Search Results (225)

Cancer disparities in low- and middle-income countries (LMICs) arise from multifaceted interactions between environmental exposures, infectious agents, and systemic inequities, such as limited access to care. The exposome, a framework encompassing the totality of non-genetic exposures throughout life, offers a powerful lens for understanding these disparities. In LMICs, populations are disproportionately affected by air and water pollution, occupational hazards, and oncogenic infections, including human papillomavirus (HPV), hepatitis B virus (HBV), Helicobacter pylori (H. pylori), human immunodeficiency virus (HIV), and neglected tropical diseases, such as schistosomiasis. These infectious agents contribute to increased cancer susceptibility and poor outcomes, particularly in immunocompromised individuals. Moreover, climate change, food insecurity, and barriers to healthcare access exacerbate these risks. This review adopts a population-level exposome approach to explore how environmental and infectious exposures intersect with genetic, epigenetic, and immune mechanisms to influence cancer incidence and progression in LMICs. We highlight the critical pathways linking chronic exposure and inflammation to tumor development and evaluate strategies such as HPV and HBV vaccination, antiretroviral therapy, and environmental regulation. Special attention is given to tools such as exposome-wide association studies (ExWASs), which offer promise for exposure surveillance, early detection, and public health policy. By integrating exposomic insights into national health systems, especially in regions such as sub-Saharan Africa (SSA) and South Asia, LMICs can advance equitable cancer prevention and control strategies. A holistic, exposome-informed strategy is essential for reducing global cancer disparities and improving outcomes in vulnerable populations. Full article

Diabetic sensorimotor polyneuropathy (DSPN) is the most prevalent complication of diabetes, affecting nearly half of all persons with diabetes. It is characterized by nerve degeneration, progressive sensory loss and pain, with increased risk of ulceration and amputation. Despite its high prevalence, disease-modifying treatments for DSPN do not exist. Mitochondrial dysfunction and Ca²⁺ dyshomeostasis are key contributors to the pathophysiology of DSPN, disrupting neuronal energy homeostasis and initiating axonal degeneration. Recent findings have demonstrated that antagonism of the muscarinic acetylcholine type 1 receptor (M₁R) promotes restoration of mitochondrial function and axon repair in various neuropathies, including DSPN, chemotherapy-induced peripheral neuropathy (CIPN) and HIV-associated neuropathy. Pirenzepine, a selective M₁R antagonist with a well-established safety profile, is currently under clinical investigation for its potential to reverse neuropathy. The transient receptor potential melastatin-3 (TRPM3) channel, a Ca²⁺-permeable ion channel, has recently emerged as a downstream effector of G protein-coupled receptor (GPCR) pathways, including M₁R. TRPM3 activation enhanced mitochondrial Ca²⁺ uptake and bioenergetics, promoting axonal sprouting. This review highlights mitochondrial and Ca²⁺ signaling imbalances in DSPN and presents M₁R antagonism and TRPM3 activation as promising neuro-regenerative strategies that shift treatment from symptom control to nerve restoration in diabetic and other peripheral neuropathies. Full article

The diversity and distribution of medical and veterinary-relevant fungal diseases in Africa underscore the critical need for a multisectoral One Health strategy to enhance cost-effective preparedness and prevention. This review explores the geographic spread and epidemiology of key medical and veterinary fungi, including Emergomyces, Blastomyces, Coccidioides, Cryptococcus, Dermatophytes, Histoplasma, Sporothrix, Talaromyces, Paracoccidioides, Aspergillus, and Malassezia. Evidence indicates that many of these infections remain underdiagnosed and underreported, especially in vulnerable immunocompromised populations, due to limited surveillance, diagnostic capacity, and awareness. The increasing prevalence of these diseases, often in tandem with rising HIV rates and environmental changes, highlights the urgent need for coordinated efforts across human, animal, and environmental health sectors. Implementing comprehensive, multisectoral interventions—focused on enhancing diagnostic capabilities, public awareness, surveillance, and cross-sector collaboration—is vital for effective prevention and control of these emerging fungal threats in Africa. Full article

Background/Objectives: Syphilis, a re-emerging global public health issue, has shown increasing incidence over the past decade, particularly among key populations such as men who have sex with men (MSM), people living with HIV, and pregnant women. This narrative review aimed to synthesize global epidemiological trends of syphilis from 2015 to 2025, with a focus on surveillance gaps, regional disparities, and structural determinants. Methods: A broad narrative approach was used to collect and analyze epidemiological data from 2015 to 2025. The literature was retrieved from databases (PubMed, Scopus) and official reports from the WHO, CDC, and ECDC. Included materials span observational studies, surveillance reports, and modeling data relevant to global trends and public health responses. Results: Globally, syphilis incidence has increased, with notable surges in North America, Europe, and Asia. MSM remain disproportionately affected, while congenital syphilis is resurging even in high-income countries. Low- and middle-income countries report persistent burdens, especially among women of reproductive age, often exacerbated by limited screening and surveillance infrastructure. The COVID-19 pandemic disrupted syphilis-related services and further exacerbated underreporting, hindering timely detection and response efforts. Surveillance systems vary widely in their completeness and quality, which significantly hinders global data comparability and coordinated public health responses. Conclusions: Despite its curability, syphilis continues to spread due to fragmented prevention strategies, inequities in access to care, and insufficient surveillance. Strengthening diagnostic access, integrating prevention efforts into broader health systems, and addressing social determinants are essential. Improved surveillance, equitable access, and innovation—including diagnostics and potential vaccine research—are critical to controlling the global syphilis epidemic. Full article

In this paper, we develop an HIV/AIDS epidemic model that incorporates a saturated incidence rate to reflect the limited transmission capacity and the impact of behavioral saturation in contact patterns. The model is formulated as a system of seven non-linear ordinary differential equations representing key population compartments. In addition to model formulation, we introduce an optimal control problem involving three control measures: educational campaigns, screening of unaware infected individuals, and antiretroviral treatment for aware infected individuals. We begin by establishing the positivity and boundedness of the model solutions under constant control inputs. The existence and local and global stability of both the disease-free and endemic equilibrium points are analyzed, depending on the effective reproduction number (${\mathcal{R}}_e$). Bifurcation analysis reveals that the model undergoes a forward bifurcation at ${\mathcal{R}}_e=1$. A local sensitivity analysis of ${\mathcal{R}}_e$ identifies the disease transmission rate as the most sensitive parameter. The optimal control problem is then formulated by incorporating the dynamics of infected subpopulations, control costs, and time-dependent controls. The existence of optimal control solutions is proven, and the necessary conditions for optimality are derived using Pontryagin’s Maximum Principle. Numerical simulations support the theoretical analysis and confirm the stability of the equilibrium points. The optimal control strategies, evaluated using the Incremental Cost-Effectiveness Ratio (ICER), indicate that implementing both screening and treatment (Strategy D) is the most cost-effective intervention. These results provide important insights for designing effective and economically sustainable HIV/AIDS intervention policies. Full article

HIV-1 Tat acts as a central molecular switch governing the transition between viral latency and active replication, making it a pivotal target for HIV-1 functional cure strategies. By binding to the viral long terminal repeat (LTR) and hijacking host transcriptional machinery, Tat dynamically regulates RNA polymerase II processivity to alter viral transcription states. Recent studies reveal its context-dependent variability: while Tat recruits chromatin modifiers and scaffolds non-coding RNAs to stabilize epigenetic silencing in latently infected cells, it also triggers rapid transcriptional amplification upon cellular activation. This review systematically analyzes the bistable regulatory mechanism of Tat and investigates advanced technologies for reprogramming this switch to eliminateviral reservoirs and achieve functional cures. Conventional approaches targeting Tat are limited by compensatory viral evolution and poor bioavailability. Next-generation interventions will employ precision-engineered tools, such as AI-optimized small molecules blocking Tat-P-TEFb interfaces and CRISPR-dCas9/Tat chimeric systems, for locus-specific LTR silencing or reactivation (“block and lock” or “shock and kill”). Advanced delivery platforms, including brain-penetrant lipid nanoparticles (LNPs), enable the targeted delivery of Tat-editing mRNA or base editors to microglial reservoirs. Single-cell multiomics elucidates Tat-mediated clonal heterogeneity, identifying “switchable” subpopulations for timed interventions. By integrating systems-level Tat interactomics, epigenetic engineering, and spatiotemporally controlled delivery, this review proposes a roadmap to disrupt HIV-1 persistence by hijacking the Tat switch, ultimately bridging mechanistic insights to clinical applications. Full article

Neck of femur (NOF) fractures are a critical orthopaedic emergency with a high morbidity and mortality prevalence, particularly in people living with Human Immunodeficiency Virus (PLWHIV). A combination of HIV infection, combined antiretroviral therapy (cART), and compromised bone health further increases the risk of fragility fractures. Additionally, HIV-related immune dysfunction, cART-induced osteoporosis, and perioperative infection risks further pose challenges in ongoing surgical management. Despite the rising global prevalence of PLWHIV, no specific guidelines exist for the perioperative and post-operative care of PLWHIV undergoing NOF fracture surgery. This narrative review synthesises the current literature on the surgical management of NOF fractures in PLWHIV, focusing on pre-operative considerations, intraoperative strategies, post-operative complications, and long-term outcomes. It also explores infection control, fracture healing dynamics, and ART’s impact on surgical outcomes while identifying key research gaps. A systematic database search (PubMed, Embase, Cochrane Library) identified relevant studies published up to February 2025. Inclusion criteria encompassed studies on incidence, risk factors, ART impact, and NOF fracture outcomes in PLWHIV. Data were analysed to summarise findings and highlight knowledge gaps. Pre-operative care: Optimisation involves assessing immune status (namely, CD4 counts and HIV-1 viral loads), bone health, and cART to minimise surgical risk. Immunodeficiency increases surgical site and periprosthetic infection risks, necessitating potential enhanced antibiotic prophylaxis and close monitoring of potential start/switch/stopping of such therapies. Surgical management of neck of femur (NOF) fractures in PLWHIV should be individualised based on fracture type (intracapsular or extracapsular), age, immune status, bone quality, and functional status. Extracapsular fractures are generally managed with internal fixation using dynamic hip screws or intramedullary nails. For intracapsular fractures, internal fixation may be appropriate for younger patients with good bone quality, though there is an increased risk of non-union in this group. Hemiarthroplasty is typically favoured in older or frailer individuals, offering reduced surgical stress and lower operative time. Total hip arthroplasty (THA) is considered for active patients or those with pre-existing hip joint disease but carries a higher infection risk in immunocompromised individuals. Multidisciplinary evaluation is critical in guiding the most suitable surgical approach for PLWHIV. Importantly, post-operative care carries the risk of higher infection rates, requiring prolonged antibiotic use and wound surveillance. Antiretroviral therapy (ART) contributes to bone demineralisation and chronic inflammation, increasing delayed union healing and non-union risk. HIV-related frailty, neurocognitive impairment, and socioeconomic barriers hinder rehabilitation, affecting recovery. The management of NOF fractures in PLWHIV requires a multidisciplinary, patient-centred approach ideally comprising a team of Orthopaedic surgeon, HIV Physician, Orthogeriatric care, Physiotherapy, Occupational Health, Dietitian, Pharmacist, Psychologist, and related Social Care. Optimising cART, tailoring surgical strategies, and enforcing strict infection control can improve outcomes. Further high-quality studies and randomised controlled trials (RCTs) are essential to develop evidence-based guidelines. Full article

Background and Objectives: This study explores the immunogenetic associations of human leukocyte antigens (HLAs) and cytokine levels in people living with HIV/AIDS (PLWH) who exhibit HIV-related skin disorders. HIV-related skin disorders, including inflammatory eruptions, atopic and seborrheic dermatitis, psoriasis, and pruritic papular eruption, are common among PLWH. These conditions may be influenced by genetic and immunological factors. This study aims to investigate the associations between HLA class II alleles, cytokine levels, and the presence of HIV-related dermatoses, providing insights into genetic susceptibility and immune mechanisms. Materials and Methods: This study included 115 PLWH with HIV-related skin disorders and a control group of 80 healthy individuals. HLA allele frequencies were analyzed, and cytokine levels (IL-1β, IL-10, IFN-y) were measured in blood samples. Statistical analyses were performed to identify significant differences in allele frequencies and cytokine responses between the groups. Results: Risk alleles (DQB1*0201:0301, OR = 19.4 and DQA1*0101:0501, OR = 4.2) and protective alleles (DRB1*07:13, OR = 0.19, DRB1*01:13, OR = 0.09, DRB1*04:11, OR = 0.07, and DQA1*0501:0501, OR = 0.24) showed statistically significant differences in frequency (p < 0.05) between PLWH and healthy controls. The protective DQA1*0501:0501 allele was associated with elevated levels of IL-1β (p < 0.001, r = 0.79) and IL-10 (p = 0.010, r = 0.63). Increased IL-1β levels may enhance immune responses, while higher IL-10 levels may exert anti-inflammatory effects, potentially reducing susceptibility to HIV-related dermatoses. Regression analysis revealed that IL-1β (Exp(B) = 0.76, p < 0.001) and IFN-γ (Exp(B) = 1.06, p = 0.043) are significant predictors for the likelihood of developing HIV-related dermatoses. An increase in IL-1β levels reduced this likelihood by 24%, while an increase in IFN-γ levels increased it by 6%. Conclusions: The findings emphasize the interaction between HLA class II alleles and cytokine profiles in determining genetic risk and clinical outcomes in PLWH with HIV-related skin disorders. Protective alleles, such as DQA1*0501:0501, may contribute to immune regulation, offering potential targets for therapeutic interventions in PLWH with dermatoses. Our results highlight the importance of IL-1β and IFN-γ as key modulators in the progression of HIV infection and the development of HIV-related dermatoses. Further research is needed to explore the mechanisms underlying these associations, particularly in the Latvian population, to inform targeted therapeutic strategies. Full article

Infants born to HIV-positive mothers remain at significant risk of HIV acquisition despite maternal adherence to antiretroviral therapy, cesarean delivery, and formula feeding. Our previous study reported that initiating early antiretroviral treatment at three days post-SIV infection resulted in approximately eighty percent of pediatric virologic remission. In this study, we investigated treatment outcomes in postnatally SHIV-exposed infant macaques when early intervention was delayed by two days, as well as the mechanisms underlying virologic control. The results showed that, although initiating treatment at five days post-exposure effectively suppressed viral replication, only one of the three infant macaques achieved a sustained state of virologic remission following analytical treatment interruption. Notably, this virus-controlled infant lacked detectable virus-specific immunity, including neutralizing antibodies, cytotoxic T cell responses, and antibody-dependent cellular cytotoxicity. These findings highlight the critical importance of early treatment initiation as a key determinant of virologic control in HIV-exposed, infected infants. This study provides valuable insights for guiding early pediatric HIV intervention strategies in clinical settings. Full article

Leishmania is an intracellular protozoan parasite that causes leishmaniasis, a disease prevalent in 97 countries. Co-infection with HIV increases susceptibility to visceral leishmaniasis (VL), accelerating HIV’s progression to AIDS. Managing VL in HIV-infected individuals is challenging due to atypical presentations and limited therapeutic responses, highlighting the need to develop new disease management strategies. Extracellular vesicles (EVs) hold great promise for this goal as they can be used for a higher understanding of biological processes and biomarker discovery. In this context, a proteomic analysis was carried out from plasma-EVs of an HIV/VL patient over two years and compared to HIV and healthy controls. The analysis confirmed classical EV markers but showed limited detection of Leishmania proteins. However, variations in human protein abundance related to relevant immunological processes were observed. Notably, the macrophage receptor with a collagenous structure (MARCO) was consistently detected only in the patient and not in the control groups. Significantly, the relevance of MARCO as a possible VL biomarker was confirmed using a validation cohort with five VL patients and its detection by Western Blot was possible. Although MARCO warrants further investigation as a VL related biomarker, the study of EVs confirmed their promise of being a privileged window into this disease. Future studies are needed to broaden data on EVs in infections to improve clinical management. Full article

Neuropathic pain is a chronic disorder that arises from damaged or malfunctioning nerves. Hypersensitivity to stimuli, also known as hyperalgesia, can cause a person to experience pain from non-painful stimuli, termed allodynia. Cannabis-based medicines (CBMs) may provide new treatment options to manage neuropathic pain. A review of the relevant studies was conducted to evaluate the effectiveness of CBMs in treating neuropathic pain. Scientific literature was systematically searched from January 2003 to December 2024 using the Web of Science Core Collection, PubMed, and MEDLINE. A total of 22 randomized controlled trials (RCTs) were identified that considered the use of 1′,1′-dimethylheptyl-Δ⁸-tetrahydrocannabinol-11-oic acid (CT-3), Δ⁹-tetrahydrocannabinol (Δ⁹-THC), cannabidiol (CBD), combinations of Δ⁹-THC with CBD, and cannabidivarin for treatment of neuropathic pain. Significant reductions in pain were reported in 15 studies focused on the treatment of multiple sclerosis, spinal cord injuries, diabetic neuropathy, postherpetic neuralgia, HIV-associated sensory neuropathy, peripheral neuropathic pain, complex regional pain syndrome, chronic radicular neuropathic pain, and peripheral neuropathy of the lower extremities. These positive outcomes often adopted personalized and adjusted dosing strategies. By contrast, seven RCTs observed no significant pain relief compared to placebo, although some had minor improvements in secondary outcomes, such as mood and sleep. Collectively, CBM treatments may improve pain scores, but study limitations such as small sample sizes and study durations, high placebo response rates, and trial unblinding because of the psychoactive effects of cannabinoids all hinder data interpretation and the extrapolation to chronic pain conditions. Hence, future RCTs will need to have larger numbers and be more extended studies that explore optimal dosing and delivery methods and identify patient subgroups that are most likely to benefit. While CBMs show potential, their current use balances modest benefits against possible adverse effects and variable outcomes. Full article

Background: Cervical dysplasia is a pre-malignant condition of the uterine cervix and is highly prevalent in Sub-Saharan Africa; especially affecting HIV-infected Black women. The anti-dysplastic effect of vitamin D hormones in cervical dysplasia is poorly understood. Therefore, we conducted a cross-sectional case–control observational study to assess the relationship between serum 25-hydroxycholecalciferol (25(OH)D) and cervical dysplasia, amongst Black women with and without HIV infection. Methods: The study participants attended a gynaecologic oncology clinic at an academic hospital in Pretoria, South Africa (n = 109). Patient clinical data were obtained during consultation. Cervical dysplasia was identified by cytology (PAP smear) which classified the case group as high-grade squamous epithelial lesions (HSILs), and the control group as <HSIL. Serum biochemistry measured 25(OH)D and its covariate biochemical variables. The data were statistically modelled to adjust for clinical and biochemical covariates, identify a significant relationship (p ≤ 0.05) between 25(OH)D and cervical dysplasia, and analyse subgroup interaction between HIV status and cervical dysplasia. Results: The data showed high levels of vitamin D insufficiency and deficiency in Black women with and without HIV infection. After covariate adjustment, 25(OH)D demonstrated an inverse relationship with HSIL in HIV-uninfected Black women. Furthermore, an interaction effect between women with and without HIV infection was observed. Conclusions: The role of 25(OH)D in the primary prevention of cervical dysplasia in Black women without HIV infection is promising, and dosing strategies require investigation. Also, future studies exploring the immunomodulatory role of 25(OH)D in cervical dysplasia in HIV-infected women is warranted. Full article

Type I interferons (IFN-Is) play a dual role in the immune response to HIV-1, providing early antiviral defense while driving immune dysfunction in the chronic phase. During acute infection, robust IFN signaling is critical in controlling viral replication, activating innate immunity, and limiting reservoir establishment. However, sustained IFN-I activation during chronic infection fuels systemic inflammation, immune exhaustion, and fibrosis, particularly in lymphoid tissues such as gut-associated lymphoid tissue (GALT). Prolonged IFN-I exposure upregulates inhibitory receptors on T cells, impairs metabolic fitness, and fosters an immunosuppressive cytokine milieu that weakens overall immune responses. In contrast to natural SIV (Simian immunodeficiency virus) hosts, IFN-I responses are tightly regulated to prevent chronic immune activation and tissue damage. However, humans and non-natural hosts experience persistent Interferon Stimulated Gene (ISG) expression and IFN-I driven inflammation. Emerging therapeutic strategies seek to harness the antiviral benefits of IFN-I while mitigating its pathogenic effects. Approaches such as the IFNAR blockade, autophagy induction, JAK-STAT inhibition, and combined immune inhibitory blockade therapy show promise in restoring immune balance and enhancing T cell function. This review examines the mechanisms of IFN-I dysregulation in chronic HIV-1 infection and highlights novel interventions aimed at finetuning IFN-I signaling for therapeutic benefit. Full article

South Africa continues to experience a high HIV prevalence, necessitating innovative prevention strategies aligned with the UNAIDS 95-95-95 targets. Long-acting injectable pre-exposure prophylaxis (PrEP), such as cabotegravir (CAB-LA), offers a promising alternative to daily oral regimens. However, the perspectives of primary healthcare workers (PHCWs)—key implementers of this intervention—remain underexplored. This scoping review aims to systematically map existing literature on PHCWs’ knowledge, awareness, perceptions, barriers, facilitators, and implementation experiences related to injectable PrEP within the South African healthcare context. The review will follow the Arksey and O’Malley framework, enhanced by Levac et al., and will be reported following PRISMA-ScR guidelines. A comprehensive search will be conducted across PubMed, Scopus, CINAHL (EBSCOhost), Web of Science, and Google Scholar, without language or date restrictions. The search strategy will employ both controlled vocabulary (e.g., MeSH and CINAHL Subject Headings) and free-text terms. Studies meeting the inclusion criteria will be managed using EndNote X20 and appraised using the Mixed Methods Appraisal Tool (MMAT) 2018 version. Data will be synthesized thematically and presented narratively and in tabular form. By consolidating PHCWs’ perspectives, this review will identify implementation challenges, training needs, and systemic barriers, informing the development of context-specific strategies for PrEP rollout. The findings are expected to support the design of effective, culturally relevant educational interventions and guide policymakers in strengthening HIV prevention efforts in high-burden settings. Full article

Background and Objectives: Malaria poses significant threats to pregnant women, particularly in endemic regions. Preventive measures against it include insecticide-treated bed nets, intermittent preventive treatment, and various supplements. We aimed to assess and compare the safety and effectiveness of malaria preventive measures in pregnant women, considering their HIV status. Methods: We conducted a systematic search of PubMed, the Cochrane Library, Scopus, Embase, and Web of Science through January 2024. A network meta-analysis was performed using R 4.3.3 software on 35 studies (50,103 participants). Results: In HIV-positive pregnant women, Co-trimoxazole with dihydroartemisinin significantly reduced malaria incidence compared to Co-trimoxazole alone (RR = 0.45, 95% CI [0.30; 0.68]) and sulfadoxine–pyrimethamine (SP) (RR = 0.14, 95% CI [0.04; 0.48]). Mefloquine was also effective compared to controls and SP. In HIV-negative women, azithromycin–piperaquine significantly reduced infections compared to SP, bed nets, and controls (RR = 0.03, 95% CI [0.00; 0.83]; RR = 0.03, 95% CI [0.00; 0.86]; and RR = 0.03, 95% CI [0.00; 0.77], respectively). Conclusion: Different combinations of preventive measures show varying effectiveness based on HIV status. Co-trimoxazole with dihydroartemisinin and mefloquine are effective for HIV-infected pregnant women, while azithromycin–piperaquine and mefloquine work well for those without HIV. Customized prevention strategies considering HIV status are crucial for optimal protection. Full article