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Hepatic venous pressure gradient (HVPG) of ≥10 mm Hg predicts clinical decompensation (CD) in compensated cirrhosis. A proportion of cirrhotic patients at presentation have high HVPG (≥20 mm Hg) and are compensated. The natural history, spectrum of CD, and mortality in this group is largely unknown. Consecutive compensated cirrhotic patients with HVPG ≥6 mm Hg (n = 741) were followed up for 3-6 months for the development of any CD. Patients were classified based on the baseline HVPG (6 to <12 mm Hg [low HVPG, Gr.A, n = 163], 12 to <20 mm Hg [intermediate HVPG, Gr.B, n = 437] and ≥20 mm Hg [high HVPG, Gr.C, n = 141]). We analyzed the predictors of first CD, HVPG response to carvedilol, and mortality in these groups. CD developed in 217 (29.3%) patients during a mean follow-up of 1.6 ± 0.4 years, and those who developed CD had higher baseline HVPG (17.02 ± 4.79 vs 14.28 ± 4.86; P < 0.001). First CD was seen earlier (1.3 ± 0.7 years vs 1.5 ± 0.6 years and 1.6 ± 0.5 years, P = 0.02) and more frequently (44.7% vs 11% and 31.1%, P < 0.01) in high HVPG groups compared with low and intermediate HVPG groups, with higher mortality rates. Patients in the high HVPG group compared with the low HVPG group more often had NASH-cirrhosis (35.5% vs 19.6%; P 0.001), higher liver stiffness values (45.06 ± 20.46 vs 20.09 ± 5.47 kPa, P < 0.001), and lower platelet counts (113.37 ± 72.57 vs 151.7 ± 87.30/cmm, P < 0.001). Patients with HVPG ≥12 mm Hg received carvedilol, and a repeat HVPG performed in a proportion after 9.3 ± 2.4 months showed response (≥20% reduction in HVPG or <12 mm Hg) in 31.6% patients (Gr. B, 44.9% > Gr. C, 22.2%, P < 0.05). Baseline HVPG (HVPG ≥12 to <20 mm Hg [Hazard ratio: 2.73] and HVPG ≥20 mm Hg [Hazard ratio: 4.48], P < 0.001) independently predicted CD. HVPG ≥20 mm Hg in patients with compensated cirrhosis independently predicts early and more frequent CD and poor outcomes. These patients should be labeled as \"high-risk compensated cirrhosis,\" and early and effective interventions to reduce portal pressure should be initiated to improve long-term outcomes.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern, yet awareness remains low. This study aimed to assess MASLD awareness and identify predictors of liver testing behavior in Jaipur, India. A cross-sectional survey of 2,102 adults was conducted from October 2023 to March 2024. Participants completed a questionnaire assessing liver health knowledge, awareness, and testing history. Logistic regression analyzed predictors of liver testing. Only 5.9% of participants had heard of fatty liver disease, with 94.0% completely unaware. Knowledge of liver functions was extremely low, with only 14.9% recognizing food digestion as a liver function. The liver testing rate was 1.8% overall. Education emerged as the strongest predictor of testing behavior, with graduates and above 8.35 times more likely to be tested than non-graduates (OR=8.35, 95% CI: 3.80-18.37, p < 0.001). Participants with higher liver function knowledge had dramatically higher testing rates of 12.9% versus 1.2% for those with low knowledge (OR=9.35, 95% CI: 4.2-20.8, p < 0.001). Employment status also significantly predicted testing (OR=5.42, 95% CI: 2.8-10.5, p < 0.001). This study reveals a catastrophic knowledge deficit regarding MASLD, with 94% of participants completely unaware of the condition. The strong association between education, knowledge, and testing behavior highlights a critical knowledge-to-action pathway. The extremely low overall testing rate (1.8%) indicates massive underutilization of liver health screening, particularly among unemployed and less educated individuals. These findings underscore the urgent need for comprehensive public health education on liver health, especially given India's rising MASLD prevalence and young demographic profile. Targeted interventions to improve awareness and facilitate testing access among socioeconomically disadvantaged groups are essential to address this public health crisis.

Introduction Eliminating Hepatitis B by 2030 is achievable through vaccination. However, despite the safety of the Hepatitis B vaccine, vaccination coverage among adults in India is suboptimal. Methods From April 2021 to August 2022, a study in New Delhi, India assessed Hepatitis B vaccination status, willingness to be vaccinated, and awareness of vaccination importance among adults. Results 7,097 participants (mean age  ±  SD = 43.3  ±  14 years; range = 18–99 years) were screened. 93.3% of participants reported not receiving even a single dose of the Hepatitis B vaccine. Only 4.4% of the participants were completely vaccinated for Hepatitis B. On Binomial Logistic Regression, we found that as the age increase [Exp(b) = 4.09; 95% CI = 2.061–8.148; p  < 0.001], females [Exp(b) = 1.327; 95% CI = 1.056–1.667; p  = 0.015], married [Exp(b) = 5.891; 95% CI = 4.610–7.528; p  < 0.001], illiterate [Exp(b) = 30.085; 95% CI = 13.307–68.020; p  < 0.001], employed [Exp(b) = 1.966; 95% CI = 1.471–2.629; p  < 0.001], Muslim population [Exp(b) = 3.031; 95% CI = 1.552–5.917; p  = 0.001], monthly salary < 10,000 INR [Exp(b) = 9.580; 95% CI = 6.172–14.872; p  < 0.001] are significantly less likely to have completed Hepatitis B vaccination. Most respondents (85.5%) were willing to receive Hepatitis B vaccination, whereas only 25% knew that Hepatitis B vaccination was an effective way to prevent and control Hepatitis B. Conclusion Targeted policies and programs are needed to improve low vaccination rates among older adults in India. The Advisory Committee on Immunization Practices recommends Universal Adult Hepatitis B vaccination, which can eliminate the need for risk factor screening, increase vaccination coverage, and reduce Hepatitis B cases.

Background Viral hepatitis, particularly B and C, is a major cause of liver cirrhosis and cancer, leading to about 1.4 million deaths annually. Alarmingly, less than 20% of those with hepatitis are aware of their status, with only 6.3% receiving treatment. School children can play a pivotal role in raising awareness and preventing the spread of infections. This intervention study focuses on understanding and enhancing the knowledge, attitudes, and practices related to Hepatitis B and C, among school children in Delhi NCR to foster dialogue and awareness. Methods An intervention study was conducted in selected schools across Delhi NCR between September and October 2022 to assess baseline knowledge, attitudes, and practices related to Hepatitis B and C. Three of seven schools were randomly selected by probability sampling, representing 9–12 grade students, and 901 students participated. Following this, an educational interventional program was conducted using educational material, interactive sessions, and audiovisual aids. Post-intervention assessments were done to measure the impact on knowledge improvement. Results The study is expected to provide insights into the current level of awareness regarding Hepatitis B and C. Furthermore, the intervention’s effectiveness was analysed using the pre-formed questionnaire. The average pre-test knowledge score was 8.9 ± 3.2, while the post-test average was 15.6 ± 4.4, indicating a substantial increase of 6.7 ± 4.7 points (+ 75.2%). There was a positive correlation of 0.240 between pre and post-test scores. Attitude change before and after the session showed a positive percentage change of + 38.0% with a correlation of 0.351. The study indicated substantial improvements in knowledge about hepatitis B and C, notably regarding awareness about transmission methods and risk factors. Conclusion This interventional study seeks to bridge the knowledge gap among school children regarding Hepatitis B and C in Delhi NCR, fostering a proactive approach towards prevention, detection, and treatment. The considerable rise in awareness and favourable changes in perspectives post-intervention say that specific health education initiatives are pivotal in raising awareness and comprehension of infectious diseases, ultimately contributing to improving community health.

Corona virus disease 2019 (COVID-19) which initially started as a cluster of pneumonia cases in the Wuhan city of China has now become a full-blown pandemic. Timely diagnosis of COVID-19 is the key in containing the pandemic and breaking the chain of transmission. In low- and middle-income countries availability of testing kits has become the major bottleneck in testing. Novel methods like pooling of samples are the need of the hour. We undertook this study to evaluate a novel protocol of pooling of RNA samples/elutes in performance of PCR for SARS CoV-2 virus. Extracted RNA samples were randomly placed in pools of 8 on a 96 well plate. Both individual RNA (ID) and pooled RNA RT-qPCR for the screening E gene were done in the same plate and the positivity for the E gene was seen. The present study demonstrated that pool testing with RNA samples can easily detect even up to a single positive sample with Ct value as high as 38. The present study also showed that the results of pool testing is not affected by number of positive samples in a pool. Pooling of RNA samples can reduce the time and expense, and can help expand diagnostic capabilities, especially during constrained supply of reagents and PCR kits for the diagnosis of SARS-CoV-2 infection.

Beta-blockers are the mainstay agents for portal pressure reduction and to modestly reduce hepatic venous pressure gradient (HVPG). We studied whether addition of simvastatin to carvedilol in cirrhotic patients for primary prophylaxis improves the hemodynamic response. Cirrhotic patients with esophageal varices and with baseline HVPG > 12 mm Hg were prospectively randomized for primary prophylaxis to receive either carvedilol (group A, n = 110) or carvedilol plus simvastatin (group B, n = 110). Primary objective was to compare hemodynamic response (HVPG reduction of ≥20% or <12 mm Hg) at 3 months, and secondary objectives were to compare first bleed episodes, death, and adverse events. The groups were comparable at baseline. The proportion of patients achieving HVPG response at 3 months was comparable between groups (group A-36/62 [58.1%], group B-36/59 [61%], P = 0.85). The degree of mean HVPG reduction (17.3% and 17.8%, respectively, P = 0.98) and hemodynamic response (odds ratio [OR]: 0.88; 95% confidence interval [CI]: 0.43-1.83, P = 0.74) was also not different between the groups. Patients who achieved target heart rate with no hypotensive episodes in either group showed better hemodynamic response (77.8% vs 59.2%, P = 0.04). Failure to achieve target heart rate (OR: 0.48; 95% CI: 0.22-1.06) and Child C cirrhosis (OR: 4.49; 95% CI: 1.20-16.8) predicted nonresponse. Three (3.7%) patients on simvastatin developed transient transaminitis and elevated creatine phosphokinase and improved with drug withdrawal. Two patients in each group bled (P = 0.99). Three patients and 1 patient, respectively, in group A and B died (P = 0.32), with sepsis being the cause of death. Addition of simvastatin to carvedilol for 3 months for primary prophylaxis of variceal bleeding does not improve hemodynamic response over carvedilol monotherapy. Simvastatin usage should be closely monitored for adverse effects in Child C cirrhotic patients.

Severe alcoholic hepatitis (SAH) is associated with iron accumulation in hepatocytes/macrophages. This possibly correlates with inflammation and stress but the exact mechanism still remains obscure. To understand the role of iron and the mechanisms of systemic iron-overload, a transcriptomic study of liver and Peripheral Blood -Mononuclear-Cells (PBMCs) was undertaken in SAH patients, with and without hepatic iron-overload. Our results show that iron-overload in hepatocytes/macrophages is due to an increased expression of iron-loading receptors and CD163 signaling cascade. Increase in labile iron pool induces expression of iron-loading, oxidative-stress and inflammatory genes along with expression of CD163 and ADAM17. Increased liver iron correlated with circulatory iron, TNF-α, macrophage activation (sCD163) and peroxide-stress in CD163 + macrophages in patients who were iron-overloaded and died. Circulatory TNF-α and sCD163 levels were associated with poor outcome. Temporal iron/Fenton stress induced in healthy monocyte-derived-macrophage (MDM)/Tohoku-Hospital-Pediatrics-1(THP1) cells showed higher expression of iron-regulatory, inflammatory and oxidative-stress genes. These genes could be suppressed by iron-chelation. These results suggest that iron mediates inflammation through ADAM17 induction, resulting in macrophage activation and increased shedding of TNF-α and sCD163. These events could be inhibited with iron chelation or with ADAM17-blockade, postulating a therapeutic strategy for SAH patients with iron overload.

ObjectiveThe monocyte–macrophage system is central to the host’s innate immune defense and in resolving injury. It is reported to be dysfunctional in acute-on-chronic liver failure (ACLF). The disease-associated alterations in ACLF monocytes are not fully understood. We investigated the mechanism of monocytes’ functional exhaustion and the role of umbilical cord mesenchymal stem cells (ucMSCs) in re-energizing monocytes in ACLF.DesignMonocytes were isolated from the peripheral blood of ACLF patients ( n = 34) and matched healthy controls ( n = 7) and patients with compensated cirrhosis ( n = 7); phagocytic function, oxidative burst, and bioenergetics were analyzed. In the ACLF mouse model, ucMSCs were infused intravenously, and animals were sacrificed at 24 h and day 11 to assess changes in monocyte function, liver injury, and regeneration.ResultsPatients with ACLF (alcohol 64%) compared with healthy controls and those with compensated cirrhosis had an increased number of peripheral blood monocytes ( p < 0.0001) which displayed significant defects in phagocytic ( p < 0.0001) and oxidative burst capacity ( p < 0.0001). ACLF patients also showed a significant increase in the number of liver macrophages as compared with healthy controls ( p < 0.001). Bioenergetic analysis showed markedly reduced oxidative phosphorylation ( p < 0.0001) and glycolysis ( p < 0.001) in ACLF monocytes. Patients with monocytes having maximum mitochondrial respiration of <37.9 pmol/min [AUC = 0.822, hazard ratio (HR) = 4.5] and baseline glycolysis of ≤42.7 mpH/min (AUC = 0.901, HR = 9.1) showed increased 28-day mortality ( p < 0.001). Co-culturing ACLF monocytes with ucMSC showed improved mitochondrial respiration ( p < 0.01) and phagocytosis ( p < 0.0001). Furthermore, ucMSC therapy increased monocyte energy ( p < 0.01) and phagocytosis ( p < 0.001), reduced hepatic injury, and enhanced hepatocyte regeneration in ACLF animals.ConclusionBioenergetic failure drives the functional exhaustion of monocytes in ACLF. ucMSCs resuscitate monocyte energy and prevent its exhaustion. Restoring monocyte function can ameliorate hepatic injury and promote liver regeneration in the animal model of ACLF.

BackgroundDecompensated cirrhosis patients are more prone to bacterial infections. Myeloid-derived suppressor cells (MDSCs) expand in sepsis patients and disrupt immune cell functions. Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy helps in restoring immune cell functions and resolving infections. Its role in MDSC modulation in cirrhosis with sepsis is not well understood.MethodsA total of 164 decompensated cirrhotic—62 without (w/o), 72 with sepsis, and 30 with sepsis treated with GM-CSF—and 15 healthy were studied. High-dimensional flow cytometry was performed to analyze MDSCs, monocytes, neutrophils, CD4 T cells, and Tregs at admission and on days 3 and day 7. Ex vivo co-cultured MDSCs with T cells were assessed for proliferation and apoptosis of T cells and differentiation to Tregs. Plasma factors and mRNA levels were analyzed by cytokine-bead assay and qRT-PCR.ResultsFrequencies of MDSCs and Tregs were significantly increased ( p = 0.011 and p = 0.02) with decreased CD4 T cells ( p = 0.01) in sepsis than w/o sepsis and healthy controls (HCs) ( p = 0.000, p = 0.07, and p = 0.01) at day 0 and day 7. In sepsis patients, MDSCs had increased IL-10, Arg1, and iNOS mRNA levels ( p = 0.016, p = 0.043, and p = 0.045). Ex vivo co-cultured MDSCs with T cells drove T-cell apoptosis ( p = 0.03, p = 0.03) with decreased T-cell proliferation and enhanced FOXP3+ expression ( p = 0.044 and p = 0.043) in sepsis compared to w/o sepsis at day 0. Moreover, blocking the MDSCs with inhibitors suppressed FOXP3 expression. GM-CSF treatment in sepsis patients significantly decreased MDSCs and FOXP3+ Tregs but increased CD4 T-cell functionality and improved survival.ConclusionMDSCs have an immunosuppressive function by expanding FOXP3+ Tregs and inhibiting CD4+ T-cell proliferation in sepsis. GM-CSF treatment suppressed MDSCs, improved T-cell functionality, and reduced Tregs in circulation.

ABSTRACT Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon form of primary liver carcinoma. It is heterogenous in terms of morphology, immunohistochemistry, radiology, and clinical features; making it a challenging entity for diagnosis. Aims: The purpose of the present study was to evaluate clinicopathological characteristics of patients with cHCC-CCA. Settings and Design: Retrospective observational study. Materials and Methods: The patients diagnosed with cHCC-CC were identified from hepatic surgical specimens and were evaluated. Statistical Analysis: Survival was estimated as per Kaplan-Meier method. Results: Out of six patients, five had undergone resection while one had liver transplant. Five were male and one was female and the mean age was 52 years. Tumor markers revealed raised serum alfa-fetoprotein and CA19.9 in four and three patients, respectively. Five of the liver specimens were cirrhotic. Diagnosis was predominantly based on tumor morphology. All cases were of Allen and Lisa type B and cHCC-CCA as per WHO (2019) classification. Stem cell features <5% were noted in two cases. Immunohistochemistry for programmed death 1/programmed death ligand 1 (PD1/PDL1) was negative in both the hepatocellular and cholangiocellular components in all six cases. Mismatch repair (MMR) protein expression was retained in two and deficient in four cases. The median follow-up after surgery was 21.3 months (range, 5-46.2 months). Five patients had intrahepatic and/or extrahepatic recurrence on follow-up after surgery. The median recurrence-free survival was estimated at 13.1 months (95% CI 5.67-20.6). Three patients had received salvage treatment. The median overall survival was estimated at 20 months (95% CI 0-45.3). Conclusions: The present study highlights the role of morphology in the diagnosis of cHCC-CCA. The choice of locoregional and/or systemic therapy after surgery may be individualized based on the clinicopathological characteristics.