Search Results (1,048)

Background: Amoxicillin–clavulanate (AC) is the antibiotic most frequently implicated in idiosyncratic drug-induced liver injury (DILI) worldwide, and it characteristically produces a cholestatic or mixed pattern in older adults. A predominantly hepatocellular presentation is distinctly less common in this age group, and reports from the Arabian Peninsula are scarce. Case presentation: A 66-year-old Saudi man developed painless, progressive jaundice after a seven-day course of oral AC (500/125 mg three times daily) prescribed for a thumb laceration. He described a similar self-limiting jaundice after the same antibiotic approximately five years earlier, an episode that was never investigated and had not been entered in his allergy record, so the drug was prescribed again unknowingly. Liver biochemistry, documented as normal four months earlier, showed alanine aminotransferase (ALT) peaking at 587 U/L (14.3 × the upper limit of normal, ULN) and aspartate aminotransferase at 335 U/L, with total bilirubin 249 µmol/L (11.9 × ULN) and a 69% conjugated fraction, whereas alkaline phosphatase (ALP) never exceeded 245 U/L (1.9 × ULN). The R-value at the ALT peak was 19.3 using the same-day ALP, and 7.6 even when the peak ALT is paired with the highest ALP recorded at any point in the illness; the pattern was therefore hepatocellular (R > 5) throughout the injury phase. Hy’s law criteria were met, although the international normalised ratio remained 1.0 and no encephalopathy developed. Peripheral eosinophilia (peak 1.05 × 10⁹/L) was documented. Hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody and HIV serology were non-reactive; antinuclear, anti-smooth-muscle, anti-liver-kidney microsomal type 1 and antimitochondrial antibodies were negative and serum ceruloplasmin was normal; ultrasound with contrast-enhanced triphasic computed tomography excluded biliary obstruction and malignancy. Hepatitis A and E serology and cytomegalovirus/Epstein–Barr studies were unavailable at our institution, which we report as a limitation. AC was withdrawn and management was supportive. Liver biochemistry normalised completely over the following three months (ALT 25 U/L, ALP 103 U/L, and total bilirubin 22 µmol/L). Updated Roussel Uclaf Causality Assessment Method (RUCAM) scoring on the hepatocellular scale gave 7 points (probable); no credit was taken for the historical episode, since RUCAM requires documented enzyme re-elevation for a positive re-administration response. Conclusions: AC can cause hepatocellular, Hy’s-law-positive injury in older adults, not only the cholestatic phenotype emphasised in the literature. The decisive failure here was administrative rather than diagnostic: an adverse drug reaction that is never recorded will be repeated. Full article

Curcumin derivatives (curcuminoids) exhibit considerable antiparasitic and antiviral activities. In this study, EF24-like bis-2-fluorobenzylidene piperidone derivatives were synthesized and evaluated for antiprotozoal activity and inhibition of the human immunodeficiency virus (HIV)-1 reverse transcriptase (RT)-associated RNase H (HIV-1 RNase H). A series of bis-arylidene piperidones and tetrahydro(thio)pyranones bearing halogen or nitro substituents were tested against Leishmania major (promastigotes and amastigotes) and Toxoplasma gondii. L. major promastigotes were the most sensitive parasitic model, with several compounds exhibiting low-nanomolar IC₅₀ values, while ortho- or para-halogenated analogues demonstrated submicromolar activity against T. gondii. Among them, 3,4-dichlorophenyl (HPip-DC) and 4-bromophenyl (HPip-4Br) derivatives showed potent activity against L. major and HIV-1 RNase H. The entropy-uncorrected MM-GBSA effective binding energy estimates were −33.41, −9.29, −8.37, and −4.27 kcal/mol for the predicted L. major squalene monooxygenase–HPip-DC, bovine cytochrome bc₁–DiFiD (2,4-difluorophenyl derivative), RNase H–HPip-4NO (4-nitrophenyl derivative), and RNase H–HPip-DC complexes, respectively. During 300 ns simulations, the ligands remained associated with their binding pockets. The Arg557 residue was crucial for HPip-4NO-mediated RNase H inhibition while the inhibitory activity of HPip-DC was much less dependent on this amino acid. These findings identify EF24-like curcuminoids with potent in vitro antiprotozoal activity and biochemical inhibition of HIV-1 RNase H. Antiviral activity was observed but confounded by host cell toxicity. Full article

Hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis D virus (HDV), together with HIV and bacterial sexually transmitted infections (STIs), account for a rising toll of more than one million deaths annually and overlap within shared behavioral and social networks, yet are still diagnosed through separate, pathogen-specific pathways. This narrative review synthesizes contemporary evidence on the convergence between viral hepatitis, HIV, and high-risk STI groups—men who have sex with men, pre-exposure prophylaxis (PrEP) users, people practicing chemsex, people who inject drugs, incarcerated populations, and migrants from endemic regions—and characterizes the diagnostic technologies and linkage-to-care models available to address it. Despite effective antivirals, the diagnostic cascade remains the principal bottleneck: most people with chronic HCV are undiagnosed, and HDV—with a pooled anti-HDV seroprevalence of approximately 4.5% among HBsAg-positive individuals—is its clearest expression, as most carriers are never tested. Reflex algorithms, multiplex panels, point-of-care assays, dried blood spots, and electronic health record alerts are validated but unevenly implemented. We argue that, alongside persistent resource, political, and equity-related constraints, a substantial share of the remaining barriers is operational rather than purely technological, and propose a practical, STI-clinic-centered framework integrating reflex testing, population-specific periodicity, and explicit linkage pathways toward the WHO 2030 elimination targets. Full article

Hepatitis B virus (HBV) infection remains a major concern among people living with HIV (PLWH), particularly in high-endemic settings such as Vietnam. The study evaluated the serological and molecular characteristics of HBV among PLWH receiving antiretroviral therapy (ART) in southern Vietnam. A cross-sectional study was conducted among 316 HIV-infected patients receiving ART. Serological markers (HBsAg, anti-HBs IgG, and anti-HBc IgG) and HBV DNA were assessed using highly sensitive assays, and the Pre-S1/Pre-S2/S regions were sequenced for genotype and mutation analysis. Associations were evaluated using appropriate statistical methods. HBV DNA was detected in 32.6% of the patients, whereas HBsAg was present in only 16.1%. The most common serological profile was susceptibility (36.4%), followed by occult HBV infection (OBI) (17.4%), including 6.6% with completely seronegative OBI, and chronic HBV (CHB) (15.8%). Males and older individuals showed a significantly higher risk of CHB (adjusted odds ratio [aOR] = 2.58 and aOR = 1.87, respectively). Genotype B predominated (78.4%) overall, but genotype C was significantly more frequent in OBI than in CHB patients (31.5% vs. 8.3%, p = 0.008). Moreover, the burden of surface S gene escape mutations was significantly higher in the OBI group (p = 0.023). The LASSO model showed a moderate discriminatory ability for predicting OBI status (Area Under the Receiver Operating Characteristic [ROC] Curve [AUC] = 0.76). Lamivudine-associated resistance (rtM204I/V) was the most common RT mutation detected in the overlapping RT/S region. HIV-infected individuals in southern Vietnam face a burden of both CHB and OBI, including a high proportion of seronegative OBI. The presence of seronegative OBI further supports the risk of underdiagnosis when relying only on standard serological markers, and reflects the need for integrated strategies combining highly sensitive serological assays with molecular diagnostics to improve HBV detection among high-risk populations. Full article

Anti-interferon-γ (IFN-γ) autoantibody (AAb)-associated adult-onset immunodeficiency (AOID) is an emerging disorder in East Asian adults characterized by severe opportunistic infections despite negative HIV status. The mechanisms driving anti-IFN-γ AAb production remain unclear. This study investigated B-cell gene expression, serum cytokine profiles, associations with AAb levels, and IFN-γ genetic variations in AOID patients. A cross-sectional study was conducted in 63 AOID patients and 30 healthy controls at Chiang Mai University Hospital, Thailand. Patients were classified as active or inactive according to infection status. B-cell gene expression, serum cytokines, anti-IFN-γ Aabs levels, and IFN-γ polymorphisms were analyzed by quantitative PCR, multiplex assays, ELISA, and nucleotide sequencing, respectively. AOID patients exhibited increased PAX5 and BLIMP1 expression and reduced XBP1, BCL6, KRAS, and BAFF expression. Active patients had higher levels of TNF-α, IL-6, IL-17A, IL-10, IL-21, and more chemokines than inactive patients. AAb levels positively correlated with TNF-α, IL-6, and IL-10. Correlation analysis showed positive associations among PAX5, XBP1, and KRAS, and a negative association between BLIMP1 and BCL6. No significant IFN-γ sequence differences were identified within the analyzed transcript region. These findings suggest altered B-cell gene expression and inflammatory cytokine profiles in AOID, which may be associated with the immunological alterations observed in these patients and may provide insights into potential mechanisms underlying anti-IFN-γ AAb production. Full article

Antiretroviral therapy (ART) has proven effective in suppressing HIV-1 replication, but further development of HIV-1 inhibitors is continually driven by the challenge of drug resistance and viral adaptation. The HIV-1 capsid is a promising target for treatment due to its high sequence conservation as well as its crucial role in the viral life cycle. Recently, we have developed a novel capsid-targeting biologic that prevents HIV-1 replication by efficient degradation of newly synthesized capsid. Here, we have investigated the sensitivity to viral escape as well as the breadth of this biologic against HIV-1 subtypes. The capsid-targeting biologic efficiently blocked replication of different primary HIV-1 isolates, and continuous exposure of these viruses to the biologic resulted in viral breakthrough of two out of ten primary HIV-1 isolates tested. Notably, the breakthrough variants did not have amino acid changes in the nanobody epitope but primarily in the matrix region. The breakthrough variants remained sensitive to the biologic albeit to a lesser extent. In the absence of the biologic, breakthrough variants showed increased replication kinetics when compared to their parental virus, suggesting that adaption to the biologic is likely due to the increased viral production and that the target area of the biologic is too conserved for actual escape. This is further underscored by the broad specificity of the biologic as importantly the biologic blocked infection of different HIV-1 subtypes that occur worldwide (A, B, C, D, CRF01_AE, CRF02_AG). These results demonstrate the broad neutralization potential of anti-capsid biologics with a high barrier to resistance, making capsid-targeting inhibitors important for novel antiretroviral drug strategies worldwide. Full article

Introduction: The Awareness/Acceptance/Action Model (AAAM) was initially developed by one of the authors to explore stigma and prejudice towards people living with HIV/AIDS. In the present study, the AAAM was examined for its personal and professional relevance to people affected by the Troubles, 30 years of sectarian conflict in Northern Ireland. When unchecked, judgmental or reactive attitudes can undermine intentions to consistently deliver services in line with professional standards and human rights. Methods: Despite a devolved, power-sharing government and steps to address longstanding political and religious grievances, cultural sensitivities and animosity remain on both sides of the divide. A university in Northern Ireland recruited 11 practice teachers and 18 social work students, who participated in one of four focus groups. Mindfulness principles and techniques were used to allow participants to visualise “the other” before exploring how prejudice might impact personal and professional interactions. Thematic analysis of focus group transcripts was conducted using Braun and Clarke to assess the presence and nature of labelling, stereotyping, out-grouping and discriminating against people perceived as “the other”. Findings: Given the potential differences in identity, background, and experiences of social work practitioners and service users, it is important that we critically reflect on how we serve people based on direct or intergenerationally transmitted encounters. The AAAM was then piloted in undergraduate social work degree programmes and shared with practice teachers. Feedback confirmed that it offers a theoretical framework to promote anti-oppressive practice and critical reflection during professional social work training. Using Mindfulness techniques to visualise “the other” prompted participants to listen well and look deeply at the origins of their prejudices or fear, and how these could lead to biased interactions with service users. Full article

Background: Sexually transmitted infections (STIs) remain a major global health concern, with over one million new curable cases reported daily and limited long-term treatment options. Additionally, there are limited treatment options for women with bacterial vaginosis (BV), a dysbiotic condition predisposing them to STIs. Computationally designed human-milk-inspired antimicrobial peptides (AMPs) are promising candidates for novel antiviral and antibacterial therapies. This study evaluated the cervicovaginal mucosal safety and antiviral activity of three human-milk-inspired AMPs (MAT-006, UCD-MAT-001, and UCD-MAT-002) previously shown to exhibit antimicrobial activity against BV-causing pathogens. Methods: AMP cytotoxicity and inflammatory responses were assessed in relevant genital tract cell lines and cervicovaginal tissues in vitro. AMP anti-HIV-1 and anti-HSV-2 activities were characterized in female genital tract cell lines, TZM-bl cells and HEC-1-A cells, respectively, and in time-of-addition (pre-, co-, and post-HIV-1 challenge; and post-HSV-2 challenge) experiments. The impact of seminal plasma on AMPs’ activity was also evaluated. Results: At the concentrations tested, all three AMPs showed minimal cytotoxicity and no pro-inflammatory responses in cellular and ectocervical tissue explant models. In both co- and post-exposure models, all three AMPs inhibited HIV-1 and HSV-2 replication with IC₅₀ values ranging from 0.78 to 7.72 mg/mL. MAT-006 further showed pre-exposure anti-HIV-1 activity after 6 h (IC₅₀ = 1.07 ± 0.515 mg/mL) and 24 h (IC₅₀ = 0.69 ± 0.152 mg/mL) of incubation. Seminal plasma did not significantly impair MAT-006 and UCD-MAT-001 antiviral activity under experimental conditions. Conclusions: These findings demonstrate the antiviral activity of human-milk-inspired AMPs against HIV-1 and HSV-2 at concentrations that are safe to the cervicovaginal mucosa in vitro, warranting further preclinical evaluation as microbicide candidates with dual antibacterial and antiviral properties. Full article

During HIV infection, the immune system initiates an immune response to control the viremia. In this in vitro study, we investigated the immunomodulatory and anti-HIV potential of a traditional medicine formulation, Product Nkabinde (PN). A freeze-dried extract of PN was used to determine cytotoxicity in MT4 cells. Non-cytotoxic doses were used to evaluate the immunomodulatory and anti-HIV effects of PN using neutralization, prophylactic and treatment approaches. Post-treatment, cytokine quantification and p24 detection were performed. In the neutralization strategy, PN restored IL-1α (p = 0.0389) and IL-10 (p = 0.0443) to levels of uninfected cells. It also reduced HIV-induced elevations in IL-8 (p = 0.035), IP-10 (p = 0.0886), and MCP-1 (p = 0.0733) compared to HIV-infected cells. In the prophylactic approach, HIV infection upregulated IL-1α (p = 0.676), which was suppressed by PN. In the treatment strategy, PN reversed the elevated levels of IL-1α (p = 0.049). IL-10 was fully restored by PN to levels of uninfected cells. In all strategies, PN induced a significant and dose-dependent decrease in HIV replication. These findings demonstrate that PN exerts potent immunomodulatory effects all strategies used by reversing HIV-induced cytokine dysregulation, thereby inducing significant anti-HIV effects. Full article

Tuberculosis (TB) continues to be a significant public health challenge in Europe, despite a sustained decline in disease incidence over recent decades. This narrative review briefly traces the historical development of TB diagnosis and focuses on the evolution of TB control protocols from the early twentieth century to the present across Europe, through a longitudinal comparative analysis of its geographical regions. A literature search was conducted using publications, guidelines, and surveillance reports from the World Health Organization (WHO), the European Centre for Disease Prevention and Control (ECDC), and national public health authorities. The analysis follows a geographical framework encompassing Eastern, Western, Northern, and Southern Europe, reflecting historical, socioeconomic, and healthcare system differences. This study presents the transition from traditional diagnostic approaches based on clinical assessment, chest radiography, and smear microscopy to modern molecular and immunological techniques, including Xpert MTB/RIF assays and interferon-gamma release assays (IGRAs). Similarly, treatment strategies have evolved from sanatorium-based supportive care to standardized, evidence-based short-course regimens employing first- and second-line anti-TB drugs. However, marked regional differences remain in the implementation of contemporary protocols. Western and Northern European countries have largely adopted advanced diagnostic technologies and comprehensive surveillance systems and are approaching TB elimination targets. In contrast, Eastern Europe continues to bear a disproportionate disease burden, driven by multidrug-resistant TB, HIV co-infection, and socioeconomic disparities. TB control protocols in Southern Europe are progressively converging with those of Western Europe through the adoption of modern diagnostic approaches, standardized treatment regimens, and WHO-endorsed guidelines. The findings of this study underscore the need for greater harmonization of TB control protocols across Europe through an initiative coordinated by the ECDC/WHO. Accelerating progress toward TB elimination in the European Region will depend on expanding access to modern diagnostic technologies, implementing targeted interventions in high-burden settings, and strengthening cross-border collaboration through coordinated public health policies. Full article

To predict the anti-HIV-1 activity of biphenyl-DAPY-based non-nucleoside reverse transcriptase inhibitors (NNRTIs), a quantitative structure–activity relationship (QSAR) analysis was conducted. Using the heuristic method (HM) for descriptor selection, four predictive models were established: support vector regression (SVR), kernel ridge regression, linear mixed-kernel SVR, and Linear Residual Network (LRNet). Rigorous validations, including leave-one-out cross-validation, fivefold cross-validation, and Y-randomization tests, confirmed their reliability. The LRNet model exhibited the best performance, achieving an average training set $R^2$ of $0.8838\pm 0.0090$ and an average test set $R^2$ of $0.9026\pm 0.0187$ over 50 random train–test splits, with $Q_{5-fold}^2$ and $Q_{LOO}^2$ being 0.8533 and 0.8541, respectively. To further verify the robustness and generalizability of LRNet, independent validation was performed using an external dataset, where LRNet also achieved better generalization performance. The HM and LRNet models were employed to guide the design of novel compounds. Their favorable binding modes with the 1RT2 protein and pharmacokinetic properties were verified via molecular docking and in silico ADMET profiling, respectively. Furthermore, 100 ns molecular dynamics simulations demonstrated the robust dynamic stability, structural compactness, and thermodynamic convergence of the designed candidate within the 1RT2 binding pocket. This study provides a useful computational framework for the rational design and activity prediction of biphenyl-DAPY-based NNRTIs. Full article

Cutaneous co-infection with Mycobacterium tuberculosis (MTB) and Mycobacterium avium complex (MAC) is extremely rare and easily missed due to overlapping histopathological features. We report a previously healthy, HIV-negative middle-aged woman who presented with a progressive destructive mass in the left inguinal-perineal region. Imaging revealed sinus tract formation, osteolytic bone lesions, and chronic inflammation in the right middle lobe of the lung. Initial metagenomic next-generation sequencing (mNGS) detected 3756 reads of the Mycobacterium tuberculosis complex (MTBC) and 111 reads of Mycobacterium intracellulare (M. intracellulare); the latter was interpreted as possible colonization or contamination because of its low abundance. Empirical anti-tuberculosis therapy produced only transient partial improvement, followed by paradoxical worsening, local recurrence, and new bone destruction. After a high suspicion of mixed infection, a MAC-directed combination regimen (including azithromycin and a short course of amikacin) was added, leading to complete clinical cure; subsequent repeat cultures confirmed the presence of MAC. This is the first report of cutaneous MTB-MAC co-infection in the inguinal-perineal region of an adult without overt immune abnormalities, accompanied by disseminated bone lesions. This case highlights that in regions where nontuberculous mycobacteria (NTM) are co-endemic, atypical destructive skin lesions with paradoxical worsening despite initial response to anti-tuberculosis therapy should raise suspicion of MAC co-infection. The combination of mNGS and conventional culture facilitates identification of mixed infections and guides precision therapy, but mNGS results must be interpreted cautiously in the clinical context. Full article

The human APOBEC3 (A3) family of cytidine deaminases, including A3G, A3F, and A3H, participates in cellular anti-retroviral immunity. In contrast, to antagonize the anti-retroviral activities of these A3 family proteins, HIV-1 produces its gene product called viral infectivity factor (Vif) in infected cells. Vif is a pleiotropic hub protein that specifically binds to various A3 proteins with the aid of host core-binding factor subunit β (CBF-β) and mediates their proteasomal degradation. To date, numerous biological and structural studies have been performed to understand the arms race between A3 and Vif. Previous extensive mutagenesis and structural analyses have suggested that there are three distinct types of Vif-binding interfaces among human A3s and three largely nonoverlapping interfaces on Vif for binding with these A3s. Moreover, recent cryo-electron microscopy (cryo-EM) structural analyses have clarified further details of the different intermolecular interactions of Vif with each of three human A3s (A3G, A3F, and A3H) and have proposed a possible mechanism by which one Vif molecule can recognize all three types of A3s. In this review, we summarize the current understanding of the structural basis of the interaction between A3 and Vif. This information may be helpful for developing drugs targeting these interfaces. Full article

Hepatitis B virus (HBV) infection remains a major driver of liver-related morbidity and mortality among people living with HIV (PLWH), yet vaccine-induced protection is frequently suboptimal. HIV-associated immune dysfunction, including CD4⁺ T-cell depletion, altered antigen presentation, impaired T follicular helper cell support, and B-cell dysregulation, reduces seroprotection after standard recombinant HBV vaccines and may limit durability of antibody responses. Vaccine response is further influenced by HIV viral suppression, age, comorbidities, prior vaccine history, and baseline HBV serologic status, including isolated hepatitis B core antibody (anti-HBc) and occult HBV infection (OBI) considerations. Although antiretroviral therapy (ART) improves vaccine responsiveness, many PLWH fail to achieve protective hepatitis B surface antibody (anti-HBs) titers (≥10 mIU/mL) after conventional schedules, or experience antibody waning over time. Current guidelines recommend HBV vaccination for all susceptible PLWH with post-vaccination serologic testing and revaccination for nonresponders. Persistent implementation barriers, including incomplete series, vaccine hesitancy, stigma, and logistical constraints, continue to limit real-world impact. Emerging clinical trial data support CpG-adjuvanted HBV vaccines (HepB-CpG/Heplisav-B) and intensified dosing and schedules (double-dose or four-dose regimens) to improve seroprotection and generate higher peak anti-HBs titers, which may enhance durability. This review synthesizes guideline recommendations, immunologic mechanisms of hyporesponsiveness, predictors of vaccine response, and practical strategies to optimize HBV vaccination in PLWH. Full article

Background: As a major regulator, methyltransferase-like 3 (METTL3) catalyzes N6-methyladenosine (m⁶A) modification in mRNA. The m⁶A modifications mediated by METTL3 influence RNA splicing, nucleocytoplasmic distribution, stability, and other functions, thereby playing a vital and indispensable role in genetic regulatory network. Although several studies have shown its critical role in mRNA fate, the global pattern of mRNA methylation alteration driven by METTL3 remain unclear. Methods: Here, a HEK293T cell line with METTL3 depletion was constructed, and RNA sequencing (RNA-seq) and methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) were implemented. Additionally, quantitative Reverse Transcription PCR (qRT-PCR) technology was used to confirm some of the differentially expressed genes. Result: The mRNA methylation alteration landscape was clarified and the regions altered by m⁶A modification due to METTL3 deletion that was annotated and characterized, with 5763 hypomethylated/269 hypermethylated genes after METTL3 silence. Several methylation-related innate anti-infection immune genes, including MYD88, RIG-1, CYLD and IRF9, were exposed through comprehensive analysis to MeRIP-seq and RNA-seq data, and these genes were principally enriched in pathogen infection and innate immune response pathways such as Shigellosis, Yersinia infection, and the HIV-1 viral life cycle. Conclusion: Our study discovered that the METTL3 association with differentially expressed genes, suggested that METTL3 and the genes it regulates might serve as targets for defense against infection. Full article