Historically endemic to parts of South America, Oropouche virus (OROV) has caused an estimated 500,000 infections since its discovery, with a marked geographic expansion beyond the Amazon basin into other regions of South America and the Caribbean since late 2023. This Review synthesises current evidence on OROV epidemiology, transmission dynamics, clinical manifestations, diagnostics, viral diversity, and public health impact, with the primary objective of identifying critical knowledge gaps and outlining priorities for surveillance, research, and control. Human transmission occurs primarily via Culicoides paraensis midges, while the competence of other vectors, the role of animal reservoirs in sustaining sylvatic transmission, and the contribution of vertical and sexual transmission remain incompletely understood. Although most infections are self-limiting, reports of neurological disease, Guillain-Barré syndrome, adverse pregnancy outcomes, and rare fatalities highlight uncertainties regarding pathogenicity, risk factors for severe disease, and long-term sequelae. The known teratogenicity of related Simbu serogroup orthobunyaviruses in animals further raises concerns about foetal risk in humans. Environmental change, expanding vector ranges, and viral evolution are likely contributing to outbreak emergence and geographic spread. Based on the available evidence, this review highlights priority gaps in epidemiological surveillance, diagnostics and genomic monitoring, vector competence and ecology, transmission pathways, and countermeasure development. Addressing these gaps through coordinated surveillance, improved laboratory capacity, targeted vector control, and focused research will be essential to mitigate the public health impact of OROV and reduce the risk of further spread.

Dengue is hyperendemic in Singapore and typically presents as an acute febrile illness. Neurological complications, such as dengue encephalitis and encephalopathy, are increasingly recognized; however, dengue-associated posterior reversible encephalopathy syndrome (PRES) remains rare. We report a 90-year-old woman with primary dengue virus serotype 3 infection who developed persistent altered mental status during the critical phase of illness. Neuroimaging revealed bilateral asymmetric parieto-occipital vasogenic edema with focal hemorrhage, consistent with PRES, together with small acute infarcts in the deep watershed and left middle cerebral artery territories. Cerebrospinal fluid analysis demonstrated mildly elevated protein without pleocytosis; dengue IgM and IgG were positive, while dengue PCR was negative. She was managed with supportive care with close neurological monitoring. Follow-up imaging at two months showed near-complete radiological resolution accompanied by significant clinical improvement. This case highlights two important considerations. First, altered mental status in elderly patients with dengue should not be attributed solely to delirium, and prompt neurological evaluation is essential. Second, dengue infection may be associated with overlapping neurological manifestations, including dengue encephalitis, PRES and ischemic stroke. Recognition of such overlap is important for accurate diagnosis and management of dengue-related central nervous system involvement. Not applicable.

Dengue is spreading globally, and there is urgent need to define immune correlates of protection for this disease. Dengue infection first occurs in the skin following the bite of an infected mosquito; however, knowledge of host immune responses within this site remains sparse. We investigated the phenotypic, functional, and transcriptional profiles of skin and blood T cells in 73 patients with dengue and 10 healthy volunteers. We show that the skin T cell compartment undergoes marked reshaping and is strongly enriched with proliferating CD4+ and CD8+ T cells compared with the blood of patients. Activated skin CD8+ T cells expressed a core transcriptional signature of tissue-resident memory T (TRM) cells, supporting their differentiation to the TRM cell lineage during infection. The magnitude of skin and blood CD8+ T cell responses were associated with protection from hospitalization in this cohort. These data support a protective role of skin-resident and circulating CD8+ T cells in dengue and warrant evaluation of vaccination strategies inducing skin TRM cells to enhance protective immunity.

Human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) have declined in recent years, but continued surveillance and research is needed to understand this trend and mitigate future zoonotic threats.

BACKGROUND:The immunopathogenesis of dengue infection and immune correlates of protection are uncertain, no therapeutic anti-viral is available, and the long-term risks of severe breakthrough infection after vaccination remain of concern. Dengue controlled human infection models (DCHIM) have found increasing utility and have the potential to address these unmet needs. We reviewed the clinical, biochemical and immunologic features of modern day DCHIMs. METHODS:A systematic review protocol was developed and registered with PROSPERO [CRD42024558534]. We searched MEDLINE, Cochrane and Embase for controlled human infection studies using attenuated dengue virus strains from January 2000 - December 2025. No restriction was placed on study setting (dengue endemic/non-endemic) or whether the study was conducted in seronegative or seropositive individuals. The primary outcome was the proportion of inoculated participants who developed viraemia ('attack rate'). RESULTS:Our search yielded 1181 results, and identified 11 published studies, recruiting 248 participants aged 18-55 years. All studies were performed in non-dengue endemic areas and were models of primary dengue. Four studies challenged previously vaccinated individuals, and one utilised DCHIM to assess antiviral efficacy. Attenuated dengue virus strains of all four DENV 1-4 serotypes were utilised as challenge agents. Attack rate across all serotypes was 50-100% in seronegative participants and 0-83% in previously vaccinated participants and was strain-dependent. Clinical and biochemical features of dengue fever varied between strains, with peak viral load and probability of fever being highly correlated (r = 0·91, p < 0·01). There were no serious adverse event reported, and 9 (4%) participants met protocol criteria for hospitalisation. Viral and/or immune evidence of disease enhancement was observed in 5/81 (7%) of challenged seropositive participants. CONCLUSION:DCHIMs of primary dengue are a valuable and safe tool that has supported vaccine development. Further work is needed to expand DCHIMs to endemic settings and as a model of secondary dengue.

Background Dengue is hyperendemic in Singapore and typically presents as an acute febrile illness. Neurological complications, such as dengue encephalitis and encephalopathy, are increasingly recognized; however, dengue-associated posterior reversible encephalopathy syndrome (PRES) remains rare. Case presentation We report a 90-year-old woman with primary dengue virus serotype 3 infection who developed persistent altered mental status during the early recovery phase of illness. Neuroimaging revealed bilateral asymmetric parieto-occipital vasogenic edema with focal hemorrhage, together with small acute infarcts in the deep watershed and left middle cerebral artery territories. Cerebrospinal fluid analysis demonstrated mildly elevated protein without pleocytosis; dengue IgM and IgG were positive, while dengue PCR was negative. She was managed as dengue encephalitis with PRES-like neuroradiological features and concomitant ischemic stroke. Follow-up imaging at two months showed near-complete radiological resolution. Conclusion This case highlights two important considerations. First, altered mental status in elderly patients with dengue should not be attributed solely to delirium, and prompt neurological evaluation is essential. Second, dengue infection may be associated with overlapping neurological manifestations, including dengue encephalitis, PRES-like vasogenic edema and cerebral infarct. Recognition of such overlap is important for accurate diagnosis and management of dengue-related central nervous system involvement.

Importance:With increasing global incidence of acute dengue virus (DENV) infection, more accurate estimates of the burden of neurological events following infection are required; however, population-based estimates are lacking. Objective:To evaluate the risk and excess burden of neurological events in a cohort of DENV-infected adults in the acute postinfectious period vs population-based comparators without DENV infection. Design, Setting, and Participants:This was a retrospective, population-based cohort study in Singapore. National registries were used to construct a cohort of all adults (aged ≥18 years) infected with DENV from January 1, 2017, through December 31, 2023, for whom the index date (time 0 [T0]) was taken as the date of notification, and a cohort of uninfected population-based comparators, for whom T0 was randomly assigned to match T0 distribution in DENV-infected cases. As the period overlapped with the COVID-19 pandemic, individuals infected with SARS-CoV-2 within 30 days of T0 were additionally excluded, as were individuals who died before T0 and uninfected comparators with no prior health care contact. Data analysis was performed from January 1, 2017, through March 30, 2024. Exposure:DENV infection recorded in the national registry. Main Outcomes and Measures:New-incident neurological events, including any neurological event, memory loss, movement disorders, and other neurological disorders (eg, fatigue or malaise, encephalitis or encephalopathy), following DENV infection were identified using national health care claims records, and risk was assessed over the acute follow-up period. Odds of new-incident neurological events in DENV-infected cases vs uninfected comparators were estimated using overlap-weighted logistic regression at 30 to 90 days after T0. Results:A total of 65 207 confirmed DENV-infected cases (mean [SD] age, 48.4 [17.8] years; 34 876 [53.5%] male) were compared against 1 616 865 uninfected comparators (mean [SD] age, 54.8 [18.3] years; 730 702 [45.2%] male). At 30 days following DENV infection, individuals with DENV infection, compared with uninfected individuals, had elevated odds of any new-incident neurological event (adjusted odds ratio [aOR], 9.69; 95% CI, 6.59-14.90), memory loss (aOR, 3.19; 95% CI, 1.36-8.69), movement disorders (aOR, 7.10; 95% CI, 2.49-29.18), and other neurological events (aOR, 14.32; 95% CI, 8.61-26.04); risk trajectories diverged up to 90 days after infection. However, the overall excess burden was modest, with less than 1 excess event per 100 cases. The DENV-infected cases, compared with uninfected individuals, had increased odds of memory loss (aOR, 2.99; 95% CI, 1.30-7.87) and movement disorders (aOR, 6.38; 95% CI, 2.23-25.96) only among those aged 60 years or older and in cases infected during DENV serotype 3 transmission. Conclusions and Relevance:DENV infection was associated with significantly higher odds of acute new-incident neurological events following infection, although the excess burden was modest. Older adults should be monitored for a wider spectrum of potential neurological complications following DENV infection.

BACKGROUND:This guideline aims to address key clinical questions of long COVID, and to provide evidence-based recommendations. The target population is adults with long COVID. The primary users of the guideline are clinical physicians, clinical pharmacists, nurses and general practitioners in community healthcare institutions worldwide. METHODS:The guideline was registered at the Practice guideline REgistration for transPAREncy platform (PREPARE-2024CN123) and followed a pre-specified protocol. A multidisciplinary working group was established and comprised 60 members from 10 countries and 10 areas of expertise, with a strong background in long COVID research and clinical practice, and methodology of guideline development. Through a two-step process, we determined eight PICO (Population, Intervention, Comparator, Outcome) questions focusing on prevention and treatment of long COVID. After comprehensively searching literature, conducting systematic reviews and investigating patients' values and preferences, three rounds of Delphi survey were conducted among 24 international experts to reach consensus. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach was applied to rate the certainty of evidence and determine the strength of recommendations. RESULTS:The guideline presents 10 specific recommendations, each supported by existing, updated or newly conducted systematic reviews. The key recommendations are pertinent to the following issues: 1) suggestion of vaccination or use of antiviral agents during the acute phase of COVID-19 to prevent long COVID; 2) suggestions against the use of nirmatrelvir/ritonavir and glucocorticoids (patients with persistent respiratory symptoms and olfactory disorders) for long COVID treatment; 3) suggestions supporting the use of multispecies probiotics, cognitive behavioural therapy (patients with fatigue), and personalised rehabilitation (after ruling out post-exertional malaise) for long COVID treatment. CONCLUSIONS:This guideline provides evidence-based recommendations for the prevention and treatment of long COVID. Given the limited and often low-methodological-quality evidence, all recommendations are supported by very low to moderate certainty. Further high-quality studies are needed to strengthen the evidence base.

Dengue virus, with all four serotypes in cocirculation, has created significant epidemiological and economic burdens in Singapore. Despite integrated vector control programs, the magnitude and frequency of dengue outbreaks has increased over the last few decades, which highlights the limits of existing strategies. In this context, vaccination has emerged as a promising approach to enhance population immunity and complement ongoing efforts. Qdenga (TAK-003), a commercially available dengue vaccine, has been recommended by the World Health Organization Strategic Advisory Group of Experts (WHO-SAGE) for use in high-transmission settings. Although classified as a low transmission setting, Singapore faces a recurring public health burden from dengue, with high costs associated with both healthcare and sustained vector control. The age distribution of dengue in Singapore differs from high transmission settings, with more cases in young adults and hospitalizations concentrated among older individuals. These factors, combined with the complex efficacy profile of Qdenga, varying by baseline serostatus, infecting serotype, make it challenging to directly apply global vaccination recommendations to Singapore. Therefore, the population-level impact of introducing dengue vaccination remains uncertain, underscoring the need for context-specific evaluation. To estimate the potential public health impact of introducing routine dengue vaccination in Singapore, we develop an age-stratified, multi-serotype, compartmental transmission model informed by age-specific dengue seroprevalence and routine surveillance data. Our model predicts that vaccination can avert up to on average 9%, 12%, 7%, and 5% cases in DENV-1-4 dominant serotype scenarios respectively, over a 10-year routine vaccination program with 80% vaccine coverage. Moreover, dengue hospitalizations can be reduced up to 15% across all dominant serotype scenarios. Our results suggest that, in Singapore, targeting older age groups will be more beneficial than the 6-16-year window recommended by the WHO-SAGE for high-transmission settings. Vaccinating individuals aged 17-30 years achieves the greatest reduction in cases, whereas targeting those aged 51-70 years leads to the highest reduction in hospitalizations. Our model-based analysis provides useful insights to support policymakers and public health authorities in designing evidence-based, dengue vaccination strategies in Singapore. The findings also underscore the importance of tailoring dengue vaccination programs to local epidemiological conditions for effective disease control.

Persistent inflammation and tissue injury may contribute to post-acute COVID-19 syndrome (PACS). However, direct tissue evidence from mildly-infected individuals sampled long after recovery remains exceptionally limited. Here, we performed post-mortem bulk RNA-seq and GeoMx digital spatial profiling of lung, heart, and brain tissues from four individuals who recovered from mild COVID-19 more than 250 days before death from unrelated causes. Samples were collected during the early phase of the national vaccination program, before widespread vaccine uptake and recurrent infection, providing a rare reference cohort for defining tissue responses to SARS-CoV-2 in the absence of major confounding from vaccination and/or reinfection; such a cohort can no longer be prospectively assembled. We observed residual SARS-CoV-2 nucleocapsid antigen within tissues and revealed organ-specific immune alterations. Lung and heart tissues exhibited a coordinated, self-sustaining inflammatory response, whereas brain tissue showed vascular dysfunction and altered neuroimmune homeostasis. These findings showcase the distinct tissue responses following mild infection and provide a spatially resolved view of sub-clinical long-term tissue sequelae. Collectively, our data establish a unique baseline for persistent viral antigen and tissue-specific immune dysregulation underlying PACS.

ABOUT THIS GUIDELINE:This BMJ Rapid Recommendation is a summary of a World Health Organization guideline published 12 September 2024. The full guideline is available in MAGICapp and in PDF on the WHO website. The WHO guideline is primarily for healthcare providers and takes a patient-centred perspective on benefits and harms. Other considerations include resource implications, acceptability, feasibility, equity, and human rights of relevance to healthcare systems. Recommendations were developed according to standards and methods for trustworthy guidelines by a panel of non-conflicted experts, as delineated in the WHO handbook (https://www.who.int/publications/i/item/9789241548960). CLINICAL QUESTIONS:What is the role of medications in treating non-severe and severe influenza including zoonotic disease (novel influenza A), and in preventing infection among contacts? Which diagnostic testing strategies best enable rapid and accurate treatment decisions? CONTEXT AND CURRENT PRACTICE:New randomised controlled trial (RCT) evidence, ongoing concerns about zoonotic disease, and the increasing availability of rapid diagnostic tests require updated guidance. RECOMMENDATIONS:apply to seasonal influenza and zoonotic influenza. There are 29 recommendations; 21 related to antiviral medications and six to adjunctive therapies to prevent and treat influenza. Recommendations are stratified by severity of disease and risk of disease progression. For seasonal influenza, WHO conditionally recommends treatment within 48 hours of symptom onset with oseltamivir for severe illness, and baloxavir for patients at high risk of progression from non-severe to severe illness. WHO also conditionally recommends prophylaxis (using baloxavir, laninimavir, oseltamivir, or zanamivir) for anyone exposed to zoonotic influenza, and for those exposed to seasonal influenza who are at extremely high risk. The panel issued recommendations against the use of adjunctive therapies in patients with non-severe influenza (strong recommendation against antibiotics) and severe influenza (conditional recommendation against corticosteroids, macrolides, mTOR inhibitors, non-steroidal anti-inflammatory drugs, and passive immune therapy). A recommendation is made for diagnostic testing strategies in non-severe and severe influenza disease. THE EVIDENCE:Four systematic reviews of RCTs provided low to very low certainty evidence on benefits and harms of antiviral medications and adjunctive therapies. A systematic review of prognostic factors provided baseline risk estimates and information on individual risk factors for disease progression. A decision analysis model informed recommendations for testing based on alternative potential diagnostic pathways.

Background: Dengue is a dynamic illness with an initial febrile phase followed by critical and recovery phases. Predicting disease progression during the febrile phase is essential for management. We evaluated whether a dengue-adapted modified pan-immune-inflammation value (mPIV) improves risk stratification compared with prior PIV model and neutrophil-to-lymphocyte ratio (NLR). Methods: We conducted a retrospective analysis of adults with dengue using data from previously published ARDENT cohort (2005–2008), excluding patients with dengue hemorrhagic fever or shock (DHF/DSS) at enrolment. PIV, mPIV, and NLR were calculated from complete blood counts (CBCs) longitudinally up to illness day 10 before DHF/DSS onset. Predictive performance was evaluated using generalized estimating equations, mixed-effects logistic regression, and time-dependent Cox models, adjusted for illness day, age, gender, ethnicity, Charlson score, and day-specific AUC-ROC. Results: Overall, 1,621 (22%) patients progressed to DHF/DSS. PIV and mPIV showed opposing associations: higher PIV was associated with lower risk, whereas higher mPIV was associated with increased risk. In phase-specific analyses, PIV performed best during the early febrile phase, with peak performance on day 2 (AUC 0.819, 95%CI: 0.709–0.929), surpassing mPIV and NLR. mPIV showed better discrimination during later illness (day 5 AUC 0.684, 95%CI: 0.652–0.717), while NLR consistently underperformed. Conclusions: Utilizing routine daily CBCs, PIV serves as a valuable predictor during the early febrile phase. As illness progresses and platelet counts decline, mPIV offers a slight advantage for risk stratification. Although NLR performance is slightly lagging, these indices provide objective clinical monitoring and could optimize resource allocation in adult dengue management.

Background:DENV-infection and SARS-CoV-2 are now endemic in tropical regions; interactions may exist, given antigenic cross-reactivity and cross-protection. Risk of subsequent DENV-infection following prior COVID-19 was evaluated in a population-based adult cohort. Methods:Retrospective cohort study including all Singaporeans ≥18 years. National registries were used to construct contemporaneous SARS-CoV-2-infected/test-negative cohorts from 1st Sept 2021-31st Dec 2022 during Delta/Omicron emergence. COVID-19 vaccination status was classified using the national-immunization-registry. Risk of DENV-infection recorded in the national registry 31-300 days post-COVID-19 was contrasted against test-negatives using overlap-weighted Cox regression. Risk of other infections (invasive-pneumococcal-disease/tuberculosis/melioidosis/leptospirosis) were assessed as negative-outcome controls, and risk of DENV-infection post-influenza vaccination was assessed as a negative-exposure control. Findings:1,324,250 COVID-19 cases (predominantly vaccine-breakthrough mild Omicron infections) and 1,434,851 test-negatives were included. Significantly increased risk of DENV-infection was observed 31-300 days post-COVID-19 (adjusted-hazards-ratio, aHR = 1.10[95%CI = 1.05-1.15]), during a DENV3 surge. Excess-burden of DENV-infection post-COVID-19 was 0.36 cases (95%CI = 0.11-0.61) per-1000-individuals. Risks of subsequent DENV-infection were numerically highest in unvaccinated COVID-19 cases but not elevated in doubly-boosted cases (≥4 vaccine-doses). Risk of negative-outcome controls (other-infections) was not significantly elevated 31-300 days post-COVID-19, and risk of DENV-infection was not significantly elevated post-influenza vaccination. Interpretation:Increased risk of DENV-infection (primarily DENV3) was observed up to 300 days post-SARS-CoV-2 infection (predominantly Omicron). While not irrefutable proof for possible antibody-dependent enhancement of DENV3-infection post-Omicron COVID-19, given modest effect sizes, future studies can shed more light on potential interactions. Public health strategies (e.g., vaccination) remain important in tropical/subtropical regions where COVID-19/DENV are now endemic. Funding:National-Medical-Research-Council, Singapore.

Dengue virus infection can cause severe complications due to vascular leakage. Angiopoietin-like protein 4 (ANGPTL4) regulates vascular permeability, but its role in dengue pathogenesis is unclear. This study investigated the association between plasma ANGPTL4 levels and dengue severity in Singapore adults. Plasma samples from 48 dengue patients (24 severe and 24 non-severe) during acute and convalescent phases were selected from the prospective COhort study on progression of DENgue severity in Singapore adults (CODEN) cohort. The CODEN was conducted at the National Centre for Infectious Diseases, Tan Tock Seng Hospital, from June 2016 to January 2020. ANGPTL4 levels were measured and compared to 152 healthy controls. Logistic regression assessed the relationship between plasma ANGPTL4 concentrations and disease severity. There were no statistically significant differences in ANGPTL4 levels between severe and non-severe dengue patients during acute (677.4 vs. 909.1 pg/mL, p = 0.4) or convalescent phases (793.7 vs. 565.6 pg/mL, p = 0.96). Plasma ANGPTL4 levels were significantly elevated during acute dengue (4634.3 pg/mL) versus healthy controls (907.4 pg/mL), declining during convalescence. Compared to the lowest tertile, the adjusted odds ratios for severe dengue were 0.36 (95%CI: 0.08–1.65, p = 0.190) for medium tertile and 0.57 (95%CI: 0.13–2.49, p = 0.456) for high tertile. Among patients with high ANGPTL4 levels (>5000 pg/mL), 36.4% developed severe complications, including significant plasma leakage. Plasma ANGPTL4 levels were significantly higher in dengue patients than controls, suggesting its potential as a biomarker, which warrants future detailed investigations. Larger prospective studies with serial sampling, including pediatric populations, may clarify the role of ANGPTL4 in severe dengue.

The envelope (E) protein of dengue virus (DENV) is glycosylated at two highly conserved asparagine (N) sites (N67 and N153). The role and importance of these N-linked glycans in DENV pathogenesis has been elusive. Here, we report the critical role of N153-linked glycans on E protein in preventing antibody-mediated viral clearance. A DENV2 mutant lacking N153-linked glycans (N153Q mutant) was engineered and found to be mildly impaired in vitro but drastically attenuated in a symptomatic mouse model of severe dengue, as evidenced by accelerated viral clearance. In B cell-deficient mouse models, N153Q mutant displayed parental virulence and viremia profile. Homologous and heterologous passive transfers of purified IgM from infected B cell-proficient mice into B cell-deficient mice demonstrated the role of N153Q-specific IgM in N153Q attenuation and accelerated clearance, while WT DENV was unaffected by IgM from both WT- and N153Q-infected mice. Furthermore, in vitro neutralization assay supported that the accelerated clearance of N153Q mutant in mice was mediated by non-neutralizing IgM. Furthermore, using plasma samples from convalescent dengue patients and monoclonal antibodies, in vitro neutralization assays showed that N153Q virus was more susceptible than WT to IgG-mediated neutralization. Glycoproteomics combined with molecular dynamics (MD) simulations revealed that glycan composition on E protein influenced IgG binding. Our findings were extended to all DENV serotypes and ZIKV, hence supporting that the N153 glycans-mediated immune evasion strategy is conserved across orthoflaviviruses. ### Competing Interest Statement The authors have declared no competing interest.

The emergence and re-emergence of mosquito-borne arbovirus (MBV) diseases pose a rapidly expanding global health threat fueled by the convergence of multiple ecologic, economic, and social factors, including climate change, land use, poverty, deficiencies of water storage and sanitation, and limitations of vector control programs. On December 6, 2023, the Wellcome Trust and the University of Minnesota's Center for Infectious Disease Research and Policy held a meeting titled "An integrated approach to mosquito-borne arboviruses: a priority research agenda." The meeting comprised presentations, panels, and facilitated discussions aimed at describing the state of the field, highlighting recent accomplishments, identifying novel strategies, and defining priority research goals and approaches for addressing MBV disease preparedness and response. This report summarizes meeting discussions in 3 key areas: the changing epidemiology of MBV disease, current and potential transmission- and disease-monitoring strategies, and evolutionary impacts on disease burden and transmission. It concludes with a list of priority strategies for research and investment in MBV disease prevention, preparedness, and control. To prepare for future epidemics of MBV diseases, research and policy will benefit from a multipathogen approach to MBVs. Building on existing knowledge and systems, these efforts must address social and ecological factors and connect with other global health agendas.

INTRODUCTION:We report Singapore's convalescent plasma (CP) programme during the first year of the COVID-19 pandemic. Based on historical data and its potential therapeutic promise, CP was offered as an experimental treatment option for severe or high-risk COVID-19 patients when established therapeutics were lacking. METHODS:The CP programme was implemented under monitored expanded access approved by Singapore's Ministry of Health. CP donors were primarily selected based on specific antibody titres, while suitable recipients were chosen based on risk factors and disease severity. Operational protocols and logistical considerations are discussed in-depth. RESULTS:Between April 2020 and September 2020, the CP donor programme successfully collected 33 plasma units from 27 qualified donors. Seven patients received CP treatment under this programme. Six of the seven recipients of CP survived for more than 28 days post-transfusion and were discharged alive. Given the availability of other validated therapeutic options, the CP programme was officially suspended in September 2021. CONCLUSION:This study provides a comprehensive overview of the intricacies of Singapore's CP programme, from its operational challenges to the observed clinical outcomes, while highlighting the potential benefits and complexities of CP as a therapeutic option. Successful implementation of the CP programme requires robust collaboration across multidisciplinary teams. Access to serological tests was crucial for donor selection. Both the selection of CP with high neutralising antibodies and careful selection of appropriate recipients are key aspects to optimise the therapeutic success of CP. A meticulous approach is warranted if CP were to be used in future pandemics.

Global warming is expanding mosquito habitats and increasing mosquito-borne diseases. In tropical and sub-tropical regions, chikungunya virus (CHIKV) transmitted by Aedes mosquitoes has become a major concern due to the debilitating chronic joint disease it causes. Mosquito saliva contains bioactive factors that enhance viral infection, with sialokinin identified as a key contributor to vascular leakage and viral spread in mice. Here, we demonstrate that sialokinin binds to neurokinin receptors and restricts the activation of human myeloid cells. Mechanistically, sialokinin facilitates early viral dissemination, as evidenced by increased viral load in the contralateral footpad at 1 day post-infection, and significantly reduces circulating CD169+ monocytes while suppressing IFN-γ-producing T-cell-driven inflammation, as reflected by reduced joint footpad swelling in female CHIKV-infected mice. Clinically, patients with severe CHIKV disease exhibited higher levels of IgG antibodies against sialokinin, which correlated with higher viral loads and systemic inflammatory markers. Our findings highlight the multifaceted role of sialokinin in facilitating early viral dissemination and modulating host immunity during CHIKV infection. Given the growing threat of mosquito-borne diseases in a warming, disease-burdened world, targeting mosquito salivary factors like sialokinin could offer a novel therapeutic strategy to mitigate viral-induced inflammation and improve clinical outcomes.

OBJECTIVES:Prophylactic platelet transfusion is frequently used in managing hospitalized dengue patients. Our earlier study identified a subset of patients who, despite receiving prophylactic transfusions, exhibited delayed recovery of peripheral platelet counts. This study investigated the underlying mechanisms of this impaired response. METHODS:We measured cytokine/chemokine concentrations in plasma samples from 197 patients in the multicentre, randomized Adult Dengue Platelet (ADEPT) Study of prophylactic platelet transfusion. Patients were divided into a control group (supportive therapy only) and a transfusion group (supportive therapy plus prophylactic platelet transfusion). Baseline cytokine profiles, along with clinical and biochemical data, were correlated with platelet recovery outcomes. RESULTS:Plasma cytokine/chemokine levels were similar across both groups at baseline. Poor responders in both groups had higher levels of IL-10 and IL-1RA, while IFN-α, RANTES, SDF-1α, IL-13, and WBC count were specific biomarkers for poor platelet recovery in the transfusion group. These findings suggested cytokine-mediated disruptions in platelet production and increased platelet destruction in poor responders who received platelet transfusions. Decision tree analysis showed that IFN-α, RANTES, and WBC counts predicted platelet recovery with 75% accuracy in transfused patients. CONCLUSIONS:Our findings highlight that individual differences in immune response exist regardless of transfusion, underscoring the potential for personalized treatment in managing hospitalized adult dengue patients. The identified immune signature suggests that more targeted therapies may benefit patients unlikely to respond to platelet transfusion.

Blood pressure monitoring is crucial for early detection of complicated dengue. We investigated the association between blood pressure indicators and complicated dengue hazard over the course of dengue hospitalization in a well-characterized dengue cohort. This study involved 4789 adult dengue patients hospitalized between 2005 and 2008 who did not have complicated dengue (defined as dengue haemorrhagic fever and/or severe dengue) initially. Cases (n = 689) included patients who progressed to complicated dengue during hospitalization, while controls were patients who did not (n = 4100). We used Cox models with time-dependent covariates to estimate hazard ratios for blood pressure indicators' impact on complicated dengue hazard. Additionally, we employed the overlap weighting approach to balance clinical characteristics and conducted subgroup analyses based on age, sex and warning signs. Results indicated that modified shock index (MSI) ≥0.8 was associated with a higher time-averaged hazard in the main cohort (HR: 1.72 [1.36, 2.19], p-value: <0.01). Shock index (SI) ≥0.7 also indicated increased hazard in the main cohort (HR: 1.64 [1.37, 1.95], p-value: <0.01) and among patients without mucosal bleeding (HR: 1.42 [1.19, 1.72], p-value: <0.01). A DBP <60 mmHg led to higher hazards of complicated dengue (HR: 1.45 [1.23, 1.72], p-value: <0.01) in the main cohort. In conclusion, DBP <60 mmHg, shock index ≥0.7 and modified shock index ≥0.8 may be reliable predictors for complicated dengue during hospitalization in adult dengue patients. Clinicians should consider these indices during patient assessment.