Background: Postoperative delirium is a frequent, serious complication triggered by various factors including systemic inflammation. Dexamethasone, an inexpensive anti-inflammatory steroid frequently administered for prophylaxis of postoperative nausea and vomiting, attenuates inflammation. We hypothesised that intraoperative dexamethasone administration is associated with a lower risk of postoperative delirium and assessed whether this is modified by the occurrence of its key side effect, hyperglycaemia.
Methods: This retrospective cohort study analysed electronic health data from adult hospitalised patients undergoing non-cardiac, non-neurosurgical, and non-transplant procedures at Beth Israel Deaconess Medical Center (Boston, MA, USA) between January 1, 2008, and January 15, 2024. Patients with missing data, preoperative delirium or glucocorticoid use, mechanical ventilation for 72 h or more, and those not expected to survive without the procedure, were excluded. The primary exposure was intraoperative administration of intravenous dexamethasone. The primary outcome was 7-day postoperative delirium, identified by keyword-triggered manual discharge note reviews, diagnostic codes, and the Confusion Assessment Method. Hyperglycaemia was defined as peak 24-h postoperative blood glucose of more than 180 mg/dL. All analyses were adjusted for 43 patient-related and procedure-related variables.
Findings: 92,832 patients were included (55.8% female, median age 60 years [IQR 48-70]), of which 41,983 (45.2%) received dexamethasone at a median dose of 8 mg (IQR 4-8). 2575 (2.8%) patients developed postoperative delirium. Emergency procedures accounted for 11,970 (12.9%) of cases. Intraoperative administration of dexamethasone was associated with a lower risk of delirium (adjusted odds ratio [aOR] 0.63, 95% CI 0.56-0.70; p < 0.001; adjusted absolute risk difference -1.1%, 95% CI -1.3 to -0.8). The exploratory four-way mediation analysis suggested a 10.4% greater dexamethasone-associated reduction of postoperative delirium risk when hyperglycaemia did not occur (no hyperglycaemia aOR 0.59, 95% CI 0.51-0.67; p < 0.001; hyperglycaemia aOR 0.85, 95% CI 0.68-1.07; p = 0.17).
Interpretation: Intraoperative dexamethasone administration is associated with a lower risk of postoperative delirium, although this association was not evident in patients experiencing hyperglycaemia. Prospective studies should investigate the role of dexamethasone and optimised blood glucose control in delirium prevention.
Funding: Unrestricted philanthropic grant by Dr. J. and J. Buzen.
Background: Accumulation of score distribution towards the high end of the measurement scale is an important source of bias related patient-reported outcome measures (PROM). The aim was to evaluate how PROM score distributions, scale boundaries, and sampling variability influence the likelihood of detecting a minimal clinically important difference (MCID) of 10 points between surgical and non-surgical groups in randomised controlled trials (RCTs) of musculoskeletal disorders.
Methods: We did a systematic review and meta-epidemiological analysis of 129 RCT studies comparing surgical and non-surgical interventions in patients with musculoskeletal complaints using a PROM as an outcome measure (1771 group-level PROM measurements) from PubMed and Scopus published until February 26, 2025. Simulations assessed each comparison's likelihood of detecting a difference of 10 points or more.
Findings: The mean difference between groups was 4.6 (SD 7.1) points favouring surgery, with surgical arms scoring higher in 72% of comparisons. The mean likelihood of detecting at least a 10-point difference was 19%, meaning fewer than one in five of such comparisons would detect a true difference. Detection likelihood peaked (35%) at a mean score of 70, declining toward scale extremes. Comparisons with significant observed differences (>10 points, p < 0.05) had a 54% likelihood versus 17% in non-significant comparisons, strongly linking detection likelihood to observed differences.
Interpretation: The majority of the PROM-based RCTs were unlikely to detect differences due to ceiling effects with a constant underestimation of surgical benefit. PROMs with adequate content coverage, better discrimination, and reduced ceiling susceptibility should be selected for clinical practice. Future research should align outcome selection and follow-up timing with expected treatment effects and ensure that measurement properties do not mask meaningful clinical differences.
Funding: None.
Background: The interaction between physical activity and sleep with cardiovascular disease remains poorly understood, despite both being key risk factors. This study investigated the independent and joint associations of device-measured step count and sleep duration with incident major adverse cardiovascular events (MACE).
Methods: Prospective analysis of UK Biobank participants who wore a wrist-based accelerometer for seven days between 2013 and 2015. Open-source machine learning algorithms derived daily step count and overnight sleep duration. The outcome was incident MACE (cardiovascular death, non-fatal myocardial infarction or stroke, or revascularisation procedure), identified through electronic health record linkage. Cox proportional hazards models were used to examine independent and joint associations of median daily step count (low [<7500], intermediate [7500-11,000], high [>11,000]) and median overnight sleep duration (short [<6.5 h], intermediate [6.5-7.5 h], long [>7.5 h]) with incident MACE.
Findings: Among 88,012 participants (mean age 62.2 years [standard deviation, SD 7.8]), 3817 were diagnosed with MACE during follow-up (median 7.9 years [interquartile range, IQR 7.3-8.4]). Low step count and short sleep duration were independently associated with a higher risk of MACE, but there was no evidence of an interaction between step count and sleep duration (P for interaction = 0.42). Compared with the reference group-participants with high step count and intermediate sleep duration-the highest risk of MACE was observed in participants with both low step count and short sleep duration (hazard ratio, HR: 1.84, 95% CI: 1.62-2.10, p < 0.0001).
Interpretation: The results of this study show that higher daily step count does not fully attenuate the higher risk of cardiovascular disease associated with short sleep duration, reinforcing the importance of sufficient levels of both daily step count and sleep for the prevention of cardiovascular disease.
Funding: Wellcome Trust (223100/Z/21/Z).
Background: Knowledge about environmental and demographic determinants of tuberculosis is largely limited to studies with ecological designs. We explored the association between these determinants and tuberculosis prevalence in an individual participant dataset aggregated across seven African countries.
Methods: Data of nationally representative tuberculosis prevalence surveys (2012-2019) from highly endemic countries were supplemented with publicly accessible data at district level. Associations between individual-level diagnosis of bacteriologically confirmed tuberculosis and district-level environmental-demographic variables were investigated in generalised linear mixed-effects models accounting for the multi-level structure of the data.
Findings: Of 322,615 participants aged ≥15 years across 400 districts, 976 were newly diagnosed with tuberculosis (prevalence 183-638/100,000 across the countries). Living at latitude 7.6-14.6° (adjusted odds ratio, aOR 2.07, 95% confidence interval, 95% CI 1.48-2.90) or in higher population density (aOR 1.07 per percent increase in mean population density, 1.01-1.13), or urban districts (aOR 1.31, 1.11-1.54) were independently associated with higher prevalence. Living in distsricts above 900 m altitude (aOR 0.52, 0.32-0.84), with 50-100 mm precipitation (aOR 0.62, 0.46-0.84), or at higher temperature (aOR 0.93 per degree Celsius, 0.88-0.98) was independently associated with lower tuberculosis prevalence. No significant associations were observed with fine particulate matter (aOR 1.04, 0.70-1.54 for 20-40 μg/m3, 0.82, 0.44-1.53 for >40 μg/m3), solar radiation (aOR 1.04, 0.93-1.15) or International Wealth Index (aOR 1.01 (1.00-1.02).
Interpretation: Our results suggest that in high-burden African countries, some of the variation in tuberculosis prevalence can be explained by environmental and demographic factors that merit further investigation.
Funding: Mr Willem Bakhuys Roozeboom Foundation.
Background: Sepsis in people living with HIV (PLWH) in East Africa has high mortality. Regionally, the etiology of sepsis is incompletely understood. We performed a planned analysis of the microbiological data obtained from a randomised clinical trial of early empiric anti-Mycobacterium tuberculosis (Mtb) therapy for sepsis (ATLAS) in Tanzania and Uganda.
Methods: We present a prespecified, secondary analysis of a phase three, open-label, multicentre, randomised, controlled trial conducted at four regional referral hospitals in Tanzania and Uganda. Participants were adults living with HIV admitted with concern for infection and a modified quick sepsis-related organ failure assessment (qSOFA) ≥2. Participants were randomised to (1) immediate or diagnosis-dependent antituberculosis therapy and to (2) high-dose or conventional-dose antituberculosis therapy. Tests for sepsis etiology included bacterial blood and urine cultures, multi-pathogen qPCR from blood, GeneXpert MTB/RIF Ultra from sputum and urine, urine lipoarabinomannan (LF-LAM), and Mtb cultures from sputum and blood. We used multivariable logistic regression analysis and random forest analysis to determine variables that predicted Mtb as the sepsis etiology. The trial is registered with ClinicalTrials.gov, NCT04618198.
Findings: From January 5, 2022 through December 9, 2024, we randomised 437 participants to receive immediate and/or high dose antituberculosis therapy. Mtb was the most common pathogen, detected in 229 (52%) of 437 participants, and in 54 (50%) of 108 participants with a bloodstream infection. Combined urine LF-LAM and sputum GeneXpert MTB/RIF testing missed 17 (32%) of 54 Mtb bloodstream infections. The most frequent non-mycobacterial bacteria were Klebsiella species and Escherichia coli, which were identified in 39 (9%) and 33 (8%) of 437 participants, respectively. We detected ceftriaxone resistance in 21 (64%) of 33 bacterial isolates. In a random forest prediction model (accuracy: 0.6; precision: 0.5; recall: 0.6; F1-score: 0.5), the best indicators of Mtb as a sepsis pathogen were a greater number of ill-days before presentation (mean decrease in accuracy [MDA] 10.1), younger age (MDA 8.7), a longer duration of cough (MDA 7.7), and low CD4+ T-cell concentration (MDA 3.7).
Interpretation: Mtb was the most common pathogen causing sepsis and bloodstream infection and was frequently missed by conventional rapid diagnostics. We also identified a high prevalence of non-mycobacterial pathogens resistant to ceftriaxone in blood and urine cultures. Limitations of our study included exclusion of cryptococcal antigen positive participants, non-systematic drug susceptibility testing, and potential regional differences in sepsis etiology and resistance patterns.
Funding: NIH.
Background: Neoadjuvant immunotherapy improves outcomes compared to adjuvant therapy in stage III melanoma and reduces costs when adjuvant therapy is omitted following a major pathological response (MPR). However, adjuvant therapy remains the sole systemic treatment for patients identified as stage III by sentinel lymph node biopsy (SLNB). Detecting nodal metastases prior to this procedure could be beneficial.
Methods: We conducted a systematic review and meta-analysis to determine the accuracy of preoperative ultrasound and fine-needle aspiration cytology (FNAC) and the healthcare costs of implementing this strategy. PubMed, Embase, and Web of Science were searched up to March 21, 2025. Diagnostic cohort studies were included when preoperative ultrasound and/or FNAC were performed in patients with cutaneous melanoma eligible for SLNB, with histopathological confirmation. Studies that lacked individual patient-level diagnostic data were excluded. Two reviewers independently screened and extracted data. The pooled sensitivity and specificity were calculated using bivariate or univariate random-effects models. The associated healthcare costs for each strategy were calculated using the pooled estimates, costs of the procedure, therapies and follow-up.
Findings: Of 1315 records screened, 19 diagnostic studies comprising 7396 patients were included. For ultrasound, pooled sensitivity was 33.6% (95% CI: 23.5-45.5%) and specificity 92.4% (87.3-95.6%). For FNAC, pooled sensitivity and specificity were 92.6% (15.9-99.9%) and 99.1% (96.6-99.8%). Most studies had unclear risk of bias in patient selection and index test domains, while applicability concerns were generally low. Substantial heterogeneity was observed across studies. Ultrasound-FNAC was estimated to detect approximately 31% (8/25.5) of nodal metastases preoperatively. Implementation of this strategy was cost saving across multiple scenarios where adjuvant immunotherapy was omitted following MPR.
Interpretation: Implementation of ultrasound-FNAC prior to sentinel lymph node biopsy enables neoadjuvant immunotherapy and is cost saving, indicating potential value in routine clinical practice.
Funding: None.
Background: Patients with osseous metastatic breast cancer receive bone-modifying agents (BMAs) as part of their standard care. Medication-related osteonecrosis of the jaw (MRONJ) is one of the most important toxicities of this class of drugs. MRONJ heavily impacts patients' quality of life and represents a major medical burden necessitating a discontinuation of treatment. Currently, the diagnosis of MRONJ is established upon the manifestation of clinical symptoms like exposed necrotic jawbone, pain, swelling or signs indicative of infection of the jaw. The objective of this study was to assess the potential of imaging modalities, specifically FDG-PET/CT (positron emission tomography with computed tomography) in the early detection of MRONJ.
Methods: This cohort study in Austria included all patients with metastatic breast cancer who were receiving denosumab and regular PET/CTs, diagnosed with MRONJ between 2000 and 2022 at the Department of Obstetrics and Gynecology Innsbruck. For each of the patients in the study cohort, two control patients with comparable clinical characteristics were matched to serve as a control group. Control patients with metastasized breast cancer did not develop MRONJ but did receive denosumab and regular FDG-PET/CTs. Imaging data were independently assessed by two experienced nuclear medicine physicians.
Findings: Baseline characteristics were well balanced. Patients received 120 mg denosumab once per month subcutaneously without de-escalation of therapy. The median time to develop MRONJ was 23 months (range 5-71, lower Quartile (Q1), upper Quartile (Q3) 16, 40 months). Nuclear medicine physicians detected jaw alterations in 91% (19/21) of MRONJ cases (sensitivity, 95% CI: 70%-98.8%) and in 29% (12/42) of controls, corresponding to a specificity of 71% (30/42; 95% CI: 55%-84%). Median lead time of imaging by demonstrating lesion in the jaw was 238 days (range 11-1118, Q1, Q3 106,494) prior to MRONJ diagnosis. In 68% (13/19) of MRONJ cases the nuclear medicine physicians were able to predict the exact tooth location of MRONJ with a deviation of no more than two teeth.
Interpretation: The high sensitivity and negative predictive value of imaging for early detection of MRONJ underscore its significance for clinical practice. Given that the majority of patients receive regular PET/CTs, our results provide an excellent opportunity for early intervention when MRONJ is detected with a considerable lead time.
Funding: This study received no external funding.
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