Clinical Microbiology and Infection

Aim: Brucellosis remains endemic throughout the Mediterranean basin, the Middle East and Central Asia. Genitourinary involvement is an uncommon but clinically consequential focal complication that closely mimics urological emergencies and may precipitate unnecessary surgery. Contemporary data describing its frequency, laboratory signature and treatment outcomes in endemic settings remain limited. Material-Methods: We retrospectively screened all adults ([≥]18 years) with confirmed brucellosis managed at a tertiary infectious diseases unit between January 2008 and December 2020. Genitourinary involvement was defined as epididymo-orchitis, orchitis, epididymitis and/or brucellar pyelonephritis. Clinical, laboratory, ultrasonographic, therapeutic and outcome variables were abstracted using a standardised form. Proportions are reported with Wilson score 95% confidence intervals (CI). Reporting followed the STROBE statement. Result: Genitourinary involvement was identified in 18 of 125 patients with brucellosis (14.4%; 95% CI 9.3-21.6); 16 (88.9%) were men and the mean age was 35.2 years (range 22-62). Scrotal disease dominated the male presentation: epididymo-orchitis in 10 of 16 men (62.5%; 95% CI 38.6-81.5), orchitis in 4 (25.0%) and epididymitis in 2 (12.5%). Both women presented with pyelonephritis, one of whom developed a tubo-ovarian abscess requiring drainage. Constitutional features were near-universal (fatigue 100%, night sweats 88.9%, fever 77.8%). Leukocyte counts remained within the reference interval in every patient (mean 5,680/mm3), whereas erythrocyte sedimentation rate (mean 32 mm/h) and C-reactive protein (mean 24.2 mg/L) were only mildly to moderately raised. The Coombs anti-Brucella test was positive in 18 of 18 patients (100%) and the standard agglutination test in 17 of 18 (94.4%), whereas blood culture yielded Brucella melitensis in only 1 of 18 (5.6%). Concomitant extragenitourinary focal disease was present in 8 patients. All patients received doxycycline plus rifampicin; none required modification of the regimen or orchiectomy, and no treatment failure occurred (0 of 18; 95% CI 0-17.6). Median follow-up was 12 weeks (range 6-52) and no relapse was documented within this interval. Conclusions: In endemic regions, genitourinary brucellosis should be suspected in any patient with acute scrotal or flank symptoms accompanied by constitutional complaints, even when the leukocyte count is normal and acute-phase reactants are only marginally elevated. Coombs anti-Brucella serology rather than blood culture is the diagnostic cornerstone, and prompt doxycycline-rifampicin therapy averts surgical intervention.

Objectives To evaluate the impact of COVID-19 vaccination on the prevention of long COVID (LC) in the Omicron era through an updated systematic review and meta-analysis. Methods We performed an update of our previously published systematic review and meta-analysis of vaccination and LC risk (searches between 1 January 2022 and 1 March 2024). Databases (Embase, MEDLINE, PubMed, Europe PMC, LILACS, Cochrane COVID-19 Study Register) were searched for studies published between 1 March 2024 and 13 July 2026. Observational studies assessing the impact of vaccination on the risk of LC four or more weeks after SARS-CoV-2 infection were included. Vaccines were restricted to those centrally authorised in the European Union. Random-effects meta-analyses, restricted to adults, were performed to calculate pooled odds ratios (OR) of LC in three comparisons: vaccinated (any dose) versus unvaccinated; booster vaccination versus unvaccinated; and booster vaccination versus primary course vaccination only. Results Nineteen new studies were identified, of which ten were included in the updated meta-analyses alongside eight studies from the original review. The pooled OR of LC in vaccinated adults (any dose) versus unvaccinated was 0.75 (95% confidence interval [CI] 0.67-0.84; 13 studies). ORs were also lower for booster vaccination versus unvaccinated (0.73; 95% CI 0.65-0.82; 6 studies), and booster vaccination versus primary course vaccination (0.63; 95% CI 0.53-0.75; 6 studies). Significant associations between vaccination and lower LC odds were observed in subgroup analyses of mRNA-only vaccination and LC outcomes three or more months after infection. Conclusions This updated review and meta-analysis reinforces our previous finding that vaccination may reduce the burden of LC in the Omicron era, with booster doses potentially providing additional protection. Although evidence in high-risk groups now prioritised for vaccination in most countries remains limited, these findings clearly demonstrate the benefits of vaccination and support current seasonal vaccination strategies.

Purpose: To compare the efficacy and safety of intravenous cefazolin versus antistaphylococcal penicillins for the treatment of MSSA bacteremia in adults using evidence exclusively from randomized controlled trials. Methods: We searched 5 databases for RCTs comparing definitive intravenous cefazolin with ASPs (oxacillin, cloxacillin, flucloxacillin, nafcillin) in adults with MSSA bacteremia. Primary outcomes were 90-day all-cause mortality and acute kidney injury (AKI). Secondary outcomes included adverse event-related treatment discontinuation and persistent bacteremia (>72h). Dichotomous outcomes were synthesized as risk ratios (RRs) with 95% confidence intervals (CIs) using random-effects models with Paule-Mandel estimation and Hartung-Knapp-Sidik-Jonkman inference. Fixed-effect Mantel-Haenszel models were performed as sensitivity analyses. Results: Two RCTs randomized 1,656 participants (SNAP, n = 1,341; CloCeBa, n = 315), of whom 1,579 contributed to the 90-day mortality analysis. There was no statistically significant difference in 90-day mortality (RR 0.90, 95% CI 0.57-1.41; I2 = 0%). Both trials favoured cefazolin for acute kidney injury, but the random-effects estimate was highly imprecise (RR 0.26, 95% CI 0.00-939,970.59; I2 = 81.7%). Treatment discontinuation also favoured cefazolin directionally, although the random-effects estimate was imprecise (RR 0.24, 95% CI 0.00-24.41; I2 = 36.2%). Microbiological outcomes were synthesized narratively because definitions and assessment time points differed between trials. Conclusion: Randomized evidence supports cefazolin as a potential definitive treatment option when adequate source control, appropriate antimicrobial dosing, and clinical monitoring can be achieved. However, the limited number of trials and imprecision in pooled estimates warrant cautious interpretation.

Objectives: To evaluate the epidemiological evolution of unique pneumococcal serotypes covered by either PCV20 or PCV21, common serotypes by both vaccines and non-vaccine serotypes in adults. Methods: We characterized all national IPD clinical isolates from January 2009 to June 2026. Results: The highest burden of IPD was caused by serotypes shared between PCV20 and PCV21 with serotypes 3 and 8 the most prevalent in adults of all ages. During the pre-pandemic period, IPD caused by unique-PCV20 serotypes declined probably due to herd protection by paediatric vaccination with PCVs. In contrast, unique-PCV21 serotypes increased in incidence accounting for more cases than unique-PCV20 serotypes. However, after the COVID-19 pandemic, a different pattern was observed with unique-PCV20 serotypes increasing in incidence due a marked rise in IPD caused by serotypes 4 and 14 that has progressively reduced the gap in disease coverage. In adults aged 18-64 years, the fraction of disease that could be prevented with PCV20/PCV21 changed from 5% in favour of PCV21 (years 2022/2023) to 15% in favour of PCV20 (year 2026) whereas in adults [≥]65 years the vaccine contribution declined from 20% in favour of PCV21 (year 2022) to 8% in 2026. Conclusions: IPD trends in adults have changed after the COVID-19 pandemic, especially in recent years. Our study emphasizes the rapid re-emergence of infections caused by traditional PCV7 serotypes especially serotypes 4 and 14 and reinforce the idea that the use of broader PCVs must be accompanied by an increase in the uptake rates in adults of all ages.

Background: Child-friendly sample collection methods are needed to improve microbiological tuberculosis diagnosis in children. We assessed the feasibility, diagnostic yield, safety, tolerability, and acceptability of nasopharyngeal aspirates (NPA) and stool sample collection for XpertMTB/RIF Ultra (Ultra) testing in children <5 years with severe pneumonia in six high tuberculosis incidence countries. Methods: We conducted a cross-sectional mixed-methods study (10/2020-03/2021) nested within the TB-Speed Pneumonia trial (NCT03831906) in 15 tertiary hospitals. Uptake and diagnostic yield of NPA and stool, sampled by trained nurses, were computed. Nurses documented NPA feasibility and related adverse events. NPA tolerability was assessed through discomfort/distress/pain scales completed by nurses, parents/caregivers, and children >3 years. Individual interviews investigated nurses and parents/caregivers perceptions and experiences of both procedures. Results: Of 542 children enrolled, 541 (99.8%) and 423 (75.5%) had NPA and stool samples successfully collected, respectively; 8 (1.5%) had positive Ultra on any sample, 8 (1.5%) on NPA, and 3 (0.6%) on stool samples. Nurses reported that NPA was difficult to collect in 27 (5.0%) children. 130 (24%) children had bloodstained NPA samples and <5% experienced transient heart rate deceleration, digestive or respiratory distress during NPA. Median nurse-assessed tolerability scores were 1/10 [0,3] before and 5/10 [2,6] during NPA. Although most respondents perceived NPA as painful, all appreciated that NPA aimed to improve child health. Nurses reported that NPA and stool collection was quicker, less invasive than gastric aspiration. Parents/caregivers trusted nurses skills and valued the novelty of NPA. All respondents easily engaged in stool collection, but were frustrated to depend on children passing stool. Nurses underlined that continuous staff training and mentoring would sustain feasibility and self-efficacy in obtaining adequate samples. Conclusions: NPA and stool are viable specimen collection options for microbiological diagnosis of tuberculosis in young children <5 years with severe pneumonia in high tuberculosis incidence countries.

Background: Treponema pallidum quantitative polymerase chain reaction (qPCR) positivity and cycle threshold (Ct) by rapid plasma reagin (RPR), disease stage, and other characteristics are poorly characterized in routine-care specimens, leaving it unclear when qPCR of such specimens is informative for diagnosis. Methods: This Japanese multicenter cross-sectional study explored qPCR positivity and Ct by these characteristics. Nonblood specimens collected during routine care underwent qPCR at a central laboratory for this study. Bayesian logistic and normal regressions modeled positivity and mean Ct of TP0574 and polA with stage-specific continuous automated RPR terms, patient characteristics, collection site, and facility random intercepts. Estimates were standardized over the analyzed specimens. Population-group predictions were instead averaged within each group. Results: Among 154 nonblood specimens from 145 patients (71.7% non-MSM men and women) at 14 facilities, 109 (70.8%) were qPCR positive. At RPR 1, adjusted positivity was 72.2% (95% credible interval, 60.9%--82.9%) in primary and 43.8% (16.7%--69.9%) in secondary syphilis. Positivity showed a modest downward trend with RPR in primary but increased in secondary syphilis, reflecting a stage-by-RPR interaction (secondary-to-primary ratio of odds ratios, 1.78; 1.25--2.65). Predicted positivity showed an upward trend with RPR values among MSM; adjusted positivity was relatively high for genital/urethral/urinary and anal/perianal/rectal specimens. Adjusted mean Ct increased with RPR in primary and followed an inverted-U pattern in secondary syphilis. Conclusions: In primary syphilis, nonblood qPCR positivity was high even at low RPR. When serologic findings remain inconclusive in this stage, qPCR is highly recommended for securing an early diagnosis.

Incidence of ventilator-associated pneumonia (VAP) is increased in patients admitted for brain injury. Staphylococcus aureus appears to be a particularly common pathogen in these respiratory infections. Our aim was to confirm the extent of S. aureus involvement in VAP among patients with neurological injuries. We conducted a retrospective, multicenter study including patients with and without neurological injuries who developed VAP during their ICU stay. Among 15 702 patients admitted in the participant centers during the study period. 407 were finally included in the study. S. aureus was involved in 122 (61.6%) VAP in brain-injured patients and 63 (30.1%) of non-brain-injured patients. In brain-injured patients, multivariate analysis identified age (0.97 [0.95; 0.98]), antibioprophylaxis (0.31 [0.18; 0.53]; p < 0.0001), subarachnoid hemorrhage (2.18 [1.01; 4.68]; p=0.0461), lower Glasgow coma score (0.92 [0.87; 0.97]; p= 0.004) and SAPS II (0.98 [0.97; 1]; p=0.0174) as critical factors associated with the risk of S. aureus in VAP. In the non-brain-injured population, multivariate analysis identified antibioprophylaxis (0.38 [0.22; 0.65]; p=0.0006), age (0.96 [0.95; 0.98]; p<0.0001), SAPS II (0.98 [0.97; 1]; p=0.0265), thoracic surgery (0.21 [0.09; 0.48]; p=0.0002) and peripheral neurosurgery (1.95 [1.2; 3.19]; p=0.0076) as critical factors. A total of 172 patients (42.3%) died during their ICU stay and 90-days mortality was 194 (47.7%). No difference of mortality was noticed function of VAP-associated pathogen.

Interferon-gamma release assays detect Mycobacterium tuberculosis infection but cannot distinguish infection from active tuberculosis (TB). We evaluated the diagnostic information provided by QuantiFERON-TB Gold Plus (QFT-Plus) among adults investigated for active TB in Brazil and South Africa. Adults with presumptive TB were prospectively enrolled by convenience sampling. QFT-Plus was the index test, and diagnostic classification required microbiological confirmation of TB or an established alternative diagnosis. QFT-Plus results did not inform diagnostic classification. Accuracy was assessed among participants with determinate results, primarily using likelihood ratios. Of 723 participants tested, 48 (6.6%) had indeterminate results, all due to low mitogen responses. Among 675 participants with determinate results, 147 (21.8%) had confirmed TB. Sensitivity was 68.0% (95% CI, 60.1-75.0), specificity was 59.3% (95% CI, 55.0-63.4), and the negative likelihood ratio was 0.54 (95% CI, 0.42-0.69). At the observed prevalence, a negative result left a 13.1% probability of active TB. Negative likelihood ratio confidence intervals included 1 in both South African HIV strata. Specificity was higher among participants with HIV in both countries. Adding TB2 to TB1 alone identified 15 additional TB cases and generated 18 additional positive results among participants without active TB. HIV and active TB were independently associated with indeterminate results in exploratory regression. A negative QFT-Plus result provided insufficient information to exclude active TB. Higher negative predictive values among participants with HIV reflected lower disease prevalence and higher specificity rather than greater sensitivity. Negative or indeterminate results should not terminate diagnostic evaluation.

Background: European Association of Urology (EAU) Guidelines identify urogenital infections as a possible treatable cause of infertility, yet the current recommendation for antibiotic treatment remains weak due to a lack of high-quality evidence. We evaluated the effect of antibiotic treatment of asymptomatic urogenital infections on both conventional and apoptosis-related (flow cytometry sperm apoptosis test, FACS-APO) sperm parameters, as well as on pregnancy outcomes, in infertile couples. Methods: In this retrospective, single-centre study, we analysed 265 couples with an asymptomatic urogenital infection (Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium, and Chlamydia trachomatis) confirmed in at least one partner by first-void urine testing, who received simultaneous antibiotic treatment. Paired conventional semen analysis and FACS-APO were performed before and 0-9 months after treatment completion. Partner infection concordance, the effect of follow-up timing on treatment response, and pregnancy outcomes within 12 months were also assessed. Results: Sperm concentration, total sperm count, total and progressive motility, and the proportion of viable sperm increased significantly after treatment, while the proportion of late apoptotic / necrotic sperm and calculated sperm DNA fragmentation decreased significantly (all p<0.05); the proportion of early apoptotic sperm remained unchanged, and semen volume did not change. Among 244 couples with complete bilateral microbiological testing, Ureaplasma urealyticum was by far the most prevalent pathogen (57.8% of men, 87.7% of women), and female partner positivity given male positivity was 83.0%. The improvement in sperm concentration and total sperm count was most pronounced within 3 months after treatment and diminished, or reversed, beyond 6 months. Pregnancy was achieved in 127 of 265 couples (47.9%; per-protocol rate 53.4%) within 12 months, most commonly following in vitro fertilization (72/127) or spontaneously (21/127). Conclusions: Antibiotic treatment of asymptomatic urogenital infections in infertile couples was associated with significant improvement in conventional semen parameters and a reduction in sperm apoptosis and calculated DNA fragmentation. Given the retrospective, uncontrolled design, these findings should be regarded as hypothesis-generating rather than definitive proof of a causal, fertility-enhancing effect, and warrant confirmation in prospective controlled studies.

Background: Long-term mortality data among Brazilian police officers and firefighters are scarce. This study investigated the leading causes of death in Brazilian male military police officers and firefighters over three decades, comparing their mortality and mean age at death with those of the male population. Methods: We retrospectively analyzed death records of male military police officers and firefighters from Espirito Santo (ES), Brazil, from 1988 to 2019. Mortality was analyzed across three decades and the standardized mortality ratios (SMRs) for the three leading causes were calculated using the male populations of ES and Brazil as references. Results: Overall, 2,198 deaths were identified, with a mean age at death of 59 {+/-} 18.5 years, compared with 60.5 {+/-} 23.9 years among men in ES and 63.4 {+/-} 23.7 years among Brazilian men. Mean age at death was 36 {+/-} 9 years among active-duty and 68 {+/-} 13 years among inactive personnel. Across the study population, the leading causes of death were circulatory system diseases (32%), external causes (26%) and neoplasms (15%). Circulatory disease mortality was higher in the second and third decades compared with both reference populations, whereas external-cause mortality shifted from higher, in the first two decades, to lower than expected in the last decade. Neoplasm mortality was higher relative to Brazil only in the last decade. Conclusion: Mortality patterns differed by cause and over time. The younger mean age at death among active-duty personnel, together with cause-specific excess mortality, highlights the importance of long-term occupational health surveillance and preventive strategies.

Background. Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events in almost any organ. While myocarditis has received the most attention, data on pericardial disease with ICI use are limited. We examined pericardial adverse event reporting with nine ICIs using the FDA Adverse Event Reporting System (FAERS). Methods. We combined legacy AERS and current FAERS quarterly files from January 2011 to June 2026 into 18,629,240 unique cases, deduplicated by case number, and removed cases the FDA had listed as deleted. ICI exposure was identified from generic names, brand names, development code names and the active-ingredient field. Pericardial events were defined by seven MedDRA preferred terms. We estimated reporting odds ratios (ROR), proportional reporting ratios (PRR), Bayesian information components (IC) and empirical Bayes geometric means (EBGM). We also examined myocarditis co-reporting, time trends, a comparison with other antineoplastic agents, a MedDRA query-based outcome, and 14 alternative definitions. Results. The analysis included 18,514,045 cases: 277,434 involved an ICI, 34,792 carried a pericardial term, and 1,680 had both. Pericardial events were reported disproportionately with ICIs (ROR 3.35 (95% CI 3.19 to 3.52); PRR 3.34; IC025 1.62). Eight of nine agents had a ROR above 1 (3.32 to 5.63). Among the most frequently reported terms, estimates were highest for cardiac tamponade (5.59 (95% CI 4.98 to 6.28)), followed by pericardial effusion (3.83 (95% CI 3.60 to 4.07)) and pericarditis (2.09 (95% CI 1.89 to 2.31)). After removing cases that also reported myocarditis, the ROR was 3.13 (95% CI 2.98 to 3.30). Most sensitivity analyses gave similar estimates (ROR 3.13 to 3.47); defining exposure by generic drug names alone, which identified only 44% of exposed cases, gave 3.99. Compared with cases naming other L01 antineoplastic agents, the ROR was 1.13 (95% CI 1.08 to 1.19): 1.28 (95% CI 1.20 to 1.36) for ICI-only cases and 0.96 (95% CI 0.89 to 1.04) when another antineoplastic was also named. The ICI-specific reporting odds ratio fell each quarter (odds ratio 0.977 per quarter, 95% CI 0.973 to 0.980). Conclusions. In FAERS, pericardial events were reported more often with ICIs than with other drugs across most agents and terms; however, incidence and causation cannot be determined. The excess over other antineoplastic agents was small, and reporting disproportionality declined over time. These findings support clinical awareness of pericardial disease in patients receiving ICIs and warrant study in data that can measure incidence.

Abstract Background. Enteric hyperoxaluria (EH) causes calcium oxalate kidney stones, oxalate nephropathy, and chronic kidney disease (CKD), and can progress to end-stage kidney disease. It occurs in Crohn's disease (CD), cystic fibrosis (CF), chronic pancreatitis, celiac disease, short bowel syndrome, and after bariatric surgery. Its prevalence in these populations has not been synthesized. Methods. PROSPERO CRD420261364424. PubMed and Embase were searched to 24 August 2026 for studies reporting 24-hour urinary oxalate. Prevalence was pooled using the Freeman-Tukey double arcsine transformation with a DerSimonian-Laird random-effects model; unweighted crude prevalence is also reported. Because heterogeneity was high, the narrative synthesis stratified by testing condition is the primary result. Prespecified subgroups addressed oxalate load before collection, diagnostic threshold, ileal resection, age, and urine collection format. Results. Forty-seven studies were included. In CD (17 studies, 471 patients; 204 with EH), crude prevalence was 43.3% and pooled prevalence 49.3% (95% CI 38.9-59.8; I^2 = 95.3%). With an oxalate load, prevalence was 64.7% (pooled 74.0%, 55.9-88.6) versus 38.6% without (pooled 39.1%, 28.7-50.0). Among CD patients, EH was more frequent with ileal resection (48.8% vs 31.7%; OR 1.62, 0.91-2.89) and with steatorrhea (62.5% vs 29.3%; OR 9.88, 3.81-25.61). In CF (7 studies, 348 patients; 179 with EH), pooled prevalence was 49.8% (40.5-59.1; I^2 = 91.9%). After bariatric surgery (15 studies, 849 patients; 474 with EH), pooled prevalence was 54.7% (45.4-63.9; I^2 = 96.7%). Conclusions. Roughly half of these patients have EH, but the proportion depends heavily on whether an oxalate load precedes urine collection (39% unprovoked vs 65%-74% provoked); because most studies do not state this condition, published prevalence estimates are not directly comparable. Ileal resection and steatorrhea identify those who should be screened.

Background: Half of US children are prescribed an antibiotic by age 2. Maternal education and socio-economic factors influence prescribing but the role of other factors, such as age of solid food introduction is unknown. Objectives: We assessed risk factors for time to first antibiotic use between birth to age 2 to identify modifiable drivers of antibiotic use. Methods: We analyzed interviews from mothers of 1032 children participating in the mother-child Center for Oral Health Research in Appalachia cohort 2 between 2011 and 2017. The cohort enrolled healthy, English-speaking, pregnant White women > 18 years with singleton pregnancies. We used time-to-event analyses and a Cox Proportional Hazards model to describe and estimate hazard ratios (HRs) for time to first antibiotic. Results: By age 2, 78% of children received at least one antibiotic (median age at first antibiotic: 12.5 months). Over half (58%) of antibiotics prescribed were for ear infections. After adjustment for household income and birth quarter as fixed variables, time of solid food introduction (aHR: 4.75; 95% CI: 3.19, 7.07), time of first ear infection (aHR: 3.28; 95% CI: 2.58,4.17), and time of first illness (aHR: 4.60; 95% CI: 3.32,6.36) were significantly associated with time of first antibiotic use. Conclusions: Earlier time of solid food introduction was associated with earlier antibiotic use. Childhood illnesses, especially ear infections, also strongly influence antibiotic initiation. These modifiable factors offer targets to reduce unnecessary early antibiotic use.

BackgroundFebrile neutropenia requires rapid empirical antibiotic therapy, with regimen selection shaped by local prescribing practice and pathogen patterns. We described starting treatment, later drug changes, microbiological findings, and inpatient outcomes. MethodsThis ambispective cohort comprised 96 episodes from 90 patients admitted to a tertiary-level teaching hospital. Treatment and outcome analyses used each episode as the unit of observation. Recorded variables included the starting antibiotics, later regimen modification, microbiology, hospitalization length, invasive fungal infection (IFI) as captured in study records, and disposition. Comparisons based on escalation status were exploratory. ResultCefoperazone-sulbactam appeared in 62/96 initial regimens (64.6%), amikacin in 42 (43.8%), teicoplanin in 28 (29.2%), and meropenem in 14 (14.6%). Eighteen episodes (18.8%) required a change that broadened or substituted antibacterial therapy. Among 31 microbiologically documented infections, 22 (71.0%) yielded Gram-negative organisms and 9 (29.0%) were polymicrobial. Median length of admission was 18.5 days in the escalation group and 9 days in the remainder (p<0.001). Mortality was 27.8% (5/18) with escalation and 5.1% (4/78) without it (p=0.011), with nine inhospital deaths overall (9.4%). ConclusionAntibacterial management differed within this cohort, with treatment escalation required in 18 of 96 episodes. Gram-negative organisms comprised most microbiologically confirmed infections. Escalation marked a clinically complex course with prolonged hospitalization and greater observed mortality; the observational design does not establish comparative efficacy or causation.

Background: Both over- and under-antibiotic use pose major global health challenges, yet there is no consensus on how to quantify deviations from optimal prescribing or set evidence-based targets. We developed a benchmarking tool for inpatient antibiotic use and evaluated its application in 10 countries. Methods: We developed decision-tree models to estimate expected empiric antibiotic use for 11 indications, based on the WHO AWaRe book for two age groups: 28 days to 12 years and >12 years. We parameterised the models using country-specific antimicrobial resistance estimates in the 10 countries and cross-sectional Global Point Prevalence Survey (Global-PPS) case-mix data from 2021 for 10 countries and from 2015-2022 in a subset of five countries. We then compared estimated expected antibiotic use with observed empiric use (from Global-PPS) in defined daily doses for adults and days of therapy for children, across indications and AWaRe categories. Findings: In 2021, among patients aged >12 years, in all countries but one, observed empiric Access antibiotic use, as a proportion of total antibiotic use, was lower than expected and empiric Watch antibiotic use was higher than expected. Similar patterns were observed in all countries but one in patients aged 28 days to 12 years. The magnitude of discrepancies between expected and observed Access and Watch antibiotic use varied across indications and countries. The median observed-to-expected ratios of usage across countries ranged from 0.3-0.8 for Access antibiotics, and 0.7-5.3 for Watch antibiotics in patients aged >12 years in 2021. Temporal trends from repeated surveys from 2015 to 2022 showed little change in observed-to-expected ratios for Access and Watch antibiotics. Interpretation: This benchmarking tool uses Global-PPS data to quantify differences between observed antibiotic use and WHO AWaRe recommendations. Our tool can be adaptable to local guidelines, provides policy-relevant estimates of expected antibiotic use to support monitoring, procurement planning, and targeted stewardship intervention.

Background: TB vaccine development is hampered by the natural history of M. tuberculosis: most infected people rarely progress to disease, so trials must be very large and long to accrue sufficient disease endpoints. Current trials enrol IGRA-positive participants (IGRA: Interferon-Gamma Release Assays), but IGRAs remain positive for many years and cannot distinguish recent from remote infection. Tests for recent infection are now in development, and we argue they could make trials substantially more efficient. Here, we investigate how screening participants prior to enrolment with a test for recent M.tb infection could impact the total number of enrollees required for an adequately-powered TB vaccine trial. Methods: Using a statistical model of vaccine trial recruitment, we estimated the number needed to contact, test, and enrol to achieve an 'effective' trial (defined as 50 disease endpoints), under IGRA-gated enrolment (life-long duration of positivity) vs. enrolment with a test for recent infection. We considered five recruitment strategies: non-test-based enrolment for ages 15-49, ages 12-34, and household contacts of recent cases; and test-based enrolment using IGRA, and a test for recent infection with two-year duration of positivity. The model explored trial recruitment in South Africa, Kenya, and India. Results: Compared with an extended-positivity test, a test for recent infection reduced the median number needed to enrol by 4.2- to 6-fold under favourable conditions. It also outperformed non-test-based strategies, including enrolling household contacts. This comes at the cost of substantially more testing, but crude estimates suggest recency-based enrolment would still be cheaper overall provided the new test does not cost more than roughly 5-10 times an IGRA. Conclusions: Diagnostics for recent M.tb infection have the potential to improve vaccine trial efficiency, but more research is now needed to understand test characteristics and to evaluate their use in this setting. Our Viewpoint sets out the test attributes that would need to be established, such as time to positivity, duration of positivity, sensitivity, and specificity, before such tests could be used in vaccine trials.

To characterise temporal changes in antimicrobial resistance (AMR) among clinically important bacterial pathogens in Iraq during 2021-2024 and examine their implications for empirical antimicrobial therapy and stewardship. We conducted a retrospective longitudinal analysis of aggregated national AMR surveillance data for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus. Annual resistance proportions were evaluated across clinically relevant antimicrobials. Temporal change was characterised using absolute percentage-point changes and exploratory linear regression. Resistance trajectories were interpreted in relation to empirical treatment options and antimicrobial stewardship. The analysis included 92,338 organism records: 40,496 (43.9%) E. coli, 24,621 (26.7%) S. aureus, 18,223 (19.7%) K. pneumoniae and 8,998 (9.7%) P. aeruginosa. In 2024, ceftriaxone resistance reached 82.9% in E. coli and 65.2% in K. pneumoniae, while ciprofloxacin resistance was 55.4% and 57.9%, respectively. Meropenem resistance reached 37.4% in K. pneumoniae and 62.3% in P. aeruginosa. Conversely, resistance declined for amoxicillin-clavulanate in E. coli (83.5% in 2021 to 57.2% in 2024) and piperacillin-tazobactam in P. aeruginosa (46.4% to 32.9%). Several pathogen-antimicrobial combinations showed marked year-to-year variation, and no temporal trend remained statistically significant after false discovery rate correction. Resistance to several agents central to empirical therapy remains high in Iraq, while substantial carbapenem resistance constrains reliance on carbapenem escalation when resistance to other {beta}-lactams is suspected. Heterogeneous trajectories indicate that empirical recommendations should not rely on single-year national antibiograms alone and support regular integration of national and local resistance surveillance into empirical treatment and antimicrobial stewardship strategies.

Background. Tuberculosis preventive treatment (TPT) with levofloxacin reduces tuberculosis disease incidence in multidrug-resistant or rifampicin-resistant (MDR/RR)-tuberculosis household contacts. However, with age, disease progression risk falls and the frequency of adverse events (AE) rises. Methods. To inform decision-makers, we evaluated the cost-effectiveness of expanding the use of MDR/RR-TPT by age, with and without tests of tuberculosis infection. We modelled MDR/RR-household contact management (HHCM) in 189 countries, incorporating age-dependent risks of disease progression, death and AEs. Incremental cost-effectiveness ratios were calculated as USD/disability-adjusted life year (DALY) averted, and as a fraction of per capita gross domestic product (GDP). Findings. Compared to baseline of MDR/RR-HHCM with TPT for those <15 years, adding TPT up to 45 years was cost-effective at a threshold of 30% GDP in 160/189 modelled countries including 17 of the 30 highest incidence countries. Of these 160 countries, the intervention was cost-saving in 46. Strategies targeting TPT to those testing positive for M. tuberculosis infection were dominated by those without testing. Globally, full use of MDR/RR-HHCM with TPT for all would avert 11,900 (10,400 to 13,800) episodes of tuberculosis, 9,960 (9,100 to 10,900) deaths, and 289,000 (262,000 to 321,000) DALYs, but would result in 71,000 (68,000 to 74,000) SAEs and cost $359 million (294 to 449). Interpretation. Expanding MDR/RR-TPT use to older ages without testing appears cost-effective in most settings, but may require substantial resources and result in large numbers of AEs. Funding. Unitaid

Encephalopathy is a lethal manifestation of global cerebral dysfunction spanning hypoxic, metabolic, toxic, and vascular etiologies, yet its population burden is difficult to quantify because it predominantly appears as a contributing rather than underlying cause of death. Here, we analyzed US multiple-cause death records from 1999 through 2024 using harmonized CDC WONDER datasets. A longitudinally consistent core definition of 10 ICD-10 codes identified 953,846 encephalopathy-associated deaths. The national age-adjusted mortality rate increased 28.4%, from 9.143 per 100,000 in 1999 to 11.738 in 2024, after peaking at 14.391 in 2021. Segmented log-linear regression identified four temporal phases: 1999-2004 (annual percent change [APC],-1.76%), 2004-2018 (APC, 2.57%), 2018-2021 (APC, 6.54%), and 2021-2024 (APC, -5.98%). Encephalopathy was listed as the underlying cause in only 21.6% of deaths in 2024. Unspecified encephalopathy surged more than 3.6-fold, while anoxic brain injury remained stable. Mortality remained higher in males than females (13.973 versus 9.778 per 100,000), and rates among non-Hispanic Black individuals were 1.90-fold those of non-Hispanic White individuals. Geographically, mortality clustered in the Midwest and South (13.144 and 13.120 per 100,000 in 2024), with persistent state-level dispersion across the study period. COVID-19 accounted for 10.9% of associated deaths in 2021 before falling to 1.4% in 2024. These findings reveal a nonlinear trajectory shaped by diagnostic shifts, pandemic disruption, and persistent demographic and geographic disparities.

Background: Previous studies indicated that regional fluctuations in COVID-19 impact were associated with socioeconomic, demographic and environmental factors early in the pandemic. It is unclear whether factors associated with regional COVID-19 mortality and SARS-CoV-2 infections changed over the course of the pandemic. Methods: We evaluated the association of ecological factors with municipality-specific COVID-19 mortality in the national population of Austria between January 2020 and June 2023. Analyses were conducted separately per calendar year and pooled across years via random-effects meta-analysis. Outcomes were analysed using univariable and multivariable zero-inflated negative binomial (ZINB) regression, including annually averaged environmental exposome exposure (including air pollution and UV radiation), socioeconomic, demographic and infection dissemination predictors with significance threshold set to p<0.005. Secondary analysis modelled SARS-CoV-2 infections using of negative-binomial model (NB). Two additional approaches for smaller predictor set selection were applied as sensitivity analyses. Results: Within the entire observation period 18,430 COVID-19 deaths were reported. In univariable analyses (pooled RR (99.5% CI)), COVID-19 mortality was significantly associated with the proportion of commuters (0.79 (0.73-0.86)), residents aged 75-84 (1.18 (1.01-1.37)) and [&ge;]85 years (1.29 (1.04-1.60)), residents with at most compulsory education (1.15 (1.02-1.29)), employed residents aged 15-64 (0.89 (0.85-0.93)), and homeowners (0.91 (0.83-0.99)), as well as with precipitation (0.94 (0.89-0.99)) and the average time with a mean temperature of 5-15 C (0.95 (0.90-0.99)). In multivariable analyses the share of population aged 85 or older (1.30 (1.09-1.54)) and home ownership (0.92 (0.87-0.98)) were independently significant. Mortality predictor estimates were relatively stable across pandemic years. Across 5,963,882 documented SARS-CoV-2 infections share of employed in 15- to 64-year-olds (1.01 (1.01-1.02)), part-time employment rate (1.01 (1.00-1.02)) and district level nursing care allowance recipiency (0.97 (0.95-0.98)) were associated with detected infections. Overnight stays, population 85 or older, income, compulsory education or less and air pollution all had multiple significant estimates with opposite directionality, leading to non-significant overall associations. Sensitivity analyses outcomes mirrored main analyses outcomes. Conclusions: Throughout the pandemic in Austria, demographic and socioeconomic factors were associated with COVID-19 mortality and infections, but many associations, especially for infections, were unstable over time. These findings underscore the importance of structural vulnerabilities in epidemic impact.