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关键词： HIV-1   doravirine   islatravir   antiretroviral therapy   meta-analysis   two-drug regimen   virological suppression  

摘要： Background: The combination of doravirine and islatravir (DOR/ISL) is a novel two-drug regimen for HIV-1. Early development faced challenges due to dose-dependent immunological signals. We aimed to synthesize the evidence on the efficacy and safety of DOR/ISL across all treatment-experience categories, specifically evaluating the impact of islatravir dosage (0.25 mg vs 0.75 mg) on clinical and immunological outcomes. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) following PRISMA guidelines. We searched PubMed, Embase, Cochrane Library, and Google Scholar from inception through April 2026. Primary outcomes were virological suppression (<50 copies/mL) and mean change in CD4+ T-cell count at week 48. Data were pooled using random-effects models. Islatravir dose was evaluated as a pre-specified moderator. Quality was assessed using Cochrane RoB 2.0 and certainty of evidence was graded using the GRADE approach. Results: Seven RCTs (n = 3,600 participants) were included. At Week 48, DOR/ISL showed non-inferior suppression rates (RR 1.01 [95% CI 0.99-1.02];p = 0.516;moderate-certainty evidence) and a statistically significant reduction in virological failure risk (RR 0.55 [0.33-0.92];p = 0.022) compared to active control. Overall CD4+ gain was lower with DOR/ISL (MD -34.55 cells/mu L;low-certainty evidence);however, a profound moderator effect of dose was observed (p < 0.0001). The 0.75 mg dose was associated with significant CD4+ and lymphocyte declines, whereas the approved 0.25 mg dose was immunologically neutral. DOR/ISL was weight-neutral compared to bictegravir/emtricitabine/tenofovir alafenamide (MD -0.25 kg [-0.66 to 0.16];low-certainty evidence). Conclusion: DOR/ISL 100/0.25 mg once daily achieved virological suppression comparable to standard-of-care ART regimens and was associated with lower rates of virological failure compared with active comparators. The immunological safety concerns observed in early trial

关键词： HIV-1   ARV   cabotegravir   rilpivirine   zidovudine   intestinal failure   parenteral antiretroviral therapy  

摘要： Introduction: In patients with severe surgical and gastrointestinal complications, standard oral combination antiretroviral therapy (ARV) may be temporarily impossible. Long-acting cabotegravir/rilpivirine (CAB/RPV LA) is approved for virologically suppressed individuals pretreated with oral therapy, but data on its use in treatment-na & iuml;ve, critically ill patients with absent enteral absorption are extremely limited. Clinical presentation: We report a 26-year-old male admitted with fulminant hypertriglyceridaemic necrotizing pancreatitis complicated by abdominal compartment syndrome, multiple laparotomies, open abdomen with enteric fistulae, short bowel syndrome type I, chronic intestinal failure requiring parenteral nutrition, portal vein thrombosis, and prolonged intensive care. HIV-1 infection was diagnosed early (HIV RNA 5,000 copies/mL;CD4+ 780 cells/& micro;L). Within three months, HIV RNA rose to 320,000 copies/mL and CD4+ declined to 570 cells/& micro;L. Given absent gastrointestinal passage, standard ARV was initially deferred, but rapid virological rebound necessitated urgent treatment. An off-label fully parenteral regimen was initiated: intravenous zidovudine (AZT) with intramuscular CAB/RPV LA. Therapy was well tolerated alongside surgery, parenteral nutrition, antimicrobials, and anticoagulation. HIV RNA decreased to <20 copies/mL within 65 days and remained suppressed, with CD4+ recovery. Intravenous AZT was discontinued after 35 days, and CAB/RPV LA continued as maintenance during recovery and home parenteral nutrition. Discussion: Fully parenteral ARV, including CAB/RPV LA, may provide a safe and effective bridge to durable viral suppression in patients with absolute contraindications to oral therapy, warranting further evaluation.

关键词： A/Astrakhan   adults   AS03(A)   AS03(B)   immunogenicity   influenza   influenza vaccines   H5N8 subtype  

摘要： Influenza pandemics arise from novel influenza A viruses. Recent emergence of a new clade (2.***.4.4.b) of the highly pathogenic H5N1 in animals and humans highlighted its pandemic potential. We evaluated the immunogenicity and safety of GSK's AS03-adjuvanted H5N8 vaccine in adults. In this phase 1/2, observer-blinded, age-stratified, randomized trial, healthy US adults (age, >= 18 y) received two intramuscular doses of hemagglutinin antigen (3.75 or 7.50 mu g) with AS03(A) or AS03(B administered 21 d apart. Immunogenicity - seroprotection rates (SPRs seropositivity, geometric mean titers (GMTs geometric mean fold rise (GMFR and seroconversion rates (SCRs) - was evaluated on day 43 using hemagglutination inhibition (HI) and microneutralization (MN) assays. Safety was monitored throughout the study. Of 520 enrolled participants, 518 were vaccinated. On day 43, the US Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research criteria for influenza vaccines were met. HI SPRs, seropositivity rates, SCRs, GMTs, and GMFR appeared to be higher in the AS03(A) vs AS03(B) group. Immune responses were generally higher in younger (aged 18-64 y) vs older (aged >= 65 y) adults. Immune responses were also detected in MN assays, with a correlation between HI and MN responses on day 43 across age groups and vaccine formulations. Safety was acceptable, with no increase in adverse events post-dose 2. Reactogenicity appeared more common in younger adults. The antigen-sparing potential of AS03 was demonstrated, with an acceptable safety profile. The benefit/risk profile was favorable for all formulations tested, including 3.75 & micro;g AS03(A licensed in the US).

关键词： Type 1 diabetes   diet   microbiome   probiotics   gluten   breastmilk   fecal microbiome transplant  

摘要： The incidence of type 1 diabetes (T1D) has risen sharply in recent decades, implicating the role of environmental factors in disease pathogenesis. Diet, a primary driver of gut microbiome development and composition, along with other environmental exposures, has emerged as a potential modulator of T1D risk and progression. While nutrients, such as certain vitamins, may exert protective effects, the roles of other dietary factors (e.g., early exposure to dietary antigens) remain unclear. Importantly, diet shapes the gut microbiome, which produces immunomodulatory metabolites, including secondary bile acids, short-chain fatty acids (SCFAs and others that directly influence immune responses. This review presents evidence on how specific dietary factors, including macronutrients (fats, carbohydrates, proteins, such as gluten and milk proteins fibers, and breastfeeding, affect the gut microbiome and T1D. We also discuss the effects of microbiome-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, on T1D and their potential as future therapeutic strategies. Although animal studies provide compelling mechanistic insights, the results from human trials remain inconsistent, underscoring the urgent need for longitudinal and interventional studies to establish causality. Understanding the complex interplay between diet, the gut microbiome, and immune homeostasis is essential for developing personalized strategies to prevent and treat T1D and delay-related complications.

关键词： Moringa oleifera seeds   cyanoglycosides   structure elucidation   diabetic nephropathy   metabolic reprogramming  

摘要： ContextDiabetic nephropathy (DN) is a major complication of diabetes. Moringa oleifera seeds are recognized as a source of bioactive compounds with potential health benefits, prompting investigation into their specific components and effects on DN.ObjectiveThis study aimed to isolate bioactive compounds from M. oleifera seeds and evaluate their renoprotective effects and underlying mechanisms of action against high-glucose-induced diabetic nephropathy.Materials and methodsFour cyanoglycosides and one cyanoaglycone were isolated from M. oleifera seeds using chromatographic techniques. The renoprotective effects of these compounds were then evaluated using an in vitro model of high-glucose-induced diabetic nephropathy in HBZY-1 mesangial cells. Mechanistic studies further investigated the compounds' effects on oxidative stress, inflammation, mitochondrial function, expression of the glycolysis-related protein PFKFB3, and the TGF-beta 1/Smad signaling pathway.ResultsTwo previously undescribed cyanoglycosides were isolated alongside three known compounds. All five compounds demonstrated significant renoprotective effects in the high-glucose-induced HBZY-1 cell model. Mechanistically, these effects were achieved by suppressing oxidative stress and inflammation, protecting mitochondrial function, modulating the expression of the glycolysis-related protein PFKFB3, and inhibiting the TGF-beta 1/Smad signaling pathway, collectively contributing to beneficial metabolic reprogramming.ConclusionsThis study isolated two novel cyanoglycosides from M. oleifera seeds. These compounds, alongside known ones, protect against high-glucose-induced renal injury. Their renoprotection involves metabolic reprogramming via suppressing oxidative stress/inflammation, preserving mitochondrial function, modulating PFKFB3, and inhibiting TGF-beta 1/Smad signaling. These findings offer insights for utilizing M. oleifera seeds and suggest these cyanoglycosides as potential diabetic nephropathy ther

关键词： Triggering receptor expressed on myeloid cell-1   myasthenia gravis   enzyme-linked immunosorbent assay   biomarker   T cell  

摘要： Triggering receptor expressed on myeloid cells-1 (TREM-1) and TREM-2, cell surface receptors involved in innate and adaptive immunity, exist in soluble (sTREM-1 and sTREM-2) and membrane-bound forms, with the soluble form serve as biomarkers in many immune diseases. However, the role of TREM-1 and TREM-2 in myasthenia gravis (MG) remains unclear. This study aims to investigate the expression of TREM-1 and TREM-2 in MG, as well as their potential role in the immunopathological mechanism of MG. We enrolled a total of 85 MG patients and 43 healthy controls (HC). Enzyme-linked immunosorbent assay and flow cytometry were used to quantify the expression of TREM-1 and TREM-2 in MG patients and HC. The levels of TREM-1 and TREM-2 mRNA of peripheral blood mononuclear cells were measured by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) in MG and HC. In vitro experiments were performed to explore the functional effects of intervening TREM-1 on CD4+T cells. We found that serum sTREM-1 levels were significantly elevated in MG patients Compared to HC, whereas sTREM-2 showed no difference. Additionally, sTREM-1 levels in MG patients positively correlated with disease severity and memory B-cell proportions. TREM-1 expression was reduced and most significantly on CD4+T and CD8+T cells in MG patients. Inhibition of TREM-1 inhibited Treg cell differentiation but had no significant effect on Th1, Th2, and Th17, indicating its pathogenic role in MG.

关键词： PD-1 blockade   gut microbiota   intestinal ischemia reperfusion injury   IL-10   gut barrier  

摘要： PD-1 blockade therapy is widely used in clinical practice. Intestinal ischemia reperfusion (IR) injury is a serious clinical complication that leads to remote organ damage through disruption of the gut barrier. However, the effects of PD-1 blockade on gut homeostasis and intestinal IR injury remain unclear. Here, we demonstrate that, in contrast to PD-1 deficiency, PD-1 blockade activates intestinal immunoglobulin A (IgA) responses in mice via a MyD88-dependent pathway. The increased production and bacteria-binding capacity of IgA induced by PD-1 blockade significantly reshape the gut microbial composition and metabolite profile. Furthermore, PD-1 blockade promotes intestinal mucosal CD4+ T cell IL-10 production. Notably, microbiota depletion by antibiotics attenuates intestinal IL-10 production, whereas transplantation of PD-1 blockade-altered microbiota facilitates IL-10 upregulation. These IL-10 enhancements appears to be driven by an increase in Lachnospiraceae_NK4A136_group, a recognized butyrate-producing bacterium, and elevated levels of microbiota-derived butyrate, which were increased after PD-1 blockade and significantly correlated with enhanced IL-10 production in the intestinal mucosa. The upregulation of intestinal IL-10 following PD-1 blockade suppresses inflammatory activation, thereby ameliorating the gut barrier impairment and remote organ injury induced by intestinal IR. In addition, we show that, in vivo and in vitro, butyrate supplementation enhances IL-10 expression in CD4+ T cells through PI3K gamma/phospho-mTOR signaling. Collectively, these findings indicate that PD-1 blockade promotes intestinal mucosal CD4+ T cell IL-10 production by modulating immune-microbiota interactions and subsequently mitigates intestinal IR-induced gut barrier dysfunction and organ damage.

关键词： Tumor immunity   tumor immunology   T cell exhaustion PD-1 LAG-3   tumor immunotherapy  

摘要： BackgroundPD-1 and LAG-3 are immune checkpoint molecules frequently co-expressed in the tumor microenvironment, where they synergistically drive T-cell exhaustion and immune escape. Dual blockade of these pathways represents a promising strategy to overcome immunotherapy resistance.MethodsThis review systematically synthesizes mechanistic studies on PD-1/LAG-3 synergy and summarizes preclinical and clinical advances in dual blockade therapies, with emphasis on bispecific antibodies and combination trial data.ResultsPD-1 and LAG-3 cooperatively suppress T-cell function via complementary signaling pathways. Combined inhibition substantially restores antitumor immunity. A PD-1/LAG-3 bispecific antibody has been approved for melanoma, with numerous trials ongoing across other malignancies.ConclusionDespite demonstrated efficacy, challenges including variable response rates, resistance mechanisms, and immune-related adverse events remain. Future efforts should prioritize biomarker identification and regimen optimization to enable precision application of dual blockade.

关键词： Care burden   family empowerment   health-promoting behaviours   type 1 diabetes  

摘要： Mothers caring for children with type 1 diabetes (T1D) face significant care burdens requiring effective interventions. This study evaluated the impact of a Healthy Lifestyle Empowerment Program (HLEP) on care burden and adherence to health-promoting behaviours in these mothers. In this experimental study in Tehran (2024 64 mothers of children with T1D were randomly assigned to the intervention (n = 32) and control (n = 32) groups. The intervention group participated in four weekly 45-60-min educational sessions focusing on health-promoting behaviours. Data were collected using the Caregiver Burden Index (CBI) and Health-Promoting Lifestyle Profile II (HPLP-II) at baseline, immediately after and 12 weeks post-intervention. Data were analysed using SPSS v.18. The intervention group showed a significant reduction in care burden immediately and 12 weeks after HLEP (p = 0.311 while their health-promoting behaviours improved significantly over time (p = 0.027). Conversely, the control group experienced increased care burden (p = 0.000) and decreased health-promoting behaviours (p = 0.017). HLEP effectively reduced the care burden and enhanced health-promoting behaviours among mothers of children with T1D. The incorporation of such empowerment programs into healthcare services is recommended to support caregivers managing chronic illnesses.

关键词： Alphavirus   mosquito   TIM-1   ONNV   phosphatidylethanolamine   PS receptor  

摘要： Human T-cell immunoglobulin and mucin domain 1 (TIM-1) facilitates infection of re-emerging viruses, including alphaviruses, through its phosphatidylserine (PS) binding domain. Although alphaviruses are transmitted to humans via mosquito bite, it is unclear whether mosquito-derived viruses also use TIM-1 to infect human cells. Since viruses acquire their PS-containing envelope from the host cell and insect cell membranes differ in lipid composition from mammalian membranes, we here investigate the role of TIM-1 at the mosquito-mammalian interface. We show that TIM-1 promotes infection with mosquito cell-derived, replication-competent alphaviruses, including Chikungunya virus, O'nyong'nyong virus (ONNV and Sindbis virus. The TIM-1 PS-binding domain is essential for enhancing mosquito cell-derived ONNV infection as shown by TIM-1 mutagenesis. According to untargeted lipidomics, mosquito cell-derived ONNV virions contain higher levels of phosphatidylethanolamine (PE) and PS compared to mammalian cell-derived ONNV. Notably, TIM-1 engages PE as well as PS, as demonstrated by liposome competition. PS decarboxylase experiments suggest that PS is an important mediator of mosquito-cell derived ONNV entry into mammalian cells. Taken together, our data show that TIM-1 promotes mosquito cell-derived alphavirus infection of mammalian cells. This work provides implications for the understanding of the TIM-1 ligand repertoire and advances our understanding of arbovirus transmission at the mosquito-mammalian interface.