Risk of hepatocellular carcinoma, liver-related complications, and death in persons living with chronic hepatitis B and D

Chronic hepatitis B virus (HBV) infection affects 257 million individuals and is a leading cause of liver-related morbidity and mortality. Hepatitis D virus (HDV) is a satellite virus, that needs HBV for packing and propagation, hence infecting only individuals with HBV infection. It is estimated that around 9-19 million individuals are living with chronic hepatitis Delta (CHD), hence it is the least common among viral hepatides. CHD demonstrates a severe course of liver disease than CHB. The treatment options are still limited, and approved therapies are at a high price. This thesis aims to characterize the natural course of HBV and HDV infection in a low-endemic setting, predictors of disease progression, and the effect of therapy on the disease course. In Study I, we identified 337 patients with positive anti-HDV antibody from 11 infectious disease clinics in Sweden assembling a nationwide cohort. During a mean follow-up of 6.5 years, HDV RNA replication was significantly associated with a composite outcome of any liver-related decompensation, HCC, and liver transplantation. The response to IFN therapy was suboptimal; 18.8% had a virological response defined as negative or more than 2 log decline of HDV RNA level and a more benign disease course was seen in virological responders compared to non-responders. HDV RNA replication was independently associated with liver decompensation events, undergoing liver transplantation, and a trend toward higher HCC risk. In Study II, we conducted a systematic review and meta-analysis of published peerreviewed cohort studies examining the risk of HCC in patients with HBV/HDV infection compared to peers with HBV mono-infection. The pooled relative risk was 2.12 (95% confidence interval CI 1.14-3.95), with a particularly higher risk in patients with HIV/HBV/HDV co-infection and substantial heterogeneity between studies. In Study III, we present the HDV cascade of care during three decades at Karolinska University Hospital (KUH) as a secondary care referral facility in the Southern Stockholm region. In 4095 patients with positive HBsAg, (90.4%, n=3703) have undergone an anti- HDV test. Anti-HDV positive was prevalent in (83.7%, n=310) and (65.2%, n=202) patients who had HDV RNA replication. Older age, cirrhosis, and getting a late anti-HDV diagnosis were independently associated with any prevalent liver outcome. Despite the high screening rate reaching 95%, 8% of persons meeting the criteria of the American Association for the Study of the Liver (AASLD) as “high-risk” of infection did not receive any screening test and 28% of persons with cirrhosis received a remote screening test (after two years). Persons with concurrent HIV and HBV infection were less likely to receive a screening test. In Study IV, we analyze a nationwide cohort of African-born Swedish residents with CHB without cirrhosis (n=3865), followed for a mean of 12 years from the date of HBV diagnosis in Sweden to the incidence of HCC. The cohort was compared to individuals without HBV in 1 to ≤3 on age, sex, and county of residence to persons from the same area of birth (n=8,488) and in 1 to ≤ 10 on age, sex, and county of residence with a cohort from the general population (n=39,278). African-born men with CHB were significantly younger at HCC development compared to women and peers from comparator cohorts. The costeffectiveness surveillance threshold at 0.2% was exceeded at age 54 years (IR=0.20/100PYs, 95%CI 0.10-0.40) in men and at age 59 years (IR=0.21/100 PYs, 95%CI 0.10-0.45) in women, while at 20-40 years in the presence of concomitant HDV and HCV co-infection in men. The probability of HCC was more pronounced at younger ages in men compared to women. African-born men with CHB had 10.6 times higher risk to develop HCC compared to African-born peers without HBV and a 35.3 times higher risk than the general population. The study provides absolute and relative estimates of HCC development in a nationwide large cohort of African-born first-generation persons with CHB, without cirrhosis at baseline living in a different environmental setting. To conclude, HDV RNA replication, older age, and cirrhosis in patients with anti-HDV positive are independent predictors of progressive liver disease and need for liver transplantation. Lack of response to IFN therapy might be associated with a worse disease outcome. Based on our pooled analyses, HDV infection is associated with two-times higher risk to develop HCC, compared to HBV mono-infection with a higher risk in persons with triple HIV/HBV/HDV infection. Nine out of 10 patients with CHB received an anti-HDV test at KUH. Delayed HDV diagnosis was independently associated together with older age and cirrhosis with a liver-related outcome. Liver cirrhosis is a fertile ground for cancer development, but some people with CHB can develop cancer without cirrhosis. Costeffectiveness analysis to surveil persons with CHB without cirrhosis identified a threshold of 2 per 1000 persons per year to conduct a semi-annual ultrasound examination. Nevertheless, the age to start liver cancer surveillance, in persons of African origin is different across guidelines due to few studies examining this risk in this population for a long time. It is unclear if the current 0.2% cost-effectiveness threshold for HCC surveillance in persons without cirrhosis might miss a population of younger patients with co-morbidities who are at increased risk to develop HCC. Our research highlights the need for cost-effectiveness studies in contemporary cohorts of persons living with CHB particularly in African-born men given the substantial number of HCCs occurring at younger ages in this population

Thin-layer agar (TL7H11) for rapid isolation of Mycobacterium tuberculosis in sputum specimens

Background: Tuberculosis (TB) remains one of the major causes of death from a single infectious agent worldwide. The early detection of new cases of pulmonary tuberculosis is an important goal in tuberculosis control program.Objective: 1n this study, thin layer agar (TLA) culture was compared with Lowenstein-Jensen (LJ) culture for rapid detection of pulmonary tuberculosis. Methods: It was a cross sectional study conducted in National Tuberculosis Reference Labora­tory (NTRL) of National Institute of Disease of Chest and Hospital (NIDCH), Dhaka, from July 2010 to June 2011. A total of 100 sputum smear positive for acid fast bacilli (AFB) by Z-N staining, pulmonary tuberculosis patients were included in this study. Samples were processed by modified Petroff method and then cultured on thin layer 7H11(TL7H11) plates and L-J tubes. TL7H11 plates were observed microscopically for rnicrocolony growth once a week for 6 weeks, and L-J tubes were observed once a week for 8 weeks. Results: The recovery rates of mycobacteria on only TLA, only LJ and on both media were 90%, 97% and 88% respectively. Overall positivity was 99% in both L-J and TLA media. Mean time for detection of mycobacteria on TLA was 9.04±1.66 days compared to 21.78±6.19 days on L-J media. The rate of contamination was higher (6%) in L-J media than in TLA media (4%). Conclusion: The TL7H11 media can be used as an alternative to the Lowenstein-Jensen medium for early isolation of mycobacteria in resource constrained settings

Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19

SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.Fil: Sekine, Takuya. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Perez Potti, André. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Rivera Ballesteros, Olga. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Strålin, Kristoffer. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Gorin, Jean Baptiste. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Olsson, Annika. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Llewellyn Lacey, Sian. University Hospital of Wales; Reino UnidoFil: Kamal, Habiba. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Bogdanovic, Gordana. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Muschiol, Sandra. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Wullimann, David J.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Kammann, Tobias. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Emgård, Johanna. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Parrot, Tiphaine. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Folkesson, Elin. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Rooyackers, Olav. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Karolinska University Hospital; SueciaFil: Eriksson, Lars I.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Henter, Jan Inge. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Sönnerborg, Anders. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Allander, Tobias. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Albert, Jan. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Klingstrom, Jonas. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Gredmark Russ, Sara. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Björkström, Niklas K.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Sandberg, Johan K.. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Price, David A.. Cardiff University School of Medicine; Reino UnidoFil: Ljunggren, Hans Gustaf. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Aleman, Soo. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: Buggert, Marcus. Karolinska Huddinge Hospital. Karolinska Institutet; Sueci

Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19

SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Association between proton pump inhibitor use and biliary tract cancer risk : a swedish population-based cohort study

Background and Aims Biliary tract cancer is a group of highly aggressive malignant disorders, yet risk factors are poorly understood. In this study, we aim to assess whether prolonged use of proton pump inhibitors (PPIs) increases the risk of incident biliary tract carcinoma in a nation-wide population-based cohort in Sweden. Approach and Results Using nation-wide registries, we identified all adults who received maintenance PPIs (>= 180 days) according to the Swedish Prescribed Drug Register from 2005 through 2012. Data on incident biliary tract cancer were retrieved from the Swedish Cancer, Death and Outpatient Registers. Risk of biliary tract cancer in persons who received PPI treatment was compared with the general population of the corresponding age, sex, and calendar year yielding standardized incidence ratios (SIRs) with 95% CIs. Of 738,881 PPI users (median follow-up of 5.3 years), 206 (0.03%) developed gallbladder cancer and 265 (0.04%) extrahepatic and 131 (0.02%) intrahepatic bile duct cancer corresponding to SIRs of 1.58 (95% CI, 1.37-1.81), 1.77 (95% CI, 1.56-2.00), and 1.88 (95% CI, 1.57-2.23), respectively. In sensitivity analyses restricted to persons without a history of gallstones or chronic liver or pancreatic diseases, SIRs were 1.36 (95% CI, 1.17-1.57) and 1.47 (95% CI, 1.19-1.80) for extra- and intrahepatic duct cancer, respectively. The risk remained higher than the corresponding general population with >= 5 years of PPIs use, ruling out confounding by indication. Conclusions In this study, long-term use of PPIs was associated with an increased risk of gallbladder, intrahepatic, and extrahepatic bile duct cancer compared with the general population

Association between proton pump inhibitor use and biliary tract cancer risk : a Swedish population-based cohort study

Background and Aims Biliary tract cancer is a group of highly aggressive malignant disorders, yet risk factors are poorly understood. In this study, we aim to assess whether prolonged use of proton pump inhibitors (PPIs) increases the risk of incident biliary tract carcinoma in a nation-wide population-based cohort in Sweden. Approach and Results Using nation-wide registries, we identified all adults who received maintenance PPIs (>= 180 days) according to the Swedish Prescribed Drug Register from 2005 through 2012. Data on incident biliary tract cancer were retrieved from the Swedish Cancer, Death and Outpatient Registers. Risk of biliary tract cancer in persons who received PPI treatment was compared with the general population of the corresponding age, sex, and calendar year yielding standardized incidence ratios (SIRs) with 95% CIs. Of 738,881 PPI users (median follow-up of 5.3 years), 206 (0.03%) developed gallbladder cancer and 265 (0.04%) extrahepatic and 131 (0.02%) intrahepatic bile duct cancer corresponding to SIRs of 1.58 (95% CI, 1.37-1.81), 1.77 (95% CI, 1.56-2.00), and 1.88 (95% CI, 1.57-2.23), respectively. In sensitivity analyses restricted to persons without a history of gallstones or chronic liver or pancreatic diseases, SIRs were 1.36 (95% CI, 1.17-1.57) and 1.47 (95% CI, 1.19-1.80) for extra- and intrahepatic duct cancer, respectively. The risk remained higher than the corresponding general population with >= 5 years of PPIs use, ruling out confounding by indication. Conclusions In this study, long-term use of PPIs was associated with an increased risk of gallbladder, intrahepatic, and extrahepatic bile duct cancer compared with the general population