Biomarkers of transfusion transmitted occult hepatitis B virus infection: Where are we and what next?

Blood transfusion is a vital procedure, where transfusion-transmitted infection of hepatitis B virus (HBV) remains an important issue, especially from blood donors with occult hepatitis B virus infection (OBI). Occult hepatitis B virus infection is a complex entity to detect using surrogate blood biomarkers for intrahepatic viral transcriptional activity, requiring a continually refined battery of tests utilised for screening. This review aims to critically evaluate the latest advances in the current blood biomarkers to guide the identification of OBI donors and discuss novel HBV markers that could be introduced in future diagnostic practice. Challenges in detecting low HBV surface antigen levels, mutants, and complexes necessitate ultrasensitive multivalent dissociation assays, whilst HBV DNA testing requires improved sensitivity but worsens inaccessibility. Anti-core antibody assays defer almost all potentially infectious donations but have low specificity, and titres of anti-surface antibodies that prevent infectivity are poorly defined with suboptimal sensitivity. The challenges associated with these traditional blood HBV markers create an urgent need for alternative biomarkers that would help us better understand the OBI. Emerging viral biomarkers, such as pre-genomic RNA and HBV core-related antigen, immunological HBV biomarkers of T-cell reactivity and cytokine levels, and host biomarkers of microRNA and human leucocyte antigen molecules, present potential advances to gauge intrahepatic activity more accurately. Further studies on these markers may uncover an optimal diagnostic algorithm for OBI using quantification of various novel and traditional blood HBV markers. Addressing critical knowledge gaps identified in this review would decrease the residual risk of transfusion-transmitted HBV infection without compromising the sustainability of blood supplies.

Reconstruction of the historic time course of blood-borne virus contamination of clotting factor concentrates, 1974-1992.

Factor VIII and IX clotting factor concentrates manufactured from pooled plasma have been identified as potent sources of virus infection in persons with hemophilia (PWHs) in the 1970s and 1980s. To investigate the range and diversity of viruses over this period, we analysed 24 clotting factor concentrates for several blood-borne viruses. Nucleic acid was extracted from 14 commercially produced clotting factors and 10 from nonremunerated donors, preserved in lyophilized form (expiry dates: 1974-1992). Clotting factors were tested by commercial and in-house quantitative PCRs for blood-borne viruses hepatitis A, B, C and E viruses (HAV, HBV, HCV, HEV), HIV- types 1/2, parvoviruses B19V and PARV4, and human pegiviruses types 1 and 2 (HPgV-1,-2). HCV and HPgV-1 were the most frequently detected viruses (both 14/24 tested) primarily in commercial clotting factors, with frequently extremely high viral loads in the late 1970s-1985 and a diverse range of HCV genotypes. Detection frequencies sharply declined following introduction of virus inactivation. HIV-1, HBV, and HAV were less frequently detected (3/24, 1/24, and 1/24 respectively); none were positive for HEV. Contrastingly, B19V and PARV4 were detected throughout the study period, even after introduction of dry heat treatment, consistent with ongoing documented transmission to PWHs into the early 1990s. While hemophilia treatment is now largely based on recombinant factor VIII/IX in the UK and elsewhere, the comprehensive screen of historical plasma-derived clotting factors reveals extensive exposure of PWHs to blood-borne viruses throughout 1970s-early 1990s, and the epidemiological and manufacturing parameters that influenced clotting factor contamination.

International review of blood donation screening for anti-HBc and occult hepatitis B virus infection.

BACKGROUND: Hepatitis B core antibody (anti-HBc) screening has been implemented in many blood establishments to help prevent transmission of hepatitis B virus (HBV), including from donors with occult HBV infection (OBI). We review HBV screening algorithms across blood establishments globally and their potential effectiveness in reducing transmission risk. MATERIALS AND METHODS: A questionnaire on HBV screening and follow-up strategies was distributed to members of the International Society of Blood Transfusion working party on transfusion-transmitted infectious diseases. Screening data from 2022 were assimilated and analyzed. RESULTS: A total of 30 unique responses were received from 25 countries. Sixteen respondents screened all donations for anti-HBc, with 14 also screening all donations for HBV DNA. Anti-HBc prevalence was 0.42% in all blood donors and 1.19% in new donors in low-endemic countries; however, only 44% of respondents performed additional anti-HBc testing to exclude false reactivity. 0.68% of anti-HBc positive, HBsAg-negative donors had detectable HBV DNA. Ten respondents did universal HBV DNA screening without anti-HBc, whereas four respondents did not screen for either. Deferral strategies for anti-HBc positive donors were highly variable. One transfusion-transmission from an anti-HBc negative donor was reported. DISCUSSION: Anti-HBc screening identifies donors with OBI but also results in the unnecessary deferral of a significant number of donors with resolved HBV infection and donors with false-reactive anti-HBc results. Whilst confirmation of anti-HBc results could be improved to reduce donor deferral, transmission risks associated with anti-HBc negative OBI donors must be considered. In high-endemic areas, highly sensitive HBV DNA testing is required to identify infectious donors.

Blood donation screening for hepatitis B virus core antibodies: The importance of confirmatory testing and initial implication for rare blood donor groups.

BACKGROUND AND OBJECTIVES: Exclusion of blood donors with hepatitis B virus (HBV) core antibodies (anti-HBc) prevents transfusion-transmitted HBV infection but can lead to significant donor loss. As isolated anti-HBc positivity does not always indicate true past HBV infection, we have investigated the effectiveness of confirmatory anti-HBc testing and the representation of rare blood groups in anti-HBc-positive donors. MATERIALS AND METHODS: Three hundred ninety-seven HBV surface antigen-negative and anti-HBc initially reactive blood donor samples were tested by five different anti-HBc assays. RESULTS: Eighty percentage of samples reactive in Architect anti-HBc assay were positive by the Murex assay and anti-HBc neutralization. Eleven out of 397 samples showed discordant results in supplementary testing from the Murex confirmatory test result, and five remained undetermined following extensive serological testing. Thirty-eight percentage of anti-HBc-positive donors identified as minority ethnic groups compared with 11% representation in anti-HBc-negative donors (p < 0.0001); the frequency of the Ro blood group in anti-HBc-positive donors was 18 times higher in non-white ethnic groups. CONCLUSION: Using two anti-HBc assays effectively enabled the identification of HBV-exposed and potentially infectious donors, their deferral and potential clinical follow-up. However, the exclusion of confirmed anti-HBc-positive donors will still impact the supply of rare blood such as Ro.

Ultrasensitive PCR system for HBV DNA detection: Risk stratification for occult hepatitis B virus infection in English blood donors.

Occult hepatitis B (HBV) infection (OBI), characterized by low viral loads, accounts for much of the risk of HBV transfusion-transmitted infection. With anticore antibodies (anti-HBc) screening introduced in England, the imperative to identify OBI donors has increased. We aimed to develop an ultra-sensitive PCR system and investigate risk factors for HBV DNA presence in blood donations. Seven extraction methods and three PCR assays were compared. The optimal system was sought to determine HBV DNA presence in anti-HBc-positive donations. Predictors of DNA positivity were subsequently investigated. Extraction from 5 mL of plasma increased sample representation and resulted in HBV DNA detection in low viral load samples (~0.5 IU/mL). Screening of 487 763 donations in 2022 identified two OBI donors and 2042 anti-HBc-positive donors, 412 of the latter with anti-HBs < 100 mIU/mL. Testing of 134 anti-HBc-positive donations utilizing the 5 mL extraction method identified two further HBV DNA-positive donations. Higher anti-HBc titer and anti-HBs negativity were significant predictors of DNA detectability in anti-HBc-positive donations. An ultrasensitive PCR assay identified potentially infectious donations increasing HBV DNA detection in anti-HBc-positive donors from 0.5% to 1.9%. Anti-HBc titers may further complement the risk stratification for DNA positivity in anti-HBc screening and minimize unnecessary donor deferral.

Patient voices and student insights into LGBTQ+ healthcare: a call for equitable healthcare through medical education.

PURPOSE: Lesbian, gay, bisexual, transgender, queer, and other sexual and gender diverse (LGBTQ+) individuals have health needs specific to their identities. However, they face discrimination and cis-heteronormativity in most patient-provider interactions, which often translate into poor healthcare. Evidence suggests doctors are inadequately trained to care for LGBTQ+ patients. Medical students are well-placed as the future workforce to establish affirming behaviours. This study garners LGBTQ+ patients' healthcare experiences, where limited qualitative evidence exists, and explores whether students have insight into these experiences. METHOD: Thirty LGBTQ+ patients and twenty students, evenly divided between Singapore and the United Kingdom (UK), two legally and culturally different countries, consented to semi-structured interviews in 2022 to evaluate their LGBTQ+ healthcare perceptions. Thematic analysis was conducted using a collaborative, iterative process involving five investigators, with frequent auditing of data interpretation. RESULTS: Most patients described implicit biases with a lack of support and professionalism from doctors, hindering health outcomes. Patients experienced misgendering and a lack of recognition of sexual and gender diversity; students appreciated the need to acknowledge patient identity. Although perceptions surrounding certain themes were similar between patients and students in both countries, patients' voices on the complexity and dissatisfaction of gender-diverse care contrasted with students' lack of insight on these themes. Singapore patients were more concerned with sociolegal acceptance affecting health needs, whilst UK patients noted more nuanced barriers to healthcare. Although many students were unsure about specific health needs and perceived a lack of training, they expressed willingness to create an equitable healthcare environment. CONCLUSIONS: LGBTQ+ patients provided powerful narratives on discrimination surrounding their healthcare needs. To address these, medical students must be encouraged by healthcare educators to develop identity-affirming behaviours as future change-makers and challenge cis-heteronormative views. Alongside vital institutional changes tailored to each country, patients' and students' collective action would create meaningful educational opportunities to reach culture change.

Stereotactic Body Radiotherapy for Management of Pulmonary Oligometastases in Stage IV Colorectal Cancer: A Perspective.

In pulmonary oligometastases from colorectal cancer (POM-CRC), metastasectomy is the primarily recommended treatment. Stereotactic body radiotherapy (SBRT) has been suggested as a viable alternative therapy. SBRT efficacy for POM-CRC is poorly delineated compared to selected non-CRC primaries. This perspective article aims to critically summarize the existing evidence regarding efficacy of SBRT in terms of overall survival (OS) and local control (LC), and factors modulating this, in the treatment of POM-CRC. Overall, reasonable LC and OS rates were observed. The wide range of expansions in planning target volume margins introduced variation in pretreatment protocols. Dose-fractionation schedules varied according to patient and tumor characteristics, though leverage of BED10 in select studies enabled standardization. An association between SBRT dose and improved OS and LC was observed across multiple studies. Prognostic factors that were associated with improved LC included: fewer oligometastases, absence of extra-pulmonary metastases, primary tumor histology, and smaller gross tumor volume. Differences in SBRT modality and techniques over time further confounded results. Many studies included patients receiving additional systemic therapies; preprotocol and adjuvant chemotherapies were identified as prognostic factors for LC. SBRT compared with metastasectomy showed no differences in short-term OS and LC outcomes. In conclusion, SBRT is an efficacious treatment for POM-CRC, in terms of OS and LC. Heterogeneity in study design, particularly pertaining to dose protocols, patient selection, and additional therapies should be controlled for future randomized studies to further validate SBRT efficacy.

Medical students' perceptions of LGBTQ+ healthcare in Singapore and the United Kingdom.

Introduction: Lesbian, gay, bisexual, transgender, queer, and other sexual and gender minority (LGBTQ+) individuals have an increased scope of healthcare needs and face many barriers to accessing healthcare. However, LGBTQ+ healthcare education remains scarce, and students' understanding of LGBTQ+ healthcare remains largely uncharacterised. This study investigated the knowledge of and attitudes toward LGBTQ+ healthcare among medical students in Singapore and the United Kingdom (UK), two culturally different countries. Methods: Medical students in two medical schools, one in Singapore and the other in the UK, completed self-administered cross-sectional surveys using multiple-choice, Likert scale, and free-text questions to explore their ideas, concerns, and expectations about LGBTQ+ healthcare education within their medical curricula. Results: From 330 responses, students' knowledge levels were moderate overall, with pronounced gaps in certain areas, including terminology, sexual health, and conversion therapy. Deficiencies in knowledge were significantly greater among students in Singapore compared to the UK (p < 0.001), whilst LGBTQ+ students and non-religious students had more positive knowledge and attitudes than students not identifying. At least 78% of students had positive attitudes towards LGBTQ+ individuals, but 84% had not received LGBTQ+-specific medical education. Although junior UK students were more satisfied with the adequacy of teaching by their medical school's incorporation of LGBTQ+ inclusive teaching in a newer curriculum, qualitative analyses suggested that students in both countries wanted to receive more training. Students further suggested improvements to the medical curriculum to meet their needs. Conclusion: Students in both schools lacked understanding of commonly-used terminology and topics such as sexual healthcare despite affirming attitudes towards LGBTQ+ healthcare. Although sociolegal contexts may affect students' perspectives, differences were less than thought, and students were equally keen to provide affirmative care to their patients. They emphasised a need for more formal teaching of LGBTQ+ healthcare professions to overcome healthcare disparities in these communities.

MicroShunt versus Trabeculectomy for Surgical Management of Glaucoma: A Retrospective Analysis.

This case-control study aims to compare the efficacy, safety, and postoperative burden of MicroShunt versus trabeculectomy. The first consecutive cohort of MicroShunt procedures (n = 101) was matched to recent historical trabeculectomy procedures (n = 101) at two London hospital trusts. Primary endpoints included changes in intraocular pressure (IOP) and glaucoma medications. Secondary outcome measures included changes in retinal nerve fibre layer (RNFL) thickness, rates of complications, further theatre interventions, and the number of postoperative visits. From the baseline to Month-18, the median [interquartile range] IOP decreased from 22 [17-29] mmHg (on 4 [3-4] medications) to 15 [10-17] mmHg (on 0 [0-2] medications) and from 20 [16-28] mmHg (on 4 [3-4] medications) to 11 [10-13] mmHg (on 0 [0-0] medications) in the MicroShunt and trabeculectomy groups, respectively. IOP from Month-3 was significantly higher in the MicroShunt group (p = 0.006), with an increased number of medications from Month-12 (p = 0.024). There were greater RNFL thicknesses from Month-6 in the MicroShunt group (p = 0.005). The rates of complications were similar (p = 0.060) but with fewer interventions (p = 0.031) and postoperative visits (p = 0.001) in the MicroShunt group. Therefore, MicroShunt has inferior efficacy to trabeculectomy in lowering IOP and medications but provides a better safety profile and postoperative burden and may delay RNFL loss.