Changes in immune cell subtypes during ageing.

BACKGROUND: The immune system comprises many different types of cells, each with different functions and properties during immune defence. The numbers and types of immune cells in the circulation is highly dynamic and regulated by infections, ageing and certain types of cancers. It is recognised that immune function decreases during ageing, but the biological age at which these functional changes occur is variable, and how ageing affects the different sub-types of lymphocytes, monocytes and NK cells in the circulation is not fully defined. METHODS: In this study, we recruited 24 healthy volunteers over the age range of 23y to 89y and measured the numbers of different subclasses of circulating cells by immuno-phenotyping and flow cytometry. RESULTS: We show increased monocyte:lymphocyte ratios in a > 50y cohort and most T cell subsets were decreased, except for CD4+ cells, which were increased in this cohort. In addition, there was NK cell expansion and increased HLA-DR+ T cells, but decreased numbers of classical monocytes and increased numbers of CD4+ monocytes in this >50y cohort. CONCLUSIONS: These data indicate that healthy ageing is associated with changes in both the major cell groups but also individual subclasses of cells, and these are likely to result from continuous immune challenge and impaired development.

Global treatment rate and barriers to direct-acting antiviral therapy: A systematic review and meta-analysis of 146 studies and 1 760 352 hepatitis C virus patients.

BACKGROUND: Global data on the treatment rate with direct-acting antivirals (DAAs) for chronic hepatitis C (CHC) are sparse. We aimed to evaluate the CHC treatment rate and barriers to treatment in the DAA era. METHODS: We searched PubMed, EMBASE and Cochrane from inception to 5 August 2021, for relevant articles. Patients treated with DAAs without interferon (IFN) therapy were categorized as IFN-free DAAs. Patients receiving DAA with IFN or unclear IFN status were categorized as DAA/IFN. RESULTS: We identified and analysed data from 146 studies (1 760 352 CHC patients). DAA/IFN treatment rate was 16.0% (95% CI: 9.9-23.3, 49 studies, 886 535 patients). IFN-free DAA treatment rate was 52.3% (95% CI: 46.2-58.4, 123 studies, 1 276 754 patients): 45.4% in North America, 64.2% in South America (1 study), 90.4% in Africa (most data from Egypt), 54.4% in Europe, 60.7% in Australia and 60.5% in Asia, (p < .0001); 49% with hepatitis B co-infection and 32.3% with hepatocellular carcinoma (HCC). Treatment was not a priority in 22.8% of patients in Europe and 16.7% in Australia, compared to only 4.8% in North America and 2.1% in Asia (p < .0001). Poor adherence to clinical follow-up was the cause of no treatment in 74.7% of patients in Australia, 37.0% in North America, 7.9% in Europe and 14.3% in Asia (p < .0001). CONCLUSION: Though a marked improvement from IFN/DAA, the treatment rate with IFN-free DAA remains suboptimal (52.3% overall, 32.3% in HCC patients). Non-adherence to clinical follow-up and lack of disease awareness were treatment barriers.

Upregulation of p16INK4A in Peripheral White Blood Cells as a Novel Screening Marker for Colorectal Carcinoma.

OBJECTIVE: Screening of colorectal cancer (CRC) is important for the early detection. CRC is relating to aging and immuno-senescence. One such senescent marker is p16INK4A expression in immune cells. The objective of the study is to investigate the protein expression of p16INK4A in peripheral white blood cells as a screening marker for colorectal cancer. METHODS: A case-control studies were conducted. Cases were patients with colorectal cancer and controls were matched with cases based on age and sex. Peripheral blood was collected from patients and controls and the protein p16INK4A was measured with immunofluorescent techniques. The p16INK4A levels from cases and controls were evaluated using ROC analysis to be used as a screening marker in CRC patients. Mean fluorescent intensity of p16INK4A of cases and controls were analyzed in CD45+, CD3+ or CD14+ cells. The p16INK4A levels of cases were also correlated with clinical data. RESULT: Statistically significant increased expression of p16INK4A levels were found in cases compared to controls. p16INK4A in peripheral immune cells had 78% sensitivity and 71% specificity which can possibly be used as a diagnosis tool for colorectal cancer. P16INK4A-positive cell percentage and mean florescent intensity were significantly higher in CD45+ cells, CD3 positive cells and CD14 positive cells. No significant correlation was observed with the clinical data and p16INK4A level of CRC patients. CONCLUSION: The significant increase of p16 INK4A expression level in peripheral immune cells represents potential for use as a CRC screening marker.

Increased Risk of Liver-Related Outcomes in Chronic Hepatitis B Patients with Metabolic Syndrome: A Systematic Review and Meta-Analysis.

INTRODUCTION: Chronic hepatitis B (CHB) patients with metabolic syndrome (MetS) may present increased risk of liver-related outcomes (LROs), but prior studies were limited by small sample size and/or conflicting results. Using a systematic review and meta-analytic approach, we aimed to determine the association between MetS and LROs in CHB. METHODS: Two researchers independently screened studies from the PubMed, Embase, Web of Science, and Cochrane Library databases from inception to January 21, 2020, and extracted the data. Estimates were pooled using a random-effects model. RESULTS: We screened 2,228 articles and included 10 eligible studies (18,360 CHB patients, 2,557 with MetS). MetS was significantly associated with LROs overall (odds ratio = 2.45, 95% confidence interval = 1.39-4.32) but not the individual LRO components but subgroup analyses were limited by small study numbers. DISCUSSION/CONCLUSION: MetS is associated with almost 3-folds higher risk of LROs in CHB and should be considered in management decisions. However, additional studies are needed.

Treatment and Renal Outcomes Up to 96 Weeks After Tenofovir Alafenamide Switch From Tenofovir Disoproxil Fumarate in Routine Practice.

BACKGROUND AND AIMS: Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. APPROACH AND RESULTS: We analyzed 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA < 20 IU/mL), biochemical (alanine aminotransferase [ALT] < 35/25 U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96 weeks after switch. Viral suppression (P < 0.001) and ALT normalization (P = 0.003) rates increased significantly after switch, with a trend for increasing complete response (Ptrend = 0.004), while the eGFR trend (Ptrend  > 0.44) or mean eGFR (P > 0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR < 90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P = 0.029) but not after TAF switch (P = 0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1. CONCLUSIONS: Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.

Differential characteristics and outcomes of Asian and non-Asian patients with HBV-related hepatocellular carcinoma.

BACKGROUND & AIMS: The epidemiology of hepatitis B virus (HBV) infection differs between Asians and non-Asians, but little is known regarding the effect of ethnicity on outcomes of HBV-related hepatocellular carcinoma (HCC). We aim to characterize the presentation and survival outcomes in Asian and non-Asian patients with HBV-related HCC. METHODS: We analyzed the baseline characteristics and long-term survival of 613 Asian and 410 non-Asian patients with HBV-related HCC from three US and one Spanish centre. RESULTS: Overall, non-Asian patients were more likely to have HIV or hepatitis C co-infection, cirrhosis, decompensated liver disease and advanced BCLC stage (all P ≤ .04). Compared with Asians, non-Asians were more likely to be listed for transplantation (P < .0001) and undergo HCC treatment with curative intent (P = .003). Propensity-score matching on HCC diagnosis year, gender and age was performed to balance the two groups for survival analysis and yielded 370 pairs of patients. There was no significant difference in survival overall (P = .43) and among patients with cirrhosis (P = .57). Among patients without cirrhosis, non-Asians had poorer 5-year survival compared with Asians (37.6% vs 53.7%, P = .01), and was associated with poorer survival after adjusting for age, gender, diabetes, alcohol, co-infections, diagnosis date, antiviral therapy, BCLC stage and HCC treatment (adjusted HR 2.01 [95% CI 1.07-3.74], P = .03). CONCLUSION: Among HBV-related HCC patients, non-Asians presented with more advanced BCLC stage compared to Asians. Non-Asian ethnicity was independently associated with twice the risk of mortality among patients without cirrhosis, but not among those with cirrhosis. Additional studies are needed to clarify this disparity.

The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040.

BACKGROUND: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD. METHODS: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD-8 studies) patients. RESULTS: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983-2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD. CONCLUSION: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.