Liver stiffness measurements predict Sinusoidal Obstructive Syndrome after hematopoietic stem cell transplantation.

Sinusoidal Obstructive Syndrome (SOS) is a life-threatening complication after hematopoietic stem-cell transplantation (HSCT), characterized by post-sinusoidal portal hypertension. FibroScan is used to assess portal hypertension non-invasively. We assessed transient elastography (TE) applicability in diagnosing SOS. The study included 27 adult patients, 11 underwent TE for high SOS risk pre-HSCT, 17 underwent TE post-HSCT due to bilirubin ≥2 mg/dl with no definite diagnosis of SOS. The first group had median Liver Stiffness Measurement (LSM) of 7.4 kPa (range, 3.3-22.5). Based on LSM results, conditioning regimen was modified for six patients and two of them developed SOS. Only one patient who did not have protocol adjustment experienced SOS. No patient with LSM < 7 kPa developed SOS. The second group had median LSM of 7.7 kPa (4.4-31.5). Median LSM after HSCT was significantly higher in patients who subsequently developed established SOS (n = 10) compared to patients who did not (n = 8), with values of 10.7 kPa (5.6-31.5) and 5.9 kPa (4.4-13.8), respectively (p = 0.02). An LSM cut-off of 7.5 kPa had a sensitivity and specificity of 75 and 80% for diagnosing SOS. In conclusion, pre-HSCT LSM can help adjustment of conditioning regimen in patients with high-risk for SOS. Post-HSCT LSM can help in early diagnosis of SOS.

Elevated hemoglobin levels in renal transplant recipients with polycystic kidney disease versus other etiologies: exploring mechanisms and implications for outcomes.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD)-related end-stage kidney disease (ESKD) often necessitates transplantation. However, the impact of ADPKD on post-transplant outcomes, specifically hemoglobin levels, remains unknown. METHODS: We retrospectively analyzed 513 Kidney Transplant Recipients (KTRs), of whom 81 had ESKD due to ADPKD (20 with pre-transplant native nephrectomy and 61 without). Hemoglobin levels were evaluated at multiple time intervals post-transplant. RESULTS: Kidney transplant recipients with ADPKD vs. KTRs with ESKD due to other causes exhibited significantly higher hemoglobin levels in repeated measurement analysis. Multivariable analyses confirmed ADPKD as an independent predictor for elevated hemoglobin levels. In a multivariable logistic regression analysis, the odds for maximum hemoglobin > 15 mg/dL at 3-12 months post-transplant were more than twice as high in ADPKD patients vs. all the other KTRs (Odds Ratio [OR] 2.31, 95% Confidence Interval [CI] 1.3-4.13, p < 0.001). Pre-transplant native nephrectomy revealed a trend toward lower hemoglobin levels. Elevated hemoglobin levels were linked to improved estimated glomerular filtration rate (eGFR) at one year post-transplant. Patient survival was enhanced among KTRs with ADPKD compared to other ESKD causes. CONCLUSIONS: Kidney transplant recipients with ADPKD exhibited elevated hemoglobin levels post-transplant, possibly due to prolonged native kidney erythropoietin production. These elevated hemoglobin levels were linked to improved outcomes, including allograft function and patient survival. Future research should further investigate the underlying mechanisms driving favorable ADPKD KTR outcomes.

Comparison of etiological and physiological characteristics of fecal incontinence in men and women.

Fecal incontinence (FI) is often underreported and underestimated in men. Our aims were to clarify the causes and the physiological characteristics of FI in men and to underline the differences between etiological and physiological factors in men and women diagnosed with FI. The study cohort encompassed 200 men and 200 women who underwent anatomical and physiological evaluation for FI in a tertiary referral center specializing in pelvic floor disorders. All patients underwent endoanal ultrasound and anorectal manometry. Evacuation proctography was performed in some patients. Demographic, medical, anatomical, and physiological parameters were compared between the two study groups. Urge incontinence was the most frequent type of FI in both genders. In men, anal fistula, history of anal surgeries, rectal tumors, and pelvic radiotherapy were common etiologic factors, whereas history of pelvic surgeries was more common in women. Associated urinary incontinence was reported more frequently by women. External anal sphincter defects, usually anterior, were more common in women (M: 1.5%, F: 24%, P < 0.0001), whereas internal anal sphincter defect prevalence was similar in men and women (M: 6%, F: 12%, P = 0.19). Decreased resting and squeeze pressures were less common in men (M: 29%, F: 46%, P < 0.0001: M: 44%, F: 66%, P < 0.0001). The incidence of rectal hyposensitivity was higher in men (M: 11.1%, F: 2.8%, P < 0.0001), whereas rectal hypersensitivity was higher in women (M: 5.8%, F: 10.8%, P < 0.0001). Anorectal dyssynergia was more common in men (M: 66%, F: 37%, P < 0.0001). Significantly different etiological factors and physiological characteristics for FI were found in men. Acknowledging these differences is significant and may yield better treatment options.NEW & NOTEWORTHY Fecal incontinence (FI) in men has different etiological factors when compared with women. The prevalence of internal anal sphincter defect among men with FI was similar to women. Different manometric measurements were found among men with FI: decreased anal pressures were less common among men, whereas rectal hyposensitivity and anorectal dyssynergia were more common among men.

Assessing Health-Related Quality of Life in Non-Directed Versus Directed Kidney Donors: Implications for the Promotion of Non-Directed Donation.

Living kidney donation has increased significantly, but little is known about the post-donation health-related quality of life (HRQoL) of non-directed donors (NDs) vs. directed donors (DDs). We thus examined the outcomes of 112 living kidney donors (82 NDs, 30 DDs). For the primary outcomes-namely, the mean physical component summary (PCS) and mental component summary (MCS) scores of the 12-item Short Form Survey (SF-12) questionnaire-scores were significantly higher for the NDs vs. the DDs (PCS: +2.69, MCS: +4.43). For secondary outcomes, NDs had shorter hospital stays (3.4 vs. 4.4 days), returned to physical activity earlier (45 vs. 60 days), exercised more before and after donation, and continued physical activity post-donation. Regression analyses revealed that donor type and white blood cell count were predictive of the PCS-12 score, and donor type was predictive of the MCS-12 score. Non-directed donation was predictive of a shorter hospital stay (by 0.78 days, p < 0.001) and the odds of having PCS-12 and MCS-12 scores above 50 were almost 10 and 16 times higher for NDs, respectively (p < 0.05). These findings indicate the safety and potential benefits of promoting non-directed donation. However, careful selection processes must be maintained to prevent harm and exploitation.

Hepatitis B virus infection and risk of colorectal cancer: a large, population-based cohort study from Israel.

BACKGROUND: Recent population-based studies have suggested a possible link between hepatitis B (HBV) infection and extra-hepatic malignancies. We aimed to evaluate the association between HBV and colorectal cancer (CRC) using a large, population-based cohort study utilizing data from a large health maintenance organization (HMO). METHODS: The study included patients with non-cirrhotic HBV based on relevant ICD-9-CM codes and supportive serology identified from the HMO's database. Age-, sex-, ethnicity-, and BMI-matched non-HBV patients in a 1:10 ratio were included in the control group. We assessed the overall diagnosis rate of CRC and hepatocellular carcinoma (HCC) during the study period and calculated the diagnosis rate of CRC in each age category (≤50, 51-70, and ≥70) in both groups. RESULTS: A total of 3430 HBV patients and 34,300 controls were included in the study. The mean age, sex, BMI, and ethnic composition were similar, and the rates of family history of CRC did not differ between both groups. The overall follow-up period was 134±16 months. The diagnosis rate of HCC (1.6% vs. 0.1%; P<0.0001) was significantly higher in the HBV patients. However, the proportion of CRC was comparable for both groups (0.6% vs. 0.8%, P=0.404), which was evident in all age subgroups. CONCLUSIONS: Our findings suggest that HBV infection is associated with an increased risk of HCC diagnosis but is not linked to an elevated risk of CRC. These findings may inform future clinical practice and research regarding the relationship between HBV and extrahepatic malignancies.

Predictors of advanced liver fibrosis and the performance of fibrosis scores: lean compared to non-lean metabolic dysfunction-associated steatotic liver disease (MASLD) patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) in lean patients differs from that of NAFLD in non-lean patients. However, current data regarding predictors of advanced fibrosis and the performance of fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) in lean compared to non-lean metabolic dysfunction-associated steatotic liver disease (MASLD) patients is insufficient. METHODS: This was a cross-sectional study. Lean was defined as Body Mass Index <25 kg/m2. Advanced fibrosis (F3-F4) was detected by liver biopsy or two-dimension shear wave elastography (2D-SWE). Predictors of advanced fibrosis were identified using logistic regression and area under ROC curves (AUROC) were derived for FIB-4 and NFS. RESULTS: Lean patients (N.=153) comprised 19.2% of the MASLD cohort. Advanced fibrosis was associated with the number of cardiometabolic risk factors (CMRF) in lean (OR=2.06, P=0.011) and non-lean (OR=1.58, P<0.001) patients, however, hypertension and diabetes or impaired fasting glucose were significant only among non-lean. Age was associated with advanced fibrosis in both subgroups with age ≥65 showing higher odds in lean compared to non-lean patients (P=0.016). Non-lean patients had higher odds for advanced fibrosis relative to lean patients (OR=4.8, P=0.048). FIB-4 and NFS predicted advanced fibrosis among lean (AUROC=0.79 and AUROC=0.85, respectively) and non-lean (AUROC=0.79 and AUROC=0.76, respectively) patients. NFS ≥-1.445 showed higher specificity among lean compared to non-lean (P<0.001) and compared to that of FIB-4 ≥1.3 in lean patients (P<0.001). CONCLUSIONS: The number of CMRF was predictive of advanced fibrosis in both subgroups while age ≥65 showed higher odds among lean patients. NFS ≥-1.445 is more specific than FIB-4 ≥1.3 for advanced fibrosis prediction in lean patients. These findings may help identify high-risk lean MASLD patients for further liver fibrosis stage assessment.

The Clinical Manifestation of Immunosuppressive Therapy as a Tool to Improve Immune Monitoring in Renal Transplant Recipients.

INTRODUCTION: Metrics for posttransplant immune monitoring to prevent over or under immunosuppression in renal transplant recipients (RTRs) are lacking. METHODS: We surveyed 132 RTRs, 38 in the first year posttransplant and 94 >1-year posttransplant, to study the clinical expression of immunosuppressive therapy. A questionnaire administered to these RTRs was divided into physical (Q physical) and mental (Q mental) symptoms. RESULTS: In multivariable models for the association between the calculated Q physical and Q mental scores and different clinical and biochemical variables in the 38 RTRs who filled out the questionnaire 130 times during the first year posttransplant, it was found that mycophenolic acid (MPA) and prednisone use increased the mean Q physical score by 0.59 (95% CI: 0.21-0.98, p = 0.002) and 0.53 (95% CI: 0.26-0.81, p = 0.00), respectively, while MPA use increased the mean Q mental score by 0.72 (95% CI: 0.31-1.12, p = 0.001). Among the 94 RTRs who each completed the questionnaire only once, the odds for the mean Q mental score to be above the median value were more than 3 times higher for RTRs treated versus non-treated with MPA (OR 3.38, 95% CI: 1.1-10.3, p = 0.03). MPA-treated RTRs had higher mean scores for questions related to sleep disorders (1.83 ± 1.06 vs. 1.32 ± 0.67 for not treated, p = 0.037), to difficulty falling asleep (1.72 ± 1.11 vs. 1.16 ± 0.5, p = 0.02), and to depression and anxiety. CONCLUSION: We concluded that prednisone and MPA use are associated with an increased Q physical and Q mental scores in RTRs. Routine monitoring of physical and mental status of RTRs should be implemented to improve the diagnosis of overimmunosuppression. Dose reduction or discontinuation of MPA should be considered in RTRs who report sleep disorders, depression, and anxiety.

Chronic hepatitis B infection and diabetes mellitus: a double liver trouble?

BACKGROUND: Concomitant Diabetes mellitus (DM) is commonly recognized in patients with chronic hepatitis B (CHB) infection, although its impact on liver-related outcomes remains controversial. We aimed to evaluate the effect of DM on the course, management and outcome of patients with CHB. METHODS: We performed a large retrospective cohort study utilizing the Leumit-Health-Service (LHS) database. We reviewed electronic reports of 692106 LHS members from different ethnicities and districts in Israel from 2000-2019 and included patients with CHB diagnosis based on ICD-9-CM codes and supportive serology results. These were divided into two cohorts of patients with CHB and DM (CHD-DM) (N.=252) and those with CHB without DM (N.=964). Clinical parameters, treatment figures and patients' outcomes were compared and multiple regression models and Cox regression analysis were performed to investigate the association between DM and cirrhosis/HCC risk in CHB patients. RESULTS: CHD-DM patients were significantly older (49.2±10.9 vs. 37.9±14, P<0.001), and had higher rates of obesity (BMI>30) and NAFLD (47.2% vs. 23.1%, and 27% vs. 12.6%, P<0.001, respectively). Both groups had a predominance of inactive carrier (HBeAg negative infection) state, but the HBeAg seroconversion rate was significantly lower in the CHB-DM group (25% vs. 45.7%; P<0.01). Multivariable Cox regression analysis showed that DM was independently associated with increased cirrhosis risk (HR 2.63; P=0.002). Older age, advanced fibrosis and DM were associated with HCC, but DM did not reach significance (HR 1.4; P=0.12) possibly due to the small number of HCC cases. CONCLUSIONS: Concomitant DM in CHB patients was significantly and independently associated with cirrhosis and possibly with increased risk of HCC.

Reduced Neutralization Efficacy against Omicron Variant after Third Boost of BNT162b2 Vaccine among Liver Transplant Recipients.

The immune responses of liver transplant (LT) recipients after the third boost of the BNT162b2mRNA vaccine improved. This study evaluates the durability of the immune response of LT recipients after the third boost, its predictors, and the impact of emerging variants. The receptor-binding domain IgG was determined at median times of 22 (first test) and 133 days (second test) after the administration of the third boost. IgG antibody titers > 21.4 BAU/mL were defined as a positive response. The neutralization efficacies of the vaccine against the wild-type, Omicron, and Delta variants were compared in the first test. The 59 LT recipients were of a median age of 61 years (range 25−82); 53.5% were male. Following administration of the third dose, the positive immune response decreased from 81.4% to 76.3% between the first and second tests, respectively, (p < 0.0001). The multivariate analysis identified CNI monotherapy (p = 0.02) and hemoglobin > 12 g/dL (p = 0.02) as independent predictors of a maintained positive immune response 133 days after the third dose. The geometric mean titers of Omicron neutralization were significantly lower than the wild-type and Delta virus (21, 137, 128, respectively; p < 0.0001). The immune response after the third BNT162b2mRNA vaccine dose decreased significantly in LT recipients. Further studies are required to evaluate the efficacy of the fourth vaccine dose and the durability of the immune response.

Real-world hepatitis B antiviral treatment trends and adherence to practice guidelines: a large cohort study.

BACKGROUND: Epidemiologic data regarding chronic hepatitis B virus infections in Israel is limited as extensive population-based studies have not been performed. OBJECTIVE: This work aimed to evaluate the current characteristics of hepatitis B infection among Israeli adults and evaluate adherence to the European Association for the Study of the Liver practice guidelines for antiviral treatment. METHODS: Clinical and demographic data of HBsAg-positive patients registered in the Leumit-Health-Service database (one of the four major health maintenance organizations in Israel) between 2000 and 2019 were retrieved. Patients were compared according to eligibility to antiviral treatment and type of nucleos(t)ide analogue (NA) treatment. RESULTS: In total, 1216 patients had documented HBsAg positivity (males 58.6%, mean age 40.2 ± 14.2 years), 90.6% of whom were HBeAg negative. Antiviral therapy eligibility was met by 37% of patients, among whom 89% received antiviral therapy. Antiviral therapies include NA with a high barrier to resistance (HBR) (64.5%) and NA with a low barrier to resistance (LBR) (35.5%). Compared to patients who received LBR NA, patients receiving HBR NA had shorter treatment (68.7 ± 50 vs. 161.5 ± 42.6 months, p < .001) and follow-up duration (125 ± 68 vs. 188 ± 48 months, p < .001); at the end of follow-up, ALT levels and APRI score were higher among patients on LBR NA compared to patients on HBR NA. CONCLUSION: Most patients received antiviral treatment according to the international practice guidelines. However, one-third of them were treated with a less potent NA, probably due to their lower cost. These findings should encourage the optimization of HBV care and full compliance with the professional practice guideline recommendations.

The impact of ethnicity on chronic hepatitis B infection course and outcome: big data analysis from Israel.

OBJECTIVES: The effect of ethnicity on chronic hepatitis B virus (CHB) infection's course and outcome has attracted little research. We aimed to compare different aspects of ethnic disparities in CHB patients, including prevalence, phenotypes, management, and outcome between two major ethnic groups in Israel. DESIGN: We conducted a large retrospective cohort study utilizing the Leumit-Health-Service database. Electronic reports of almost 700,000 members from different ethnicities and districts throughout Israel from 2000 to 2019 were reviewed. Patients' ethnicity was categorized based on the classification of the Israeli Central Bureau of Statistics into two main groups, Arabs and Jews. CHB diagnosis was based on ICD-9-CM codes and supportive serology results. Prevalence, clinical backgrounds, disease course, and patients' outcomes were compared between both groups. RESULTS: The prevalence of CHB in the Arab minority group was almost twice and a half-higher when compared to their Jewish counterparts (4.3% vs. 1.8%), but they had a lower rate of referral for HBsAg testing (7% vs. 7.9%). The Arab CHB patients were significantly younger at the time of diagnosis (37.6± 13.5 vs. 45.3± 15; P < 0.001). Male predominance was noted in both groups. The Arab patients had a higher rate of active hepatitis (HBeAg-positive and/or negative hepatitis) phase (36.4% vs. 29.8%; P = 0.01), as well as a significantly higher rate of HBeAg seroconversion (45.2% vs. 35.4%; P = 0.033). Nucleos/tide analogue treatment figures were similar, with most patients in both groups receiving a high barrier to resistance treatment. Patients' outcome was similar in both groups as the rate of hepatocellular carcinoma, cirrhosis, and advanced fibrosis (after stratification analysis) were comparable between both groups. CONCLUSION: Marked by a prominently higher prevalence of HBV infection, patients in the Arab ethnic group had a lower rate of referral for HBsAg testing but received comparable management and had a similar outcome compared to their Jewish counterparts.

High Immune Response Rate to the Fourth Boost of the BNT162b2 Vaccine against the Omicron Variants of Concern among Liver Transplant Recipients.

The immune response of liver transplant (LT) recipients to a third dose of the BNT162b2 mRNA vaccine significantly waned after four months. We aimed to evaluate the immune response and breakthrough infection rates of a fourth dose against the Omicron variants among LT recipients. LT recipients who had no past or active SARS-CoV-2 infection and received three doses of the BNT162b2mRNA vaccine were included. Of the 73 LT recipients, 50 (68.5%) received a fourth dose. The fourth dose was associated with a significantly higher positive immune response than the third dose. Receptor-binding domain (RBD) IgG and Omicron BA.1 and BA.2 neutralizing antibodies were determined at a median of 132 and 29 days after the third and fourth vaccines. They were 345 binding antibody units per milliliter (BAU/mL) vs. 2118 BAU/mL (p < 0.0001), 10 vs. 87 (p < 0.0001), and 15 vs. 149 (p = 0.001), respectively. Breakthrough infections were documented among nine (18%) LT recipients after the fourth dose and among seven (30.4%) patients following the third dose (p = 0.2); 93.5% of breakthrough infections were mild. The infection rate after the fourth dose was higher among diabetic vs. nondiabetic recipients (33.3% vs. 6.9%, respectively; p = 0.02). Further studies are needed to evaluate additional factors influencing the breakthrough infection rate among LT recipients.

Clinical and endoscopic predictors of gastric precancerous conditions: a large population case control study.

BACKGROUND: Atrophic gastritis (AG) and gastric intestinal metaplasia (GIM) are well defined intermediate precancerous conditions (PCCs) in the gastric cancer cascade. The diagnosis of PCCs may be suspected based on endoscopic findings but is established by histology. Estimates of the global prevalence of PCCs vary widely but simple clinical or endoscopic predictors of their diagnosis are ill defined. We aimed to evaluate the prevalence of gastric PCCs in our practice and to identify predictors for its diagnosis. METHODS: We analyzed electronic reports of patients referred for gastroscopy procedures over a 5-year period and included those for whom gastric biopsies were performed. We investigated demographic, clinical, and endoscopic findings to identify possible association with histologic detection of gastric PCCs and performed multivariate analysis to identify predictors of its diagnosis. RESULTS: A total of 4930 patients with full endoscopic and histologic data were included for the final analysis. Of these, 806 (16.3%) patients had a histologic diagnosis of gastric PCCs. Demographic and clinical variables including male sex (51.4% vs. 45.7%; P=0.003), age over 60 (69.8% vs. 45.2%; P<0.001), and anemia indication for gastroscopy (17.6% vs. 14.8%; P=0.04) were significantly associated with gastric PCCs diagnosis. Likewise, endoscopic findings of Barret's esophagus (2.6% vs. 1.3%; P=0.006), atrophic gastritis according to endoscopist's judgment (12.9% vs. 3.5%; P<0.01) and corpus predominant gastritis (22.5% vs. 14.7%; P=0.02) were significantly associated with gastric PCCs. In multivariate analysis, age>60 (please explain all acronyms HR 2.51, 95% CI 2.12-2.96), male sex (HR 1.235, 95% CI 1.05-1.44), corpus predominant (HR 1.284, 95% CI 1.04-1.57), and atrophic gastritis (HR 4, 95% CI 3.07-5.21) were independent predictors for PCCs diagnosis. CONCLUSIONS: Not uncommonly encountered in our practice, a judicious performance of gastric biopsies to detect gastric PCCs should be adopted especially in older, male patients with endoscopic findings of corpus predominant and/or gastric atrophy.

Research trends analysis of chronic hepatitis C versus nonalcoholic fatty liver disease: A literature review text-mining analysis of publications.

Background: Hepatits C virus (HCV) rates have lowered due to direct-acting antiviral treatment. Nonalcoholic steatohepatitis (NASH)/nonalcoholic fatty liver disease (NAFLD) is rising with no available therapy. We employed text-mining to analyze trends in HCV and NAFLD research from the past two decades. Materials and Methods: We queried PubMed for all HCV and NASH/NAFLD entries published between 2000 and 2020. We compared the total number of publications on both etiologies. We performed subanalyses for different terms of interest and for geographic origin. Results: Overall, 75,934 HCV-related entries and 24,987 NASH/NAFLD-related entries were published during the study period. Up to 2015, there was a linear upward slope in the number of annual HCV publications (154.9 publications/year, p < 0.001). In 2015, the yearly number of HCV publications started showing a downward slope (-242.2 publications/year, p < 0.001). The number of NASH/NAFLD publications showed a continuous upward slope during the study period. The NASH/NAFLD field lacks publications on screening and treatment methods. Conclusion: Trends in publications varied between both etiologies. They reflect the success of antiviral treatment for HCV. The growing rates of NAFLD/NASH and the lack of a targeted cure explain the rise in related publications.

A third dose of the BNT162b2 mRNA vaccine significantly improves immune responses among liver transplant recipients.

BACKGROUND & AIMS: Immune responses of solid organ transplant recipients to 2 doses of the BNT162b2 mRNA anti-SARS-CoV-2 vaccine are impaired. The immunogenicity and safety of a third dose among liver transplant (LT) recipients are unknown. This work aimed to evaluate the immune response of LT recipients to a third dose of the BNT162b2 mRNA vaccine. METHODS: Consecutive LT recipients (n = 61) in follow-up at Sheba Medical Center were included. Receptor binding domain (RBD) IgG, neutralizing antibody (NA) titers, and T-cell levels before and 21-28 days after a third vaccine dose were determined. Adverse effects after the third dose were monitored. RESULTS: The median age of LT recipients was 65 years and 57.4% were male. The humoral immune response rate improved significantly, with 56% of patients showing a response before the third vaccine dose compared to 98% after the third dose. The cellular response in 12 evaluated patients improved significantly (p = 0.008). The geometric mean of anti-RBD IgG levels, NA levels, and T-cell count also increased significantly after the third dose. NA titers after the third dose negatively correlated with age (p = 0.03), mycophenolate mofetil treatment (p = 0.005), and combined immunosuppression as opposed to calcineurin inhibitor monotherapy (p = 0.001). After the third dose, adverse effects were reported by 37% of recipients and were mostly mild (local pain and fatigue). CONCLUSION: After a third BNT162b2 mRNA vaccine, the immune response improved significantly among LT recipients, without serious adverse effects. Further studies are needed to evaluate immune response durability and to determine the optimal number and schedule of booster vaccine doses. LAY SUMMARY: The Pfizer-Biotech BNT162b2SARS-CoV-2 vaccine induced significant immunity among liver transplant recipients after a third dose. The majority of the patients developed sufficient levels of both humoral and cellular immune responses. Factors that predict non-response were older age and immunosuppressive medications.

HBV-RNA, Quantitative HBsAg, Levels of HBV in Peripheral Lymphocytes and HBV Mutation Profiles in Chronic Hepatitis B.

A comprehensive characterization of chronic HBV (CHB) patients is required to guide therapeutic decisions. The cumulative impact of classical and novel biomarkers on the clinical categorization of these patients has not been rigorously assessed. We determined plasma HBV-RNA and HBsAg levels, HBV in peripheral lymphocytes (PBMCs) and HBV mutation profiles in CHB patients. Patient demographics (n = 139) and classical HBV biomarkers were determined during a clinical routine. HBV-RNA in plasma and HBV-DNA in PBMCs were determined by RT-PCR. HBsAg levels were determined using Architect. In samples with HBV-DNA viral load >1000 IU/mL, genotype mutations in precore (PC), basal core promoter (BCP), HBsAg and Pol regions were determined by sequencing. Most patients (n = 126) were HBeAg-negative (HBeAgNeg) with significantly lower levels of HBV-RNA, HBV-DNA and HBsAg compared to HBeAg-positive (HBeAgPos) patients (p < 0.05). HBV genotype D prevailed (61/68), and >95% had BCP/PC mutations. Escape mutations were identified in 22.6% (13/63). HBeAgNeg patients with low levels of HBsAg (log IU ≤ 3) were older and were characterized by undetectable plasma HBV-DNA and undetectable HBV-RNA but not undetectable HBV-DNA in PBMCs compared to those with high HBsAg levels. In >50% of the studied HBeAgNeg patients (66/126), the quantitation of HBsAg and HBV-RNA may impact clinical decisions. In conclusion, the combined assessment of classical and novel serum biomarkers, especially in HBeAgNeg patients, which is the largest group of CHB patients in many regions, may assist in clinical decisions. Prospective studies are required to determine the real-time additive clinical advantage of these biomarkers.

Immunogenicity and Adverse Effects of the 2-Dose BNT162b2 Messenger RNA Vaccine Among Liver Transplantation Recipients.

The BNT162b2 messenger RNA (mRNA) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to be safe and effective in immunocompetent patients. The safety and efficacy of this vaccine in liver transplantation (LT) recipients is still under evaluation. The objective of this study was to assess the safety and efficacy of the BNT162b2 vaccine among transplant recipients. The immune responses of 76 LT recipients receiving 2 doses of the vaccine were compared with those of 174 age-matched immunocompetent controls. Postvaccination immunoglobulin G (IgG) antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 and neutralizing antibodies (NA) to the BNT162b2 mRNA vaccine were determined at least 14 days after the second dose of the vaccine. IgG antibody titers ≥1.1 were defined as positive antibodies. Adverse effects were monitored during the study period. Following administration of the second dose, transplant recipients showed reduced immune responses compared with controls (72% versus 94.2%; P < 0.001). At a median time of 38 days after the second vaccination, the geometric mean of RBD IgG and NA titers were 2.1 (95% confidence interval [CI], 1.6-2.6) and 150 (95% CI, 96-234) among transplant recipients and 4.6 (95% CI, 4.1-5.1) and 429 (95% CI, 350-528) in the control group, respectively (P < 0.001). Antibody responses were lower in transplant recipients who were receiving combined immunosuppression therapy and in those with impaired renal function. Among the LT recipients with negative antibody responses, 1 became infected with SARS-CoV-2, but no recipients with positive antibody responses became infected. Overall, most (n = 39 [51%]) adverse effects self-reported by transplant recipients were mild and occurred more often in women than in men. Compared with patients who were immunocompetent, LT recipients had lower immune responses. The durability of immune responses to the BNT162b2 vaccine among LT recipients requires further investigation.

Noninvasive Assessment of Fibrosis Regression after Direct-acting Antiviral Treatment in Hepatitis C Virus Patients.

BACKGROUND: New direct acting antiviral agent (DAA) therapies are associated with a high sustained virological response rate (SVR) in hepatitis C virus (HCV) patients. The understanding of the impact of SVR on fibrosis stage is limited. OBJECTIVES: To determine the effect of treatment with the DAAs on long-term liver fibrosis stages, as determined by shear-wave elastography (SWE) or FibroTest. METHODS: Fibrosis stage was determined at baseline and at 6-month intervals after end of treatment (EOT), using two-dimensional SWE or FibroTest©; APRI and FIB-4 scores. RESULTS: The study comprised 133 SVR12 patients. After a median follow-up of 15 months (range 6-33), liver fibrosis stage decreased by at least 1 stage in 75/133 patients (56%). Cirrhosis reversal was observed in 24/82 (29%). Repeated median liver stiffness SWE values in cirrhotic patients were 15.1 kPa at baseline (range 10.5-100), 13.4 kPa (range 5.5-51) at 6 months, and 11.4 kPa (range 6.1-35.8) at 12 months after EOT, P = 0.01. During the second year after EOT, no statistically significant differences in liver fibrosis stage in 12, 18, and 24 months were found. Splenomegaly was the only significant negative predictor of liver fibrosis regression during all time points of repetitive noninvasive assessment. CONCLUSIONS: Following successful DAA treatment, the majority of our HCV patients with advanced fibrosis demonstrated significant improvement, as assessed by non-invasive methods. Advanced fibrosis stage was a negative predictor of fibrosis regression. Longer follow-up periods are required to further establish the impact of DAAs treatment in HCV patients with advanced fibrosis.

XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are prevalent liver conditions that underlie the development of life-threatening cirrhosis, liver failure and liver cancer. Chronic necro-inflammation is a critical factor in development of NASH, yet the cellular and molecular mechanisms of immune dysregulation in this disease are poorly understood. Here, using single-cell transcriptomic analysis, we comprehensively profiled the immune composition of the mouse liver during NASH. We identified a significant pathology-associated increase in hepatic conventional dendritic cells (cDCs) and further defined their source as NASH-induced boost in cycling of cDC progenitors in the bone marrow. Analysis of blood and liver from patients on the NAFLD/NASH spectrum showed that type 1 cDCs (cDC1) were more abundant and activated in disease. Sequencing of physically interacting cDC-T cell pairs from liver-draining lymph nodes revealed that cDCs in NASH promote inflammatory T cell reprogramming, previously associated with NASH worsening. Finally, depletion of cDC1 in XCR1DTA mice or using anti-XCL1-blocking antibody attenuated liver pathology in NASH mouse models. Overall, our study provides a comprehensive characterization of cDC biology in NASH and identifies XCR1+ cDC1 as an important driver of liver pathology.