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Background. The cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC. Methods. Data were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men. Results. A total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P

Abstract Aims The application of indices in the context of metabolic dysfunction‐associated steatotic liver disease (MASLD) remains unexplored. We aimed to validate the ability of alanine aminotransferase (ALT), fatty liver index (FLI), and hepatic steatosis index (HSI) to identify MASLD during health checkups. Methods We recruited 627 participants and utilized their health checkup data and ultrasound to assess the potential of using ALT, FLI, and HSI as indices for MASLD; this was indicated by the area under the curve (AUC) and restricted cubic spline (RCS) model. The optimal, rule‐out (sensitivity ≥90%), and rule‐in (specificity ≥90%) cutoff values of each index for identifying MASLD were reported. Results Among participants with a median age of 46 years, the prevalence of MASLD was 28% in total (38% in males and 18% in females). RCS models confirmed a linear association between indices and MASLD. ROC analyses indicated that the AUC of ALT in identifying MASLD was 0.79 for the total cohort, 0.81 for males, and 0.69 for females. The optimal, rule‐out, and rule‐in cutoff values for ALT were 21, 13, and 29, respectively. Similarly, the AUC of FLI/HSI in identifying MASLD was 0.90/0.88 for the total cohort, 0.86/0.85 for males, and 0.93/0.90 for females. Considering the reference cutoff values, distinct cutoff values were observed between the sexes for FLI, while HSI had similar cutoff values. Conclusion This study demonstrated that ALT > 30 IU/L is a reasonable cutoff value to rule‐in MASLD. ALT, FLI, and HSI are reliable indices for identifying MASLD during health checkups.

Background: Interrelationship of arterial stiffness with diastolic impairments of left ventricle (LV) in healthy population has been reported in several studies; however, to the best of our knowledge, no study till date has evaluated the relationship of aortic stiffness, with LV diastolic, systolic, and strain components, in healthy adults, by conventional, tissue Doppler imaging, and speckle-tracking echocardiography. Materials and Methods: Fifty-eight healthy participants were recruited (38 males and 20 females), and their mean age was 30.53 ± 12.22 years and 35.25 ± 10.61 years, respectively. A detailed assessment of aortic stiffness and elasticity, LV systolic, diastolic, and strain parameters was performed by the ingenious technology of four-dimensional XStrain echocardiography. Moreover, Pearson's correlation coefficient was employed to investigate the association of aortic stiffness with LV diastolic, systolic, and strain functions. Results: A significant relationship was documented between aortic stiffness and a number of parameters of LV diastolic and systolic functions. On the contrary, there was an insignificant trend of positive or negative correlation of aortic stiffness with LV strain. Conclusion: This is the first study to document the correlation between aortic stiffness and various LV functions in healthy adults.

Background/Aims Non-alcoholic fatty liver disease (NAFLD) is associated with the development of cardiovascular disease. While existing studies have examined cardiac remodeling in NAFLD, there has been less emphasis on the development of carotid atherosclerosis and stroke. We sought to conduct a meta-analysis to quantify the prevalence, risk factors, and degree of risk increment of carotid atherosclerosis and stroke in NAFLD. Methods Embase and Medline were searched for articles relating to NAFLD, carotid atherosclerosis, and stroke. Proportional data was analysed using a generalized linear mixed model. Pairwise meta-analysis was conducted to obtain odds ratio or weighted mean difference for comparison between patients with and without NAFLD. Results From pooled analysis of 30 studies involving 7,951 patients with NAFLD, 35.02% (95% confidence interval [CI], 27.36–43.53%) had carotid atherosclerosis with an odds ratio of 3.20 (95% CI, 2.37–4.32; P

Background/Aims Nonalcoholic fatty liver disease (NAFLD) is closely associated with diabetes. The cumulative impact of both diseases synergistically increases risk of adverse events. However, present population analysis is predominantly conducted with reference to non-NAFLD individuals and has not yet examined the impact of prediabetes. Hence, we sought to conduct a retrospective analysis on the impact of diabetic status in NAFLD patients, referencing non-diabetic NAFLD individuals. Methods Data from the National Health and Nutrition Examination Survey 1999–2018 was used. Hepatic steatosis was defined with United States Fatty Liver Index (US-FLI) and FLI at a cut-off of 30 and 60 respectively, in absence of substantial alcohol use. A multivariate generalized linear model was used for risk ratios of binary outcomes while survival analysis was conducted with Cox regression and Fine Gray model for competing risk. Results Of 32,234 patients, 28.92% were identified to have NAFLD. 36.04%, 38.32% and 25.63% were non-diabetic, prediabetic and diabetic respectively. Diabetic NAFLD significantly increased risk of cardiovascular disease (CVD), stroke, chronic kidney disease, all-cause and CVD mortality compared to non-diabetic NAFLD. However, prediabetic NAFLD only significantly increased the risk of CVD and did not result in a higher risk of mortality. Conclusions Given the increased risk of adverse outcomes, this study highlights the importance of regular diabetes screening in NAFLD and adoption of prompt lifestyle modifications to reduce disease progression. Facing high cardiovascular burden, prediabetic and diabetic NAFLD individuals can benefit from early cardiovascular referrals to reduce risk of CVD events and mortality.

In this study, we investigate differential and integral equations of some hybrid families of truncated exponential-based Sheffer polynomials. We also derive some integro-differential equation and new recurrence relations for the truncated exponential based Sheffer polynomials by using the factorization method. We also discuss some special cases as illustrative examples.

Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis.

Background and aims: With existing literature focusing on general quality of life, the magnitude and impact of depression among recipients after liver transplantation (LT) is unclear. Hence, we aim to evaluate the prevalence, risk factors, and outcomes for recipient-related depression after LT. Methods: Medline and Embase were searched. Single-arm analysis was pooled using the generalized linear mixed model, and logistic regression was performed to analyze risk factors. Pairwise comparative meta-analysis in odds ratio was conducted for binary outcomes. Results: Of 1069 abstracts, 189 articles underwent full-text review before the inclusion of 48 articles. Pooled depression rate among 5170 recipients was 24.52% (confidence interval [CI]: 19.46%–30.41%). Depression was most prevalent in Asia compared with other geographical regions. Younger age at transplantation (P = .019) and university education (P = .051) were protective against depression. However, those transplanted for alcoholic liver disease (odds ratio: 1.14, CI: 1.10–1.18, P ≤ 0.001) were more likely to be depressed. Depression resulted in increased odds of mortality (odds ratio: 1.82, CI: 1.08–3.07, P = .04), graft loss (P = .03), and graft rejection (P = .01). Conclusion: Depression is highly prevalent after LT and may be associated with increased mortality and poorer graft outcomes. More emphasis is needed on the screening of depression among higher risk recipients.

ABSTRACT: Introduction and Objectives: Type 2 Diabetes Mellitus (T2DM) is comorbidity commonly presenting with fatty liver. A recently proposed definition of ''metabolic associated fatty liver disease'' (MAFLD) is thought to replace non-alcoholic fatty liver disease (NAFLD). Yet, despite the significant prevalence of T2DM among fatty liver, there remains limited evidence on the impact of the change in the definition of T2DM. Materials and Methods: The current study uses data from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Survival analysis was conducted with a cox regression and sub-distribution hazard ratio for competing risk events. Results: 6727 patients had a diagnosis of T2DM. 4982 individuals with T2DM had MAFLD and 2032 were MAFLD(+)/NAFLD(-), while 2950 patients were MAFLD(+)/NAFLD(+). The new definition increased fatty liver diagnosis by 68.89%. Patients who were classified as MAFLD(+)/NAFLD(-) were at a higher risk of major adverse cardiovascular events, advanced fibrosis, all-cause and cardiovascular-related mortality compared to MAFLD(+)/NAFLD(+). In MAFLD(+)/NAFLD(-), viral hepatitis significantly increases the odds of advanced fibrosis (OR: 6.77, CI: 3.92 to 11.7, p

Summary: Background: There is a growing number of trials examining the effectiveness of pharmacotherapies for obesity, however, little is known about placebo and nocebo effect in these trials. Hence, we sought to examine the effect of placebo in obesity trials, to better understand the potential factors affecting clinical endpoints in them. Methods: Medline, Embase, and Cochrane CENTRAL were searched for articles examining weight-loss RCTs examining patients with overweight or obesity in placebo-controlled arms from inception till 25 June 2022. This paper was registered online with PROSPERO (CRD42022302482). A single arm meta-analysis of proportions was used to estimate the primary outcomes, ≥5%, ≥10%, and ≥15% total weight loss – and the adverse effects that patients experienced during the trial. A meta-analysis of means was used to estimate the pooled mean differences of the secondary outcomes including, body weight measurements, lipid levels, glycemic indices, and blood pressure over time. Findings: A total of 63 papers involving 20,454 patients and 69 trials were included. The proportion of patients that had ≥5%, ≥10%, and ≥15% weight loss was 20·4% (CI:16·1% to 25·0%), 8·3% (CI:6·1% to 10·9%), and 6·2% (CI:3·8% to 9·7%), respectively. Analysis by duration of trials showed stepwise increase in proportion of patients with ≥5% and ≥10% weight loss with increasing duration of study. Analysis of secondary outcomes found modest improvement in all analyses. The pooled average rate of overall AEs, serious AEs, and discontinuation was 73·7% (CI:68·0% to 79·0%), 3·4% (CI:2·4% to 4·5%), and 5·2% (CI:4·0% to 6·5%), respectively. In psychiatric complications, the pooled rates of anxiety and depression were 2·7% (CI:1·8% to 3·7%) and 2·5 (CI:1·7% to 3·3%). Interpretation: Our meta-analysis of placebo-treated participants in weight-loss RCTs indicate a significant placebo and nocebo effect. These findings are important to quantify their effect and may inform the design of future RCTs. Funding: This research did not receive additional support from organizations beyond the authors’ academic institutions.

Background and aimsThe global prevalence of non-alcoholic fatty liver disease (NAFLD) is expected to rise continuously. Furthermore, emerging evidence has also shown the potential for concomitant depression in NAFLD. This study aims to examine the prevalence, risk factors, and adverse events of depression in NAFLD and evaluate whether treated depression can reverse the increased risks of adverse outcomes.Materials and methodsThis study analyses the 2000–2018 cycles of NHANES that examined liver steatosis with fatty liver index (FLI). The relationship between NAFLD and depression was assessed with a generalized linear mix model and a sensitivity analysis was conducted in the no depression, treated depression, and untreated depression groups. Survival analysis was conducted with cox regression and fine gray sub-distribution model.ResultsA total of 21,414 patients were included and 6,726 were diagnosed with NAFLD. The risk of depression in NAFLD was 12% higher compared to non-NAFLD individuals (RR: 1.12, CI: 1.00–1.26, p = 0.04). NAFLD individuals with depression were more likely to be older, females, Hispanics or Caucasians, diabetic, and have higher BMI. Individuals with depression have high risk for cardiovascular diseases (CVD) (RR: 1.40, CI: 1.25–1.58, p < 0.01), stroke (RR: 1.71, CI: 1.27–2.23, p < 0.01), all-cause mortality (HR: 1.50, CI: 1.25–1.81, p < 0.01), and cancer-related mortality (SHR: 1.43, CI: 1.14–1.80, p = 0.002) compared to NAFLD individuals without depression. The risk of CVD, stroke, all-cause mortality, and cancer-related mortality in NAFLD individuals with treated depression and depression with untreated treatment was higher compared to individuals without depression.ConclusionThis study shows that concomitant depression in NAFLD patients can increase the risk of adverse outcomes. Early screening of depression in high-risk individuals should be encouraged to improve the wellbeing of NAFLD patients.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is prevalent amongst overweight and obese individuals, and weight loss remains the main mode of treatment for NAFLD patients. Weight perception plays a key role in the efficacy of such treatment. The current study aims to investigate the prevalence, associating factors and implications of poor weight perception amongst such individuals.MethodsAn analysis was done on data collected from NHANES between 1999 and 2018. Comparison was made between NAFLD individuals with and without poor weight perception in terms of prevalence, associated characteristics, and clinical outcomes. Multivariate analysis was used to compare effect size of adverse events associated with NAFLD individuals with poor weight perception.ResultsOf the 12,170 NAFLD patients, 19.2% (CI: 18.5 to 19.9%) had poor weight perception. Poor weight perception was significantly associated with lower education levels, reduced levels of exercise and unhealthier lipid profiles. There was an increased risk in all-cause mortality (HR: 1.18, CI: 1.00 to 1.38, p = 0.047), cardiovascular disease mortality (SHR: 1.33, CI: 1.03 to 1.71, p = 0.026), major adverse cardiovascular events (OR: 1.21 CI: 1.10 to 1.32, p < 0.001), and advanced fibrosis (OR: 1.30, CI: 1.03 to 1.64, p = 0.025) for individuals with poor weight perception.ConclusionThis study highlights the positive association between appropriate weight perception and better outcomes in individuals with NAFLD. Poor weight perception increased the risk of adverse events and decreased inclination toward seeking weight loss treatment. Greater emphasis should be placed on dealing with weight perception in individuals with NAFLD for better treatment outcomes.

Background and aimsHypertension (HTN) is a common comorbidity in non-alcoholic fatty liver disease (NAFLD) affecting up to 40% of individuals. However, the impact of HTN and its control on outcomes in NAFLD remains unclear. Therefore, we aimed to examine the impact of HTN on survival outcomes in a longitudinal cohort of NAFLD patients.MethodsThe analysis consisted of adults in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 with data on socio-demographic characteristics and comorbidities. NAFLD was diagnosed with fatty liver index (FLI) and United States-FLI at a cut-off of 60 and 30, respectively in the substantial absence of alcohol use. A multivariate regression analysis was conducted to adjust for confounders.ResultsA total of 45,302 adults were included, and 27.83% were identified to have NAFLD. Overall, 45.65 and 35.12% of patients with NAFLD had HTN and uncontrolled HTN, respectively. A multivariate analysis with confounders demonstrated that hypertensive NAFLD had a significantly increased risk of all-cause mortality (HR: 1.39, CI: 1.14–1.68, p < 0.01) and cardiovascular disease (CVD) mortality (HR: 1.85, CI: 1.06–3.21, p = 0.03). Untreated HTN remained to have a significantly increased risk in all-cause (HR: 1.59, CI: 1.28–1.96, p < 0.01) and CVD mortality (HR: 2.36, CI: 1.36–4.10, p < 0.01) while treated HTN had a non-significant increased risk of CVD mortality (HR: 1.51, CI: 0.87–2.63, p = 0.14) and a lower magnitude of increase in the risk of all-cause mortality (HR: 1.26, CI: 1.03–1.55, p = 0.03).ConclusionDespite the significant burden of HTN in NAFLD, up to a fifth of patients have adequate control, and the lack thereof significantly increases the mortality risk. With the significant association of HTN in NAFLD, patients with NAFLD should be managed with a multidisciplinary team to improve longitudinal outcomes.

Patients undergoing liver transplant (LTX) typically confront a challenging postoperative journey. A dysbiotic gut microbiome is associated with the development of complications, including post-LTX allograft rejection, metabolic diseases and de novo or recurrent cancer. A major explanation of this are the bipartite interactions between the gut microbiota and host immunity, which modulates the alloimmune response towards the liver allograft. Furthermore, bacterial translocation from dysbiosis causes pathogenic changes in the concentrations of microbial metabolites like lipopolysaccharides, short-chain fatty acids (SCFAs) and Trimethylamine-N-Oxide, with links to cardiovascular disease development and diabetes mellitus. Gut dysbiosis also disrupts bile acid metabolism, with implications for various post-LTX metabolic diseases. Certain taxonomy of microbiota such as lactobacilli, F.prausnitzii and Bacteroides appear to be associated with these undesired outcomes. As such, an interesting but as yet unproven hypothesis exists as to whether induction of a “beneficial” composition of gut microbiota may improve prognosis in LTX patients. Additionally, there are roles of the microbiome as predictive and prognostic indicators for clinicians in improving patient care. Hence, the gut microbiome represents an exceptionally exciting avenue for developing novel prognostic, predictive and therapeutic applications.

Objectives & backgroundAnonymous live organ donors or unspecified donors are individuals willing to be organ donors for any transplant recipient with whom they have no biological or antecedent emotional relationship. Despite excellent recipient outcomes and the potential to help address organ scarcity, controversy surrounds the unconditional act of gifting one's organs to an unrelated recipient. This qualitative systematic review provides insights into the first-hand experiences, motivations, and challenges that unspecified donors face.MethodsA systematic search was conducted on Medline, Embase, CINAHL, PsycINFO, and Web of Science database for qualitative literature regarding unspecified living donors' motivations and experiences in liver and kidney transplantation. An inductive thematic analysis was conducted to generate themes and supportive subthemes.Results12 studies were included. The four major themes were (i) motivations, (ii) perception of risks, (iii) donor support, and (iv) benefits of donation. Unspecified donors demonstrated a deep sense of social responsibility but tended to underestimate health risks in favour of benefits for recipients. Despite the lack of emotional support from family and friends, the decision to donate was a resolute personal decision for donors. Majority benefitted emotionally and did not express regret.ConclusionThis qualitative review bridges the gap in literature on unspecified living donor psychology and provides a comprehensive understanding of the decision-making matrix and experiences of donors.

High-density polyethylene (HDPE) is widely used for above-ground storage tanks (ASTs). However, there are currently no guidelines for the non-destructive testing (NDT) and evaluation (NDE) of HDPE ASTs. Moreover, the feasibility, limitations, and challenges of using NDT techniques for the field inspection of HDPE ASTs have not been well established. This study used both infrared thermography (IRT) and ultrasonic testing (UT) for the field inspection of HDPE ASTs. Highlighting the implementation challenges in the field, this study determined that: (1) ambient environmental parameters can affect IRT accuracy; (2) there is an ideal time during the day to perform IRT; (3) the heating source and infrared camera orientation can affect IRT accuracy; and (4) with proper measures taken, IRT is a promising method for flaw detection in HDPE ASTs. Additionally, UT can be used following IRT for detailed investigation to quantify the size and depth of defects. The manuscript concludes with a discussion of the limitations and best practices for the implementing of IRT and UT for HDPE AST inspections in the field.

Abstract Background Seeds of plants are a confirmation of their next generation and come associated with a unique microbia community. Vertical transmission of this microbiota signifies the importance of these organisms for a healthy seedling and thus a healthier next generation for both symbionts. Seed endophytic bacterial community composition is guided by plant genotype and many environmental factors. In north-east India, within a narrow geographical region, several indigenous rice genotypes are cultivated across broad agroecosystems having standing water in fields ranging from 0-2 m during their peak growth stage. Here we tried to trap the effect of rice genotypes and agroecosystems where they are cultivated on the rice seed microbiota. We used culturable and metagenomics approaches to explore the seed endophytic bacterial diversity of seven rice genotypes (8 replicate hills) grown across three agroecosystems. Results From seven growth media, 16 different species of culturable EB were isolated. A predictive metabolic pathway analysis of the EB showed the presence of many plant growth promoting traits such as siroheme synthesis, nitrate reduction, phosphate acquisition, etc. Vitamin B12 biosynthesis restricted to bacteria and archaea; pathways were also detected in the EB of two landraces. Analysis of 522,134 filtered metagenomic sequencing reads obtained from seed samples (n=56) gave 4061 OTUs. Alpha diversity indices showed significant differences in observed OTU richness (P≤0.05) across genotypes. Significant differences were also found between the individual hills of a rice genotype. PCoA analysis exhibited three separate clusters and revealed the clusters separated based on genotype, while agroecosystem showed a minimal effect on the variation of seed microbiota (adonis, R 2=0.07, P=0.024). Interestingly, animal gut resident bacteria such as Bifidobacterium, Faecalibacterium, Lactobacillus, etc. were found in abundance as members of the seed microbiota. Conclusion Overall, our study demonstrates, indigenous rice genotypes of north-east India have a unique blend of endophytic bacteria in their mature seeds. While there are notable variations among plants of the same genotype, we found similarities among genotypes cultivated in completely different environmental conditions. The beta diversity variations across the seven rice genotypes were significantly shaped by their genotype rather than their agroecosystems.

In this article, we study multiplicative (generalized)-skew derivation G and multiplicative left centralizer H satisfying certain conditions in semiprime rings. Moreover, some examples are given to demonstrate that the semiprimeness imposed on the hypotheses of various theorems is essential.

This article has a motive to derive a new class of differential equations and associated integral equations for some hybrid families of Laguerre–Gould–Hopper-based Sheffer polynomials. We derive recurrence relations, differential equation, integro-differential equation, and integral equation for the Laguerre–Gould–Hopper-based Sheffer polynomials by using the factorization method.

Immunosuppression is a characteristic feature of chronic leishmaniasis. The dynamicity and the functional cross talks of host immune responses during Leishmania infection are still not clearly understood. Here we explored the functional aspects of accumulation of immune suppressive cellular and cytokine milieu during the progression of murine visceral leishmaniasis. In addition to IL-10 and TGF-β, investigation on the responses of different subunit chains of IL-12 family revealed a progressive elevation of EBI-3 and p35 chains of IL-35 with Leishmania donovani infection in BALB/c mice. The expansion of CD25 and FoxP3 positive T cells is associated with loss of IFN-γ and TNF-α response in advanced disease. Ex-vivo and in vivo neutralization of TGF-β and EBI-3 suggests a synergism in suppression of host anti-leishmanial immunity. The down-regulation of EBI-3 and TGF-β is crucial for re-activation of JAK-STAT pathway for induction as well as restoration of protective immunity against L. donovani infection.

Host- as well as parasite-specific factors are equally crucial in allowing either the Leishmania parasites to dominate, or host macrophages to resist infection. To identify such factors, we infected murine peritoneal macrophages with either the virulent (vAG83) or the non-virulent (nvAG83) parasites of L. donovani. Then, through dual RNA-seq, we simultaneously elucidated the transcriptomic changes occurring both in the host and the parasites. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the differentially expressed (DE) genes, we showed that the vAG83-infected macrophages exhibit biased anti-inflammatory responses compared to the macrophages infected with the nvAG83. Moreover, the vAG83-infected macrophages displayed suppression of many important cellular processes, including protein synthesis. Further, through protein-protein interaction study, we showed significant downregulation in the expression of many hubs and hub-bottleneck genes in macrophages infected with vAG83 as compared to nvAG83. Cell signaling study showed that these two parasites activated the MAPK and PI3K-AKT signaling pathways differentially in the host cells. Through gene ontology analyses of the parasite-specific genes, we discovered that the genes for virulent factors and parasite survival were significantly upregulated in the intracellular amastigotes of vAG83. In contrast, genes involved in the immune stimulations, and those involved in negative regulation of the cell cycle and transcriptional regulation, were upregulated in the nvAG83. Collectively, these results depicted a differential regulation in the host and the parasite-specific molecules during in vitro persistence and clearance of the parasites.

Leishmania donovani possesses a complex heteroxenic life cycle where infective metacyclic promastigotes are pre-adapted to infect their host and cope up with intracellular stress. Exploiting the similarities between cultured and sandfly derived promastigotes, we used early and late passage cultured promastigotes to show specific changes at genome level which compromise pathogen fitness reflected in gene expression and infection studies. The pathogen loses virulence mostly via transcriptional and translational regulations and long-time cultivation makes them struggle to convert to virulent metacyclics. At the genomic level very subtle plasticity was observed between the early and the late passages mostly in defense-related, nutrient acquisition and signal transduction genes. Chromosome Copy number variation is seen in the early and late passages involving several genes that may be playing a role in pathogenicity. Our study highlights the importance of ABC transporters and calpain like cysteine proteases in parasite virulence in cultured promastigotes. Interestingly, these proteins are emerging as important patho-adaptive factors in clinical isolates of Leishmania. We found that the currently available genome of Leishmania in the NCBI database are from late passages. Our early passage genome can act as a reference for future studies on virulent isolates of Leishmania. The annotated leads from this study can be used for virulence surveillance and therapeutic studies in the Indian subcontinent.

This paper presents a FACTS operation scheme to enhance the power system security. Three main generic types of FACTS devices are introduced. Line overloads are solved by controlling active power of series compensators and low voltages are solved by controlling reactive power of shunt compensators, respectively. Especially, the combined series-shunt compensators such as UPFC are applied to solve both line congestions and low voltages simultaneously. Two kinds of indices that indicate the security level related to line flow and bus voltage is utilized in this paper. They are iteratively minimized to determine operating points of the devices for security enhancement. The sensitivity vectors of the indices are derived to determine the direction of minimum. The proposed algorithm is verified on the IEEE 14-bus system with FACTS devices in a normal condition and in a line-faulted contingency.

BackgroundThe cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC.MethodsData were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men.ResultsA total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P

This paper presents simulation and analysis of a grid connected multi-level converter topologies. In this paper, converter circuit works as an inverter by controlling the switching angle (α). This paper, presents a MATLAB/SIMULINK model of multi-level converter topologies (topology1 & topology2). Topology1 is without transformer while topology2 with transformer. Both the topologies are simulated and analyzed for three level converters in order to reduce the total harmonic distortion (THD). A comparative study of topology1 and topology2 is also presented in this paper for different switching angles (α) and battery voltages. The results have been tabulated and discussed.

Non-melanoma skin cancer is one of the major ailments in the United States. Effective drugs that can cure skin cancers are limited. Moreover, the available drugs have toxic side effects. Therefore, skin cancer drugs with less toxic side effects are urgently needed. To achieve this goal, we focused our work on identifying potent lead compounds from marine natural products. Five lead compounds identified from a class of pyrroloiminoquinone natural products were evaluated for their ability to selectively kill squamous cell carcinoma (SCC13) skin cancer cells using an MTT assay. The toxicity of these compounds was also evaluated against the normal human keratinocyte HaCaT cell line. The most potent compound identified from these studies, C278 was further evaluated for its ability to inhibit cancer cell migration and invasion using a wound-healing assay and a trans-well migration assay, respectively. To investigate the molecular mechanism of cell death, the expression of apoptotic and autophagy proteins was studied in C278 treated cells compared to untreated cells using western blot. Our results showed that all five compounds effectively killed the SCC13 cells, with compound C278 being the most effective. Compound C278 was more effective in killing the SCC13 cells compared to HaCaT cells with a two-fold selectivity. The migration and the invasion of the SCC13 cells were also inhibited upon treatment with compound C278. The expression of pro-apoptotic and autophagy proteins with concomitant downregulation in the expression of survival proteins were observed in C278 treated cells. In summary, the marine natural product analog compound C278 showed promising anticancer activity against human skin cancer cells and holds potential to be developed as an effective anticancer agent to combat skin cancer.

IntroductionIn the absence of an effective treatment for non-alcoholic steatohepatitis (NASH), a randomized, placebo-controlled trial (RCT) remains the current gold standard study design in NASH. As NASH is a largely asymptomatic disease, the side effects of potential therapies require careful evaluation, therefore a pooled rate of the adverse events (AEs) in placebo-treated patients serves as a useful comparator for safety. Therefore, we performed a systematic review and meta-analysis to estimate the rate of AEs among participants in the placebo arm of NASH RCTs.MethodsMedline, Embase and Cochrane Central Register of Controlled Trials were searched to include clinical trials in phase 2-4 NASH RCTs with placebo treatment arms. A pooled proportions of AEs were analyzed using a generalized linear mixed model with Clopper-Pearson intervals.ResultsA total of 41 RCTs (2,944 participants on placebo) were included in this meta-analysis. A total of 68% (confidence interval [CI] 55%-77%) of participants on placebo experienced an AE, 7.8% (5.7%-10%) experienced serious AEs and 3.1% (CI: 1.9%-5.1%) experienced AEs leading to discontinuation. A significantly higher proportion of participants experienced serious AEs in phase 3 studies compared to in phase 2 studies ( P < 0.01) and in pharmaceutical funded studies as compared to studies which were federal-funded studies ( P < 0.01). An analysis of clinical trials evaluating bile acid modulating agents determined that 10% (CI: 5.5%-18%) of participants receiving placebo developed pruritus.DiscussionThe present study summarizes the AEs with NASH placebo. Among participants in the placebo arm in NASH, two-third experienced an AE, and nearly 10% experienced a serious AE.

Background: Sewage workers, because of their occupation, are exposed to different types of dusts, bio-aerosols, fumes and gases like methane, hydrogen sulfide, sulphur dioxide, etc, which contribute towards oxidative stress and detrimental effects on various body functions, especially lung functions. Aims and Objectives: This study was carried out on sewage workers (who had been working for more than five years). We wanted to study the role of oxidative stress in development of impaired lung functions among sewage workers. Materials and Methods: This cross sectional study was done in a tertiary care hospital (J.N. Medical College) in Aligarh, U.P. Study was done from March 2008 to December 2009. The study group comprised of 62 sewage workers who had been working for more than five years (32 non-smokers and 30 smokers) and 60 control subjects (30 smokers and 30 non-smokers). The pulmonary functions of these workers were assessed by using a MIR (Medical International Lab) Spiro Lab II Spirometer, with subjects in sitting position. Valid written consents were obtained from all the subjects. Malondialdehyde (MDA) is produced as a result of the action of reactive oxygen species (ROS) on the lipids present in the membranes of the cells, especially, contracting muscle cells. Serum MDA levels were assessed as an indirect measure of oxidative stress in these sewage workers and they were compared with serum MDA levels of control subjects. Appropriate statistical tests were applied for analysis of the data which was generated. Observation and Results: There were statistically significant decreases in Peak Expiratory Flow Rate (PEFR), Forced Expiratory Volume in first second (FEV1) and FEV1/FVC percent ratio (

BackgroundThe clinical presentation and outcomes of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma are unclear when compared with hepatocellular carcinoma due to other causes. We aimed to establish the prevalence, clinical features, surveillance rates, treatment allocation, and outcomes of NAFLD-related hepatocellular carcinoma.MethodsIn this systematic review and meta-analysis, we searched MEDLINE and Embase from inception until Jan 17, 2022, for articles in English that compared clinical features, and outcomes of NAFLD-related hepatocellular carcinoma versus hepatocellular carcinoma due to other causes. We included cross-sectional and longitudinal observational studies and excluded paediatric studies. Study-level data were extracted from the published reports. The primary outcomes were (1) the proportion of hepatocellular carcinoma secondary to NAFLD, (2) comparison of patient and tumour characteristics of NAFLD-related hepatocellular carcinoma versus other causes, and (3) comparison of surveillance, treatment allocation, and overall and disease-free survival outcomes of NAFLD-related versus non-NAFLD-related hepatocellular carcinoma. We analysed proportional data using a generalised linear mixed model. Pairwise meta-analysis was done to obtain odds ratio (OR) or mean difference, comparing NAFLD-related with non-NAFLD-related hepatocellular carcinoma. We evaluated survival outcomes using pooled analysis of hazard ratios.FindingsOf 3631 records identified, 61 studies (done between January, 1980, and May, 2021; 94 636 patients) met inclusion criteria. Overall, the proportion of hepatocellular carcinoma cases secondary to NAFLD was 15·1% (95% CI 11·9-18·9). Patients with NAFLD-related hepatocellular carcinoma were older (p75%), and all articles had low-to-moderate risk of bias.InterpretationNAFLD-related hepatocellular carcinoma is associated with a higher proportion of patients without cirrhosis and lower surveillance rates than hepatocellular carcinoma due to other causes. Surveillance strategies should be developed for patients with NAFLD without cirrhosis who are at high risk of developing hepatocellular carcinoma.FundingNone.