overall structure evolves as the number of user-defined components increases. We then measured how well the resulting gene clusters reflected known regulatory mechanisms, and developed a set of metrics to assess the accuracy of the decomposition at a given dimension. Results We found that over-decomposition results in many independent components dominated by a single gene, whereas under-decomposition results in independent components that poorly capture the known regulatory structure. From these results, we developed a new method, called OptICA, for finding the optimal dimensionality that controls for both over- and under-decomposition. Specifically, OptICA selects the highest dimension that produces a low number of components that are dominated by a single gene. We show that OptICA outperforms two previously proposed methods for selecting the number of independent components across four transcriptomic databases of varying sizes. Conclusions OptICA avoids both over-decomposition and under-decomposition of transcriptomic datasets resulting in the best representation of the organism’s underlying transcriptional regulatory network.

ABSTRACT Establishing transcriptional regulatory networks (TRNs) in bacteria has been limited to well-characterized model strains. Using machine learning methods, we established the transcriptional regulatory networks of six Salmonella enterica serovar Typhimurium strains from their transcriptomes. By decomposing a compendia of RNA sequencing (RNA-seq) data with independent component analysis, we obtained 400 independently modulated sets of genes, called iModulons. We (i) performed pan-genome analysis of the phylogroup structure of S. Typhimurium and analyzed the iModulons against this background, (ii) revealed different genetic signatures in pathogenicity islands that explained phenotypes, (iii) discovered three transport iModulons linked to antibiotic resistance, (iv) described concerted responses to cationic antimicrobial peptides, and (v) uncovered new regulons. Thus, by combining pan-genome and transcriptomic analytics, we revealed variations in TRNs across six strains of serovar Typhimurium. IMPORTANCE Salmonella enterica serovar Typhimurium is a pathogen involved in human nontyphoidal infections. Treating S. Typhimurium infections is difficult due to the species’s dynamic adaptation to its environment, which is dictated by a complex transcriptional regulatory network (TRN) that is different across strains. In this study, we describe the use of independent component analysis to characterize the differential TRNs across the S. Typhimurium pan-genome using a compendium of high-quality RNA-seq data. This approach provided unprecedented insights into the differences between regulation of key cellular functions and pathogenicity in the different strains. The study provides an impetus to initiate a large-scale effort to reveal the TRN differences between the major phylogroups of the pathogenic bacteria, which could fundamentally impact personalizing treatments of bacterial pathogens.

Ajay Gupta,1 Chethan Channaveera,2 Vijender Anand,1 Satyaranjan Sethi1 1Department of Physical Medicine & Rehabilitation, VMM College and Safdarjang Hospital, New Delhi, 110029, India; 2Department of Physical Medicine & Rehabilitation,AIIMS, Mangalagiri, Andhra Pradesh, 522503, IndiaCorrespondence: Satyaranjan SethiVMM College and Safdarjang Hospital, New Delhi, 110029, IndiaEmail drsatya.1979@gmail.comObjective: IA-HA is injected into the osteoarthritis knee as a viscosupplementation for therapeutic purposes. This clinical trial was carried out for evaluating the efficacy and safety of Biovisc Ortho IA-HA (20 mg/2 mL) in a 2 mL prefilled syringe.Design: The study was conducted as an open-label, single-center, single-arm clinical trial in India. Patients of knee OA with moderate to severe symptoms for a minimum duration of 3 months were included in the study. Five visits were conducted at weekly intervals and the investigational product was administered at each visit. Two follow-up visits were conducted at 3 and 6 months after the completion of the last injection cycle. The primary outcome variable was change in KOOS pain score from baseline. The secondary outcome variables were analyzed for other KOOS scales and safety of the device.Results: Change in KOOS pain score at 6 months from baseline was 29.71± 15.74 and the change in mean KOOS score for pain was statistically significant (p< 0.0001) for all post-baseline visits. Statistically significant improvement was observed for mean values of efficacy assessments (KOOS) during the study period (6 months) for all the domains evaluated, including pain, joint function and quality of life.Conclusion: Despite being an open, noncomparative study, the safety and efficacy results of IA-HA establish the therapeutic effect of the treatment throughout the study period of 6 months and are safe.Keywords: osteoarthritis, hyaluronic acid, intra-articular, IA, viscosupplementation, KOOS

Abstract Tumor cell‐intrinsic programmed death‐ligand 1 (PD‐L1) signals mediate immunopathologic effects in breast, colon, and ovarian cancers and in melanomas, but bladder cancer (BC) effects are unreported. We show here that BC cell‐intrinsic PD‐L1 signals in mouse MB49 and human RT4, UM‐UC3, and UM‐UC‐14 BC cells regulate important pathologic pathways and processes, including effects not reported in other cancers. α‐PD‐L1 antibodies reduced BC cell proliferation in vitro, demonstrating direct signaling effects. BC cell‐intrinsic PD‐L1 promoted mammalian target of rapamycin complex 1 (mTORC1) signals in vitro and augmented in vivo immune‐independent cell growth and metastatic cancer spread, similar to effects we reported in melanoma and ovarian cancer. BC cell‐intrinsic PD‐L1 signals also promoted basal and stress‐induced autophagy, whereas these signals inhibited autophagy in melanoma and ovarian cancer cells. BC cell‐intrinsic PD‐L1 also mediated chemotherapy resistance to the commonly used BC chemotherapy agents cis‐platinum and gemcitabine and to the mTORC1 inhibitor, rapamycin. Thus, BC cell‐intrinsic PD‐L1 signals regulate important virulence and treatment resistance pathways that suggest novel, actionable treatment targets meriting additional studies. As a proof‐of‐concept, we showed that the autophagy inhibitor chloroquine improved cis‐platinum treatment efficacy in vivo, with greater efficacy in PD‐L1 null versus PD‐L1‐replete BC.

Aims: To study the impact of vestibular suppressant drugs (VSD) on provocative positional tests (PPT) in patients with benign paroxysmal positional vertigo (BPPV). Settings and Design: A prospective case-control observational study. Materials and Methods: Patients with a history suggestive of BPPV were tested for PPT. Patients with vertiginous symptoms and with nystagmus on PPT were classified as objective BPPV (O-BPPV, control group), while those without nystagmus with no alternate diagnosis were classified as subjective BPPV (S-BPPV, case group). Details of VSD treatment were noted in all the patients. In both groups, patients were instructed to discontinue VSD and were further assigned as the VSD and non-VSD subgroups. Patients were followed for 2 months with PPT every week. PPT positive patients were treated by vestibular rehabilitation maneuvers. Statistics: Student t-test with two-tailed, unpaired, was used for continuous scale and Chi-square test for categorical differences between the two groups. Results: 295 consecutive BPPV patients were enrolled in the study, 55 in the S-BPPV group and 240 in the O-BPPV group. Significantly higher proportion of patients in the S-BPPV group were on VSD at presentation, 80.00% vs. 53.75% (OR 2.52; 95% CI: 1.30–4.86), P = 0.006. In an unadjusted analysis of the S-BPPV group following discontinuation of VSD, PPT became positive in 79.54% of patients as compared to 18.19% in the non-VSD group (OR 35.0; 95% CI: 6.2–197.3), P < 0.001. Conclusion: A higher proportion of S-BPPV patients were receiving VSD in comparison to O-BPPV at the initial visit. The PPT converted positive four times higher after ceasing the VSD in S-BPPV patients. Study Design: Prospective case-control observational study.

The systems-level regulatory structure underlying gene expression in bacteria can be inferred using machine learning algorithms. Here we show this structure for Bacillus subtilis, present five hypotheses gleaned from it, and analyse the process of sporulation from its perspective.

Summary: Mathematical models have many applications in infectious diseases: epidemiologists use them to forecast outbreaks and design containment strategies; systems biologists use them to study complex processes sustaining pathogens, from the metabolic networks empowering microbial cells to ecological networks in the microbiome that protects its host. Here, we (1) review important models relevant to infectious diseases, (2) draw parallels among models ranging widely in scale. We end by discussing a minimal set of information for a model to promote its use by others and to enable predictions that help us better fight pathogens and the diseases they cause.

Disproportionate addition of nutrients can alter the nutrient stoichiometric balance of surface water bodies. In the present study, we investigated the atmospheric deposition (AD) and runoff-induced nutrient enrichment and N:P stoichiometric shifts in the Ganga River along a 35 km stretch of Varanasi city. The region receives 8–42 kg ha−1 of reactive-N (NO3− + NH4+) and 0.40–3.10 kg ha−1 of PO43- through AD annually. The most polluted Rajghat Site receives ~770.50 tons of reactive-N (Nr) and ~64.50 tons of PO43- annually as AD input in the sub-watershed; and ~25.10 tons of Nr and 2.09 tons of PO43- directly on the water surface. Concentrations of nutrients in surface runoff increased with AD input irrespective of land use. Among land use categories, the runoff nitrate was highest from agricultural catchment while NH4+ and PO43- were highest from urban areas. The study showed that the AD-runoff coupled with additional supplies could substantially alter the overall load and stoichiometric ratios of critical nutrients with a consequent effect on ecological functioning of the river in long-run.

Gasper followed the fractional calculus proof of an Erdélyi integral to derive its discrete analogue in the form of a hypergeometric expansion. To give an alternative proof, we derive it by following a procedure analogous to a triple series manipulation-based proof of the Erdélyi integral, due to “Joshi and Vyas”. Motivated from this alternative way of proof, we establish the discrete analogues corresponding to many of the Erdélyi type integrals due to “Joshi and Vyas” and “Luo and Raina” in the form of new hypergeometric expansion formulas. Moreover, the applications of investigated discrete analogues in deriving some expansion formulas involving orthogonal polynomials of the Askey-scheme and a new generalization of Whipple’s transformation for a balanced 4F3 in the form of an m+4Fm+3 transformation, are also discussed.

Mechanistic insight into the regulation of transcriptional modules remains scarce. Here, the authors identify statistically independent gene sets by applying independent component analysis to a high-quality E. coli RNA-seq data compendium and find that most gene sets represent the effects of specific transcriptional regulators.

A dam is a structure constructed across river which stores water and supplies water for various purposes. Though the dams have many benefits, there is always a threat of dam break floods which are devastating in nature. Hence it becomes essential to analyze and simulate dam failure scenarios to understand the severity of dam break flood and identify areas under threat which helps in land use planning and developing emergency response plans. This study attempts to carry out dam break/breach analysis for the Hidkal dam using a one-dimensional hydraulic model called Hydraulic Engineering Center's River Analysis System (HEC-RAS). HEC-GeoRAS tool is used to extract river geometry data from the Cartosat-1 digital elevation model (DEM) and to generate the inundation map to identify the areas affected. The study involves the prediction of breach parameters, breach flood hydrograph, peak flow, flood arrival time, and generation of inundation maps. The dam break model is simulated for unsteady flow conditions using Probable Maximum Flood (PMF) corresponding to piping and overtopping failure scenarios. HEC-RAS tool is utilized to determine the breach outflow hydrograph and hydraulic conditions at critical downstream locations. Further, the breach outflow hydrographs are routed using dynamic flood wave routing. Further HEC-RAS model is simulated for breach parameters derived from five different empirical methods, and the results are compared. A sensitivity analysis is also carried out to know the variation of peak flow and maximum stage with respect to the breach parameters. The immediate downstream of the dam experience a peak flow of 72,085.45 m3/s and 78,454.82 m3/s and the corresponding inundation area of 75.224 km2 and 79.205 km2 due to piping failure and overtopping failure, respectively. Around twenty village located on the downstream of dam location gets affected due to flood produced by dam break. The analysis shows that overtopping failure is more severe than failure due to piping. The study shall further help authorities concerned to develop an emergency response plan and flood mitigation measures.

Dynamic cellular responses to environmental constraints are coordinated by the transcriptional regulatory network (TRN), which modulates gene expression. This network controls most fundamental cellular responses, including metabolism, motility, and stress responses. Here, we apply independent component analysis, an unsupervised machine learning approach, to 95 high-quality Sulfolobus acidocaldarius RNA-seq datasets and extract 45 independently modulated gene sets, or iModulons. Together, these iModulons contain 755 genes (32% of the genes identified on the genome) and explain over 70% of the variance in the expression compendium. We show that five modules represent the effects of known transcriptional regulators, and hypothesize that most of the remaining modules represent the effects of uncharacterized regulators. Further analysis of these gene sets results in: (1) the prediction of a DNA export system composed of five uncharacterized genes, (2) expansion of the LysM regulon, and (3) evidence for an as-yet-undiscovered global regulon. Our approach allows for a mechanistic, systems-level elucidation of an extremophile’s responses to biological perturbations, which could inform research on gene-regulator interactions and facilitate regulator discovery in S. acidocaldarius. We also provide the first global TRN for S. acidocaldarius. Collectively, these results provide a roadmap toward regulatory network discovery in archaea.

Introduction: One of the most effective diagnostic tools for pancreatic cancer is endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or biopsy (EUS-FNB). Several randomized clinical trials have compared different EUS tissue sampling needles for the diagnosis of pancreatic cancer. Objective: To compare the diagnostic accuracy of EUS-guided FNA as EUS-FNB needles for the diagnosis of pancreatic cancer using a systematic review and meta-analysis. Method: A literature review with a meta-analysis was performed according to the PRISMA guide. The databases of PubMed, Cochrane and Google Scholar were used, including studies published between 2011–2021 comparing the diagnostic yield (diagnostic accuracy or probability of positivity, sensitivity, specificity, predictive value) of EUS-FNA and EUS-FNB for the diagnosis of pancreatic cancer. The primary outcome was diagnostic accuracy. Random effect models allowed estimation of the pooled odds ratio with a confidence interval (CI) of 95%. Results: Nine randomized control trials were selected out of 5802 articles identified. Among these, five studies found no statistically significant difference between the EUS-FNA and EUS-FNB, whereas the other four did. The meta-analysis found EUS-FNB accuracy superior to EUS-FNA for the diagnosis of pancreatic cancer with a pooled odds ratio of 1.87 (IC 95%: 1.33–2.63). Conclusion: As compared to EUS-FNA, EUS-FNB seems to improve diagnostic accuracy when applied to suspicious pancreatic lesions.

Background: Immunosuppression and comorbidities increase the risk of severe coronavirus disease-2019 (COVID-19) in solid organ transplant (SOT) recipients. The outcomes of COVID-19 in liver transplant (LT) recipients remain unclear. We aimed to analyse the outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in LT recipients. Methods: The electronic databases were searched for articles published from 1 December 2019 to 20 May 2021 with MeSH terms COVID-19, SARS-CoV-2, and liver transplantation. Studies reporting outcomes in more than 10 LT recipients were included for analysis. LT vs non-LT patients with COVID-19 infection were compared for all-cause mortality, which was the primary outcome studied. We also evaluated the relation between the timing of COVID-19 infection post-LT (< one year vs > one year) and mortality. Findings: Eighteen articles reporting 1,522 COVID-19 infected LT recipients were included for the systematic review. The mean age (standard deviation [SD]) was 60·38 (5·24) years, and 68·5% were men. The mean time (SD) to COVID-19 infection was 5·72 (1·75) years. Based on 17 studies (I2 = 7·34) among 1,481 LT recipients, the cumulative incidence of mortality was 17·4% (95% confidence interval [CI], 15·4–19·6). Mortality was comparable between LT (n = 610) and non-LT (n = 239,704) patients, based on four studies (odds ratio [OR], 0·8 [0·6–1·08]; P = 0·14). Additionally, there was no significant difference in mortality between those infected within one year vs after one year of LT (OR, 1·5 [0·63–3·56]; P = 0·35). The cumulative incidence of graft dysfunction was 2·3% (1·3–4·1). Nearly 23% (20·71–25) of the LT patients developed severe COVID-19 infection. Before infection, 71% and 49% of patients were on tacrolimus and mycophenolate mofetil, respectively. Immunosuppression was modified in 55·9% (38·1–72·2) patients after COVID-19 infection. Interpretation: LT and non-LT patients with COVID-19 have a similar risk of adverse outcomes. Funding: None.

Antibiotic resistance is an imminent threat to global health. Patient treatment regimens are often selected based on results from standardized antibiotic susceptibility testing (AST) in the clinical microbiology lab, but these in vitro

Introduction Lipoblastoma is a rare benign tumour arising from embryonic white fat been commonly noted in limbs and trunk, but tongue involvement is rare and has not yet been reported. Case Report A child with tongue lipoblastoma is reported, whose imaging reported an encapsulated, well-delineated, fat-containing tumour. Surgical excision was performed with no post-operative morbidities. Discussion Lipoblastoma is an uncommon childhood tumour, which rarely affects the tongue. It presents as a progressive painless swelling, rarely causing any symptom. MRI is helpful to assess the precise location and extent of the lesion. Although the ratio of fat to myxocollagenous tissue in the tumour is variable, the diagnosis can be suggested in most cases based on the imaging characteristics. Recommended treatment is complete surgical excision and confirmation of diagnosis by histopathological examination.

Summary: Pyruvate dehydrogenase complex (PDC) functions as the main determinant of the respiro-fermentative balance because it converts pyruvate to acetyl-coenzyme A (CoA), which then enters the TCA (tricarboxylic acid cycle). PDC is repressed by the pyruvate dehydrogenase complex regulator (PdhR) in Escherichia coli. The deletion of the pdhR gene compromises fitness in aerobic environments. We evolve the E. coli pdhR deletion strain to examine its achievable growth rate and the underlying adaptive strategies. We find that (1) optimal proteome allocation to PDC is critical in achieving optimal growth rate; (2) expression of PDC in evolved strains is reduced through mutations in the Shine-Dalgarno sequence; (3) rewiring of the TCA flux and increased reactive oxygen species (ROS) defense occur in the evolved strains; and (4) the evolved strains adapt to an efficient biomass yield. Together, these results show how adaptation can find alternative regulatory mechanisms for a key cellular process if the primary regulatory mode fails.

Background Anti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in

The availability of bacterial transcriptomes has dramatically increased in recent years. This data deluge could result in detailed inference of underlying regulatory networks, but the diversity of experimental platforms and protocols introduces critical biases that could hinder scalable analysis of existing data. Here, we show that the underlying structure of the E. coli transcriptome, as determined by Independent Component Analysis (ICA), is conserved across multiple independent datasets, including both RNA-seq and microarray datasets. We subsequently combined five transcriptomics datasets into a large compendium containing over 800 expression profiles and discovered that its underlying ICA-based structure was still comparable to that of the individual datasets. With this understanding, we expanded our analysis to over 3,000 E. coli expression profiles and predicted three high-impact regulons that respond to oxidative stress, anaerobiosis, and antibiotic treatment. ICA thus enables deep analysis of disparate data to uncover new insights that were not visible in the individual datasets.