Infectious Diseases and Therapy

BackgroundHospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP), particularly those caused by multi-drug resistant organisms (MDROs), often require newer antibiotic treatment. The efficacy and safety of newer antibiotics compared to generic antibiotics in randomized controlled trials (RCTs) have not been evaluated before. MethodsIn this systematic review, we searched RCTs in the United States National Library of Medicine (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, Ovid MEDLINE, Clinical Trials.gov and Google Scholar databases published between 2013 and 2025. The primary efficacy endpoint was 28-day all-cause mortality. Secondary efficacy endpoints were clinical and microbiological response. Safety endpoint was nephrotoxicity. ResultsWe identified eight eligible RCTs involving 2,881 patients (1,450 patients treated with newer antibiotics and 1,431 patients treated with generic antibiotics) with HABP/VABP. The meta-analysis did not reveal any significant differences between newer and generic antibiotics for all-cause mortality at day 28 (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72-1.30), clinical response (RR 1.04, 95%CI 0.93-1.17), and microbiological response (RR 1.05, 95%CI 0.89-1.24). However, newer antibiotics showed significant lower occurrences of nephrotoxicity compared to colistin component (RR 0.30, 95%CI 0.11-0.79). In subgroup analysis, newer antibiotic regimens demonstrated significant improvement in microbiological eradication of carbapenem-resistant Gram-negative bacilli (RR 1.50, 95%CI 1.18-1.90). ConclusionsNewer antibiotics showed similar efficacy and safety in treating HABP/VABP compared to generic drugs. The superiority in microbiological eradication of carbapenem-resistant Gram-negative bacilli of newer antibiotics could suggest that future trials should be targeted for those patients to improve understanding of their therapeutic use and pathophysiology of these conditions. Key pointsNewer antibiotics, despite broader antimicrobial coverage, have not significantly outperformed generic comparators in terms of 28-day all-cause mortality, clinical, or microbiological response in patients with Gram-negative HABP/VABP. This may reflect limitations in current trial designs focused primarily on regulatory approval.

BackgroundThe epidemiology of suspected pediatric meningoencephalitis has shifted in the era of conjugate vaccines and multiplex PCR diagnostics, with viral pathogens now predominating over bacterial causes. Updated epidemiologic data are essential to adapt diagnostic and therapeutic algorithms to current clinical practice. MethodsThis retrospective single-center study included children and adolescents <18 years who underwent lumbar puncture with cerebrospinal fluid multiplex PCR for suspected central nervous system infection at a tertiary-care pediatric hospital in Germany between 2016 and 2024. Clinical, laboratory, and outcome data were extracted from electronic medical records. Cerebrospinal fluid was analyzed using the BioFire(R) FilmArray(R) Meningitis/Encephalitis Panel. Statistical analyses included descriptive statistics, nonparametric group comparisons, receiver operating characteristic analyses. ResultsAmong 1,198 included children, definite bacterial meningitis was diagnosed in 13 (1.1%), definite viral meningitis in 80 (6.7%), aseptic meningitis of unknown etiology in 131 (11.0%), confirmed/probable encephalitis in 53 (4.4%), and possible encephalitis in 34 (2.8%). Bacterial meningitis accounted for 5.8% of all meningitis cases. A causative pathogen was identified in all bacterial meningitis cases, most commonly Streptococcus pneumoniae (n = 7). Enterovirus (n = 52) and parechovirus (n = 9) predominated in viral meningitis, whereas an infectious etiology was identified in only 13 of 53 confirmed/probable encephalitis cases. The Bacterial Meningitis Score showed a sensitivity of 80.0% and a specificity of 57.6%. The recently published UK-ChiMES-pre- and post-lumbar puncture scores demonstrated sensitivities of 84.6% and 76.9% and specificities of 86.3% and 92.7%, respectively. DiscussionBacterial meningitis was rare in this contemporary cohort, while viral and etiologically unresolved infections predominated despite routine multiplex PCR diagnostics. Clinical prediction scores supported risk stratification, with the UK-ChiMES-pre-lumbar puncture score showing the most favorable balance between sensitivity and specificity and potential to guide diagnostic decisions and antiinfective therapy.

BackgroundPreoperative biliary stenting alters biliary colonization and may reduce the effectiveness of perioperative antibiotic prophylaxis in pancreatoduodenectomy. Although broader-spectrum regimens have been associated with improved infectious outcomes, their microbiological adequacy in routine clinical practice remains poorly defined. We therefore evaluated the real-world adequacy of a prolonged ampicillin-sulbactam protocol, its association with infectious outcomes and survival, and the potential impact of a universal piperacillin-tazobactam strategy. MethodsWe analyzed all consecutive patients who underwent elective pancreatoduodenectomy from 2002 to 2023 at our tertiary center. Demographic, operative, microbiological, and outcome data were retrieved from a prospectively maintained database. Patients were stratified by stent status. Adequacy of prophylaxis was defined as the full in vitro susceptibility of all bile isolates. The outcomes included 30-day infectious morbidity, clinically relevant POPF, PPH, DGE, reoperation, 30- and 90-day mortality and long-term survival. A coverage simulation was performed to compare ampicillin-sulbactam with a hypothetical universal piperacillin-tazobactam. Statistical methods included chi-square/Fishers exact tests, Mann-Whitney U tests, Cox models, McNemars test and Poisson regression. ResultsOf 956 patients, 424 (44%) had a biliary stent. Technical complications were comparable between groups, and rates of POPF and PPH were not increased. However, infectious morbidity was higher in stented patients, including sepsis (RR 1.62, 95% CI 1.05-2.51) and postoperative cholangitis (RR 2.20, 95% CI 1.36-3.56). Thirty- and 90-day mortality were increased (RR 2.88 and 2.73) but lost significance after adjustment. Bile cultures predominantly yielded Enterococcus and Enterobacterales with low ampicillin-sulbactam susceptibility. Overall adequacy was 21.7%. Among patients with bile cultures (n = 474), ampicillin-sulbactam covered 43.7% (207/474) versus 81.2% (385/474) with piperacillin-tazobactam; in stented patients with cultures (n = 397), coverage increased from 41.8% to 78.1%. Adequate ampicillin-sulbactam coverage was not associated with reduced infectious outcomes in Poisson models. ConclusionPreoperative stenting creates a polymicrobial, partially resistant biliary niche that ampicillin-sulbactam does not sufficiently cover. Our data shows that a piperacillin-tazobactam strategy substantially improves coverage and was therefore implemented at our center. Core message- Stented patients exhibit a distinct infectious risk profile characterized by Enterococcus-and Enterobacterales-dominated bile colonization rather than increased rates of technical complications. - In stented patients, real-world microbiological coverage of ampicillin-sulbactam was limited, and in vitro susceptibility did not independently translate into reduced postoperative infectious morbidity. - Broader prophylaxis, such as piperacillin/tazobactam, aligns with the actual flora and nearly doubles theoretical coverage, addressing the mismatch between stent-associated biofilms and narrow regimens.

A multiplex diagnostic test is evaluated for self-reported long COVID associated persistent symptoms and a poor recovery from a SARS-CoV-2 infection. A mass-standardised concentration of total antibodies (AC), high-quality (HQ) antibodies and percentage of HQ antibodies (HQ%) is assessed against a spectrum of spike proteins to the SARS-CoV-2 variants: Wuhan, , {delta}, and the Omicron variants BA.1, BA.2, BA.2.12.1, BA.2.75, BA.5, CH.1.1, BQ.1.1 and XBB.1.5 in three cohorts. A cohort of control patients (n = 46) recovered (CC) and a cohort of self-declared long COVID patients (n = 113) (LCC). A nested Receiver Operating Characteristic (ROC) analysis, performed for the variant with lowest HQ concentration in the spectrum, produced an area under the curve and AUC = 0.61 (0.53-0.70) for the CC vs LCC cohorts. For the LCC cohort, the cut-off thresholds for AC = 0.8 mg/L, HQ = 1.5 mg/L and HQ% of 34% were determined, leading to a 71% sensitivity and 66% specificity derived by the Youden metric. The cohorts may be fully classified based on ROC and outlier analysis to give an incidence of persistent virus 62% (95% CI 52% - 71%), hyperimmune 12% (95% CI 7% - 20%) and unclassified, 26% (95% CI 18% - 35%). The overall diagnostic accuracy for both the hyper and hypo immune is 69%. All clinical interventions can now be tailored for the heterogenous long COVID patient cohort.

Objectives: Influenza is a widespread acute respiratory illness posing a major public health challenge for both the National Health Service (NHS) and society, particularly among older adults. This study aimed to assess the cost-effectiveness of high-dose quadrivalent vaccine (HD-QIV) versus adjuvanted quadrivalent vaccine (aQIV) in older adults in Spain. Methods: Public health and economic benefits were evaluated using a decision-tree model considering influenza cases, GP and ED visits, hospitalizations, and influenza-related mortality. Deterministic and probabilistic sensitivity analyses addressed epidemiological and economic uncertainties. Results: From a societal perspective, HD-QIV prevented 54,039 influenza cases, 7,733 GP consultations, 1,585 ED visits, 27,398 episodes of hospitalization due to cardiorespiratory events over a single influenza season and 1,203 deaths compared to aQIV when vaccinating adults [&ge;]65 years old in Spain, resulting in 14,316 LYs and 12,440 QALYs gained over a lifetime horizon. The reduction in health outcomes outweighed the increase in vaccination costs, translating to a reduction in total costs with HD-QIV compared to aQIV. Therefore, vaccinating older adults in Spain with HD-QIV instead of aQIV was a dominant strategy when evaluating hospitalizations due to respiratory and cardiovascular events. HD-QIV remained dominant from a NHS perspective. Sensitivity analyses confirmed the robustness of the model. Conclusions: This analysis showed that vaccinating older adults in Spain with HD-QIV instead of aQIV would reduce influenza cases, GP and ED visits, hospitalizations, deaths, and associated costs, and thus it should be the strategy of choice in a situation of budgetary constraints from either a societal or an NHS perspective.

Objective. To evaluate the effectiveness of a bundle of interventions involving a clinical pharmacologist aimed at changing surgeons approach to perioperative antibiotic prophylaxis (PAP) in an oncourology department. Materials and Methods. A single-center retrospective observational study was conducted. Data from 226 patients who underwent prostatectomy or nephrectomy in the oncourology department of Regional Clinical Hospital No. 2 (Krasnodar, Russia) between 2023 and 2025 were analyzed. Periods before (n=125) and after (n=101) the implementation of an Antimicrobial Stewardship (AMS) strategy bundle with active participation of a clinical pharmacologist (pre-authorization, audit with feedback, education, handshake stewardship) were compared. The primary endpoint was the proportion of surgeries performed in compliance with the PAP protocol. Secondary endpoints included the incidence of infectious complications, antibiotic consumption (DDD/100 bed-days), direct costs of antibacterial drugs, dynamics of the microbial landscape, and the Drug Resistance Index (DRI). Results. After AMS implementation, the proportion of surgeries performed in accordance with the PAP protocol increased from 0% to 47.7% for prostatectomies and to 55.6% for nephrectomies. The mean duration of antibiotic use decreased from 7 to 2 days (p<0.001). Antibiotic consumption decreased by 31.2%, and costs were reduced by a factor of 4.3. The proportion of ESKAPE organisms in the microbial profile decreased from 26.3% to 16.4%. There was no statistically significant increase in the frequency of infectious complications (2.4% vs. 3.0%; p=1.000) or mortality (0% in both groups). Conclusions. AMS implementation integrating a clinical pharmacologist into the oncourology department workflow significantly improved adherence to clinical guidelines, reduced irrational antibiotic use and financial costs without compromising patient safety. This approach can serve as a model for optimizing PAP in other surgical departments. Keywords: antibiotic prophylaxis, antimicrobial stewardship, drug resistance, clinical pharmacologist, cost-benefit analysis, oncourology

BackgroundThere is a need for synthetic peptide-based serologic assays that exploit avidity to replace whole antigens while enabling low-cost diagnostics in resource-limited settings. ObjectiveTo evaluate the diagnostic accuracy of a polymeric peptide-based ELISA leveraging avidity to enhance signal. MethodA 15-member SARS-CoV-2 peptide library corresponding to multiple epitope clusters and proteins was screened by indirect ELISA using pooled sera from RT-PCR-confirmed COVID-19 patients to identify peptides with possible diagnostic utility. The identified lead candidate, S559, possessed terminal cysteine-substitution to allow disulfide polymerization, and the resulting avidity gain was evaluated by comparing the apparent dissociation constant (KDapp) before and after depolymerization with N-acetylcysteine. The performance of an optimized ELISA using S559 was evaluated on 1,222 prospectively collected COVID-19 serum samples and 218 biobanked pre-COVID control serum samples. ResultsPolymeric S559 with a KDapp of 29.26 nM-1was demonstrated to have a 218% avidity gain relative to the completely depolymerized form. At pre-defined thresholds, the optimized S559 ELISA has a sensitivity and specificity of 83.39% (95%CI: 81.18% and 85.43%) and 96.79% (95%CI: 93.50% and 98.70%), respectively. At post hoc thresholds determined by Youden index, sensitivity and specificity reached 95.01 (95% CI: 93.63% - 96.16%) and 100.00% (95% CI: 98.32% - 100.00%), respectively. ConclusionHomomultivalent epitope presentation using polymeric S559 allows a highly specific immunoassay using human sera that may have important value in detecting antibodies, whether for diagnosing infection, confirming vaccination status or conducting surveillance.

ObjectivesTo identify and validate plasma host-response protein biomarkers that improve discrimination of bacterial infection in febrile infants [&le;]90 days of age, and to assess whether novel biomarkers add value beyond established markers. MethodsSub-study of the prospective multicentre Febrile Infant Diagnostic Assessment and Outcome (FIDO) cohort. Novel biomarkers were identified through plasma proteomic profiling (Olink(R)) and combined with biomarkers and signatures from the literature for verification using Luminex and ELISA platforms. Diagnostic performance of novel biomarkers, established markers (CRP, PCT), and multi-protein signatures was evaluated. ResultsProteomic profiling of 110 samples identified 174 proteins differentially expressed between bacterial and viral infections, revealing distinct pathogen-specific immune signatures. Verification in the full cohort (n=445) demonstrated PCT had the highest individual accuracy for invasive bacterial infection (IBI) (AUC 0.89). Combining PCT with novel biomarkers, particularly lipocalin-2 (LCN2), improved discrimination (AUC 0.96). Diagnostic performance for the combined IBI/urinary tract infection (UTI) outcome was consistently lower (AUC <0.8). ConclusionsFebrile infants demonstrate biologically coherent host-response signatures that can be leveraged diagnostically. A PCT-LCN2 combination showed excellent accuracy for identifying IBI and may support future biomarker-guided diagnostic strategies, while reliable discrimination of UTI remains challenging.

AimsTo evaluate the association between platelet indices and platelet count severity in patients with primary immune thrombocytopenia during routine post-treatment follow-up. MethodsThis retrospective observational study included patients with primary immune thrombocytopenia followed at a single tertiary care center between 2011 and 2025. Demographic and laboratory data were obtained from medical records. Platelet count severity was categorized as less than 30 x 10^9/L, 30 to 100 x 10^9/L, and greater than 100 x 10^9/L. Platelet indices, including mean platelet volume (MPV) and platelet distribution width (PDW), were analyzed using the most recent complete blood count obtained during routine follow-up after treatment initiation. Continuous variables were summarized as median and interquartile range. Comparisons across platelet count categories were performed using the Kruskal-Wallis test with post hoc Mann-Whitney U testing. Correlation analysis and simple linear regression were also conducted. ResultsA total of 243 patients were identified, of whom 232 met the inclusion criteria. Platelet distribution width differed significantly across platelet count severity categories (Kruskal-Wallis p < 0.001) and demonstrated a strong inverse association with platelet count. Mean platelet volume also showed a statistically significant difference across platelet count groups (Kruskal-Wallis p = 0.007), although the association was weaker and less consistent compared with PDW. Regression analysis confirmed a significant association between platelet count and PDW. ConclusionPlatelet distribution width is more closely associated with platelet count severity than mean platelet volume in patients with primary immune thrombocytopenia during routine post-treatment follow-up. PDW may represent a useful adjunctive laboratory parameter when interpreted alongside platelet count in routine clinical practice.

BackgroundReliable identification of early predictors of adverse outcomes was essential during the pre-vaccination phase of the COVID-19 pandemic. Few studies have comprehensively integrated clinical presentation, laboratory parameters including arterial blood gas analysis, and chest computed tomography (CT) findings within a single well-characterized cohort, particularly in underrepresented regions of Brazil. MethodsThis retrospective cohort study included 482 consecutive adults (median age 61 years [IQR 49-73]; 64.3% men) with RT-PCR-confirmed SARS-CoV-2 infection hospitalized at a tertiary cardiac center in Central-West Brazil between March 2020 and January 2021. Demographic, clinical, laboratory (including arterial blood gas analysis), and chest CT data obtained within 48 hours of admission were analyzed. Univariable logistic regression was performed for 76 variables. Multivariable models were constructed using an a priori variable selection strategy based on clinical relevance, representation of distinct pathophysiological domains, and adherence to events-per-variable principles. Complete-case analyses were performed without imputation. ResultsIn-hospital mortality was 9.3% (45/482). Invasive mechanical ventilation was required in 74 patients (15.4%), with a mortality rate of 58.1% among those ventilated. In univariable analysis, 42 variables were associated with mortality (p < 0.05). In multivariable analysis (n = 438), five independent predictors of death were identified: age (adjusted OR 1.66 per 10 years; 95% CI 1.19-2.32; p = 0.003), arterial pH (adjusted OR 0.47 per 0.1-unit increase; 95% CI 0.25-0.89; p = 0.021), neutrophil-to-lymphocyte ratio (adjusted OR 1.30; 95% CI 1.18-1.44; p < 0.001), number of comorbidities (adjusted OR 1.59; 95% CI 1.25-2.02; p < 0.001), and serum creatinine (adjusted OR 1.37; 95% CI 1.05-1.77; p = 0.019). The model demonstrated good calibration (Hosmer-Lemeshow p > 0.05) and moderate-to-high explanatory power (Nagelkerke R{superscript 2} = 0.43). For the composite outcome of death or invasive mechanical ventilation (74 events; 15.4%), four predictors remained independently associated; serum creatinine showed a non-significant trend (p = 0.069). On chest CT (n = 424), analyzed descriptively and in univariable models only, pulmonary involvement > 50% was associated with increased odds of death (OR 2.87; 95% CI 1.42-5.79; p = 0.003). ConclusionsFive admission variables representing distinct pathophysiological domains--age, arterial pH, neutrophil-to-lymphocyte ratio, comorbidity burden, and serum creatinine--were independently associated with in-hospital mortality in this pre-vaccination cohort. Arterial pH provided independent prognostic information beyond inflammatory and renal markers. These findings support early risk stratification using routinely available clinical data.

BackgroundAn upsurge in Streptococcus pyogenes infections 2022-2023 highlighted potential benefits of point-of-care tests (POCT) to support clinical pathways, prevent outbreaks, and optimise antibiotic use. ObjectivesWe conducted a pilot research study in a west London paediatric emergency department (ED) to determine whether a molecular POCT had potential to alter management in children who were also having a conventional throat swab taken for culture. MethodsChildren <16 years presenting to ED who had a throat swab requested by a clinician were invited to have a second swab taken for research purposes only. Clinical management was unaffected by the research swab result, which was processed using a molecular POCT that was not approved for use in the host NHS Trust. ResultsPrevalence of streptococcal infection was low during the study (May 2023-June 2025); swab positivity in symptomatic children was 12.8% (6/47). Overall, 38/49 (77.6%) participants who had throat swabs received antibiotics. Of those children recommended to receive antibiotics, 29/38 (76.3%) had a negative POCT. Mean time to reporting of positive throat swab culture results was 3.67 days (range 3-5 days) leading to occasional delay in treatment, although POCT identified positive results within minutes. ConclusionAntibiotic use was frequent and could be avoided or stopped by use of a rule out POCT in over three-quarters of children in the ED, if suspicion of S. pyogenes is the main driver for prescribing. POCT were easy to process and produced immediate results compared with culture, in theory enabling timely decision-making and avoiding treatment delay.

ObjectivesDiagnosis of community-acquired Legionnaires disease (CALD) relies on microbiological testing. Routine testing in hospitalised CAP patients has low positivity rates. We externally validated a Legionella prediction score, assessed its applicability in routine care, and explored potential updates. MethodsWe analysed data from 196 CALD patients from 20 Swiss hospitals and 196 Legionella-negative CAP controls matched by date of diagnosis ({+/-}14 days; August 2022-March 2024). We assessed the availability of the original score predictors (fever, no/dry cough, hyponatremia, elevated CRP, elevated LDH, low platelet count) in routine care and the original scores discriminative performance. The dataset was split into development and validation cohorts to evaluate whether simplifying modifications improved predictive performance. ResultsThe original score showed 91% (95% CI: 86-96%) sensitivity and 35% (95% CI: 28-42%) specificity at a cut-off [&ge;]2; LDH was infrequently measured, and platelet count was a poor predictor. The simplified SwissLEGIO score (fever >38{degrees}C, sodium <133 mmol/L, CRP >180 mg/L, no/dry cough, prior {beta}-lactam therapy) maintained high sensitivity (88-92%) and showed improved specificity (46-58%) at cut-off [&ge;]2. ConclusionThe SwissLEGIO score is an easy-to-apply screening tool to rule out CALD in hospitalised CAP patients with scores <2 and may reduce testing by 36-52% at a CALD prevalence of 4%.

To investigate the immune mechanisms underlying extracorporeal circulation-associated anaphylactoid reactions, we inserted externally perfused cartridges into the venous circulation of pigs, including a cellulose-coated activated-charcoal adsorbent (Adsorba(R) 300C), a polysulfone hollow-fiber membrane hemofilter, and polypropylene hollow-fiber-based heart-lung machine gas-exchange oxygenators. Blood was circulated using a roller pump, and the animals were monitored for systemic and pulmonary arterial pressures (SAP, PAP) changes, blood levels of complement C3a, thromboxane B2, and hemoglobin, blood cell counts and hematocrit. None of the cartridges caused major changes in these endpoints except the Adsorba(R) 300C, which displayed a fulminant anaphylactoid reaction characterized by profound hypotension, maximal pulmonary hypertension, hemoconcentration, thrombocytopenia and a surge of C3a and thromboxane B2, i.e., hallmarks of complement activation-related pseudoallergy. Within 15 min, the reaction advanced to profound hemodynamic collapse, which was managed with norepinephrine and cardiopulmonary resuscitation. After brief rebound hypertension, shock recurred despite repeated rounds of resuscitation until death. Considering that major adverse reactions with overlapping symptoms have been reported in humans subjected to hemoperfusion with the same cartridge, this porcine model provides clinically relevant insights into the mechanisms of extracorporeal circulation-induced anaphylactoid responses. Furthermore, the Adsorba(R) 300C-induced physiological changes along the immune-cardiopulmonary axis represents a new animal model for irreversible cardiovascular collapse escalating into shock.

Background Plasma gelsolin (pGSN) is a non-immunosuppressive anti-inflammatory immunomodulator with demonstrated efficacy in animal models of acute lung injury. Its potential role in moderate-to-severe acute respiratory distress syndrome (ARDS) is currently under investigation. Methods We conducted a phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of recombinant human pGSN (rhu-pGSN) following intravenous (IV) administration to healthy volunteers. Thirty-two participants were assigned to 4 sequentially ascending dose cohorts (6, 12, 18, 24 mg/kg of body weight) to receive five IV infusions of rhu-pGSN or saline placebo. Each cohort includes 8 subjects randomized 3:1 with rhu-pGSN or placebo. Doses were administered at 0 hours, 12 hours, 36 hours, 60 hours, and 84 hours. The primary outcome is the incidence and severity of clinical and laboratory AEs regardless of causality. Secondary outcomes include the pharmacokinetics of IV rhu-pGSN and the presence of anti-rhu-pGSN antibodies at Day 28. Results Overall, 10 subjects (41.7%) who received rhu-pGSN reported a total of 13 adverse events (AEs), and 1 subject (12.5%) who received placebo reported an AE. All AEs were mild or moderate. AEs in system organ classes that were reported by 2 or more subjects in either arm were skin and subcutaneous tissue disorders (12.5% rhu-pGSN; 0% placebo), gastrointestinal disorders (8.3% rhu-pGSN; 0% placebo), and nervous system disorders (12.5% rhu-pGSN; 12.5% placebo). No AEs by preferred term were reported by more than 1 subject in either arm. Three subjects (12.5%) experienced an AE assessed as related to study drug. No serious AEs occurred, and no AEs led to study discontinuation, dose interruption/reduction, or death. There were no apparent between-treatment differences in laboratory abnormalities, vital signs, or electrocardiogram findings. Conclusions Overall, in this study, IV rhu-pGSN (up to 24 mg/kg daily) appeared safe and well tolerated compared to placebo. The median half-life of rhu-pGSN exceeded 14 h across all dosing regimens, supporting once daily IV dosing in healthy subjects. Trial registration This study was registered with ClinicalTrials.gov on 2023-03-29 under the registration identifier NCT05789745.

Background: Long COVID presents with one or multiple symptoms or diagnosable conditions after SARS-CoV-2 infection. To study whether use of the antiviral remdesivir in persons hospitalized with acute COVID-19 is associated with reduced Long COVID, we created a computational phenotype for Long COVID. Methods: In electronic health records (EHR) from a multistate healthcare system (US), hospital admissions from 5/1/20 - 9/30/22 were reviewed. The study group was hospitalized with acute COVID-19 and the control group was hospitalized for other reasons without prior SARS-CoV-2 infection. The populations were balanced with overlap weights based on a high-dimensional propensity score of pre-specified variables and the top 100 comorbidities differing between the groups. Hazard ratios (HR) were calculated for the combined primary outcome: U09.9 (Post-Covid Conditions) or any incident secondary outcome from 90 to 365 days after admission. Secondary outcomes included 27 individual incident diagnoses, corrected for multiplicity with Holm-Bonferroni. Results: Admissions included 45,540 with, and 409,186 without COVID-19 during the study period, evaluable for the primary outcome. After weighting, standardized difference was < 0.01 for all measured confounders including demographic and clinical features. In the COVID+ and non-COVID groups 38.0% and 29.3% met the combined primary outcome, respectively. Weighted HR (95%CI) for the primary outcome was 1.37 (1.35, 1.40), p < 0.0001. All secondary outcomes were associated with the COVID+ group, when adjusted for multiplicity. Incident diagnoses with strong associations (HR > 2) included thromboembolism, hair loss, diabetes mellitus, obesity, and hypoxia. Anosmia/dysgeusia was associated with COVID, but wide confidence intervals reflected few charted diagnoses. Conclusions: Manifestations of Long COVID at population scale are detectable as part of routine symptoms and clinical diagnoses in the EHR after admissions for COVID-19, compared with all other hospital admissions. This a prior computational phenotype for Long COVID will be used to assess whether remdesivir use is associated with decreased Long COVID.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSEnsuring appropriate access to essential antibiotics is a critical global public health goal. The UN General Assembly agreed that 70% of global antibiotic use should be WHO Access group. A standard method to estimate optimal antibiotic use based on burden of disease, resistance and local context is needed to inform national policies. MethodsUsing data from multiple global datasets, we clustered 186 countries, territories and areas (CTAs) into peer groups based on sociodemographic factors, infection and resistance incidence using a latent class model. Within each cluster, benchmark countries with low antibiotic use and infection mortality were identified. We estimated optimal Total DID given infection burden, Reserve DID based on relevant resistance burdens, Watch DID based on clinical infections requiring Watch antibiotics from the WHO AWaRe Book and Access DID as the residual volume. FindingsGlobally 43.0 billion DDDs (95%CI:35.4billion-57.7billion) of antibiotics in 2019 were needed in 186 CTAs, of which 76% would optimally be Access (95%CI:70%-82%). CTAs in lower-income clusters required more Watch and Reserve antibiotics than higher income CTAs. Among CTAs with actual use data available, 72% (48/67) of CTAs used more Total and 99% (66/67) used more Watch antibiotics than estimated optimal levels. ImplicationsWe present the first estimates of optimal AWaRe antibiotic levels for 186 CTAs. After accounting for country-specific needs, the UNGA 70% Access target is globally appropriate. AWaRe benchmarking enables CTAs to estimate under and overuse of AWaRe antibiotics to inform national policies. FundingThe ADILA Project funded by the Wellcome Trust [222051/Z/20/Z]. RO_SCPLOWESEARCHC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWINC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWCONTEXTC_SCPLOWO_ST_ABSEvidence before this studyC_ST_ABSMember states agreed at the 2024 United Nations General Assembly (UNGA) AMR meeting that the WHO AWaRe (Access, Watch, Reserve) system should underpin global antibiotic surveillance and that 70% of global use should be from the AWaRe Access group, while accounting for national contexts but did not agree any method for derived country-level targets. The WHO GLASS antimicrobial use (GLASS-AMU) surveillance system and other studies have reported observed antibiotic use. GLASS reports actual national medicine-level antibiotic use from 2015-2022 for 60 CTAs. The GRAM study (Browne, et al., 2021) modelled estimated total antibiotic use from 2000-2018 for 204 CTAs but were only able to estimate AWaRe antibiotic use for 76 CTAs where data from the commercial IQVIA MIDAS(R) database were available. Recent estimates from Klein et al. (2024) reported changes in antibiotic use from 2016 - 2023 for 67 CTAs in IQVIA MIDAS(R). Despite these studies quantifying estimates of current national medicine-level antibiotic use, there are very few estimates of what levels of antibiotic use are "optimal" both overall and by AWaRe group. We searched PubMed for studies from January 2015 through October 2025 on national-level antibiotic targets and AWaRe antibiotic policy using Boolean search terms. We identified few studies that estimated optimal levels of antibiotic use, but none for all AWaRe groups. As part of the Lancet AMR series, Mendelson et al. (2024) estimated expected total antibiotic use based on infection burden using the WHO AWaRe book guidance. This study developed a framework for estimating required Watch antibiotic use but did not provide comprehensive estimates for Access and Reserve use. Summan et al. (2025) estimated antibiotic needs for chronic obstructive pulmonary disease (COPD) and pneumonia in 20 CTAs using disease burden and bacterial aetiology. These estimates focused only on penicillins and cephalosporins and did not provide population based standardised measures to allow for cross-national comparison among CTAs. Mishra et al. (2025) estimated the gap in Reserve antibiotic treatment courses for use in carbapenem resistant Gram-negative infections in 8 countries using GRAM estimates and IQVIA sales data. While these studies have estimated expected antibiotic use for specific antibiotics or infections, there is no reported method to estimate optimal national levels of total and AWaRe antibiotic use. Added value of this studyWe developed a standard method for deriving optimal ranges of total and AWaRe antibiotic use in defined daily doses (DDD) per 1000 inhabitants per day (DID) accounting for national level infection and antibiotic resistance burden, population socio-demographics, national income, health system infrastructure and healthcare access using a benchmarking approach. Our study provides the first comprehensive estimates of optimal levels of total antibiotic use and disaggregated by AWaRe group in DID for a 2019 baseline for 186 CTAs and compares actual levels of AWaRe use to expected optimal use for 67 CTAs using the IQVIA MIDAS(R) dataset. We used publicly available data from the Global Burden of Disease (GBD), Global Research on Antimicrobial Resistance (GRAM) and the World Bank to provide an open-access, standardised AWaRe-clinical framework that could inform national and global evidence-based antibiotic policy development and implementation. Implications of all the available evidenceAlthough some recent studies have attempted to derive estimates for optimal levels of antibiotic use, they have been focused on specific infections or antibiotics. The UNGA AMR commitments provide a clear direction for global target setting for antibiotic use. Our study provides the first method to estimate optimal antibiotic levels at a country level for both total and AWaRe, based on local infection burden and antibiotic resistance for 186 CTAs. Estimating optimal antibiotic levels with an agreed standard methodology across CTAs would allow for benchmarking and peer-comparison, assisting with target setting and shared learning across National Action Plans from different policy initiatives and outcomes.

Circulating stem and progenitor cells (SPCs), including mesenchymal stromal cells (MSCs) and hematopoietic stem/progenitor cells (HSPCs), are mobilised after tissue injury but their temporal behaviour after hemorrhagic shock (HS) and relationship to cytokine milieus and outcome remain unclear. In a prospective observational cohort at JPN Apex Trauma Centre, AIIMS, New Delhi we studied 100 participants: 50 trauma patients with hemorrhagic shock and traumatic brain injury (HS index group), 25 trauma patients without HS, and 25 minor-injury controls. Peripheral blood was collected at admission (day 0) for all groups and additionally at days 3, 7 and 14 for the HS group. PBMCs were phenotyped by flow cytometry (HSPC markers: CD45, CD123, CD38, CD34; MSC markers: CD105, CD73, CD90) and serum SDF-1, VEGF-A, EGF, GRO- and GRO-{beta}, GM-CSF and G-CSF were measured by ELISA; group and time effects were evaluated with mixed-effects models and correlations by Spearman tests (two-tailed p<0.05). At admission, trauma patients without HS had significantly higher MSC and HSPC-like populations versus controls (p<0.0001). In the HS cohort SPC percentages rose modestly at day 0-3 then declined sharply by days 7-14 (time effect p<0.0001); non-survivors exhibited significantly higher early SPC and cytokine levels that persisted until death while survivors showed an early rise followed by decline (outcome and time interaction p<0.0001). All cytokines were up-regulated in trauma groups, peaked at day 0-3 in HS patients, and correlated positively with SPC counts (notably SDF-1, VEGF-A, G-CSF, Gro- and GM-CSF; Spearman p<0.05); higher early SPC and cytokine signatures associated with greater organ dysfunction (higher SOFA) and with timing of sepsis. These findings indicate that trauma provokes an early SPC and cytokine response that in HS is followed by later decline, and that persistent early elevation predicts worse outcomes, suggesting serial SPC and cytokine profiling may have prognostic value and identify an early therapeutic window for regenerative or immunomodulatory interventions.

COVID-19 remains a substantial public health challenge in the Netherlands. Next-generation COVID-19 vaccine, mRNA-1283, is approved in the European Union, with potential for higher relative vaccine efficacy compared with originally-licensed COVID-19 vaccines. Its potential public health and economic impact, in adults [&ge;]60 years and high-risk 18-59 years, was modelled versus no vaccination and originally-licensed mRNA-1273 and BNT162b2, adapting a published static Markov model with 1-year time horizon. COVID-19 burden reflected two full post-pandemic seasons. Vaccine efficacy versus mRNA-1273 was based on pivotal phase 3 NextCOVE trial data; efficacy versus BNT162b2 was derived from an indirect treatment comparison. The economically justifiable price (EJP) of mRNA-1283 versus no vaccination, and price premiums over existing vaccines, were determined at a willingness-to-pay threshold of {euro}50,000/quality-adjusted life-year (QALY) gained. Without COVID-19 vaccination, an estimated 460,000 infections, 23,800 hospitalizations and 5,300 deaths would occur. With current coverage, mRNA-1283 was estimated to prevent 68,000 infections, 5,400 hospitalizations, and 1,200 deaths, saving 9,667 QALYs and over {euro}66.5 million in treatment costs. The EJP was {euro}238 versus no vaccination. Compared with mRNA-1273 and BNT162b2, mRNA-1283 was estimated to prevent additional burden (e.g., 1,309 and 1,679 hospitalizations, respectively), and was cost-effective at an incremental EJP of {euro}62 versus mRNA-1273, and {euro}80 versus BNT162b2. The results support continued COVID-19 vaccination to mitigate the ongoing health and societal burden of SARS-CoV-2 in the Netherlands. The comparative analyses indicate that mRNA-1283 may be associated with substantial health benefits over originally-licensed mRNA vaccines; consequently, its use may further improve health outcomes and economic efficiency within COVID-19 vaccination programs.

BackgroundSevere Fever with Thrombocytopenia Syndrome (SFTS) is an acute infectious disease with high mortality. This study aimed to develop a quantitative scoring system for grading SFTS severity using dynamic clinical data. MethodsA retrospective study included 547 confirmed SFTS patients from two hospitals. Clinical data were collected over a 14-day course (divided into four phases). Patients were grouped into survivors (n=451) and non-survivors (n=96). Statistical analyses, including Kaplan-Meier curves and log-rank tests, were performed. An external validation cohort of 44 new patients was used to validate the scoring system via C-statistic, calibration curves, and decision curve analysis (DCA). ResultsOf 547 patients, 96 (17.55%) were non-survivors. Multivariate logistic regression identified six independent prognostic factors across phases: age, platelet (PLT), aspartate aminotransferase (AST), and creatinine (Cr) (days 5-7); age, red blood cell distribution width (RDW), Cr, and lactate dehydrogenase (LDH) (days 8-10); Cr and LDH (days 11-14). A scoring system (0-11 points) was developed, stratifying patients into low (0-3), intermediate (4-7), and high (8-11) risk groups, with adverse outcome rates of 1.04%, 22.92%, and 76.04%, respectively. Kaplan-Meier curves showed significant prognostic differences (log-rank P<0.001). External validation (44 cases) confirmed excellent performance: AUC 0.810-0.952, good calibration (Hosmer-Lemeshow P>0.05), and net clinical benefit (DCA Eavg 0.068-0.098, Emax 0.422-0.559). ConclusionA dynamic SFTS severity scoring system was developed and validated. Internal and external validation confirmed its reliability and clinical utility, providing a simple, practical tool for timely assessment and early intervention.

Crimean Congo hemorrhagic fever (CCHF) disease, caused by CCHF virus (CCHFV), poses a significant fatality risk whose underlying pathological mechanisms, including the contribution of coagulation factors imbalances and platelets abnormalities, remain poorly understood. Here we present a meta-analysis and meta-regression analysis using clinical data from coagulation assays and platelet parameters as predictive disease indices with the goal of uncovering pathognomonic factors and to pave a path for the development of effective therapeutic approaches. MethodsWe systematically analyzed published studies reporting coagulation assays and platelet indices in patients with confirmed CCHF. Data from 1,779 patients across published studies were analyzed to assess associations between laboratory parameters and fatality risk, while evaluating heterogeneity and prognostic significance. ResultsFatal outcomes were strongly associated with elevated liver enzymes (AST: 1116.71 {+/-} 1454.08 IU/mL; ALT: 446.56 {+/-} 457.41 IU/mL) and prolonged clotting times (PT: 19.53 {+/-} 6.57 s; aPTT: 64.02 {+/-} 23.13 s; INR: 1.53 {+/-} 0.56). D-dimer levels did not significantly predict fatality. Thrombocytopenia and coagulopathy emerged as independent risk factors for adverse outcomes. Notably, protein C and protein S levels did not differ between survivors and non-survivors, suggesting that the coagulopathy is not purely consumptive or a result of impaired hepatic synthesis. In contrast, mildly reduced antithrombin levels (83.65 {+/-} 19.90) were weighted toward increased mortality. Simple SummaryCrimean-Congo Hemorrhagic Fever (CCHF) causes high mortality through hemorrhage, but whether this reflects thrombocytopenia alone or combined coagulopathy remains unclear. We conducted meta-analyses of studies each of coagulation parameters (PT, aPTT, INR, fibrinogen, D-dimer, protein C and protein S, antithrombin) from survivors vs non-survivors. Fatal cases showed combined thrombocytopenia and coagulopathy (elevated PT/aPTT/INR, reduced fibrinogen/antithrombin) and liver damage (elevated AST/ALT). Protein C and protein S were unaffected, suggesting complex mechanisms beyond simple consumption or hepatic failure. These findings indicate coagulopathy contributes independently of thrombocytopenia to CCHF hemorrhage, supporting combined platelet and coagulation factor replacement therapy.