Military medicine has been organized for 2 decades around the time interval between injury and definitive surgical care. The Golden Hour mandate in Afghanistan, paired with Tactical Combat Casualty Care guidelines and damage-control resuscitation, produced some of the lowest battlefield mortality rates in the history of armed conflict. More recent conflicts complicate this framework. In northwest Syria, deliberate attacks on hospitals reduced outpatient and trauma care for weeks following each strike, with population-level reductions in service use rather than individual mortality the dominant signal. In Ukraine, drone-contested evacuation, degraded hospital function, and disrupted medical logistics have failed concurrently under large-scale combat operations, in a pattern that the Golden Hour model was not designed to address. This Commentary argues that across these 3 mature conflict settings, the dominant clinical risk has broadened from individual-casualty survival to compound treatment-system degradation. The argument describes one axis of change rather than a universal trajectory: the French experience in the Sahel illustrates that prolonged casualty care can become the dominant problem even without deliberate hospital targeting or system collapse, and other conflicts including Sudan and the occupied Palestinian territory require their own analyses. What is consistent across the contemporary record, however, is that hospital protection, logistics resilience, and continuity of evacuation now sit at the center of military-medical capability rather than at its margin. Three doctrinal implications follow. First, hospital protection and facility dispersal should be incorporated into clinical-readiness curricula. They produce measurable effects on patient outcomes and warrant treatment as clinical capabilities rather than as adjacent engineering problems. Second, prolonged field care must shift from contingency planning to baseline operational capability, as the Sahel, Syrian, and Ukrainian experiences converge on this point, even though their underlying mechanisms differ. Third, medical logistics deserves the same operational rigor as direct patient care, including blood distribution, cold-chain continuity, warehouse dispersion, and cyber resilience of supply-management systems. Preliminary signals from the ongoing 2026 U.S.-Israeli-Iranian conflict, including verified attacks on health care, regional supply-chain disruption, and a cyber-mediated interruption affecting medical-device manufacturing, are broadly concordant with this trajectory. They are presented as hypothesis-generating only, not as evidence of a validated new doctrinal phase. The main limitations are selective conceptual synthesis and the asymmetry between mature peer-reviewed evidence and ongoing-event reporting. The conclusion is operationally direct: military medicine is no longer adequately described by transport time alone. Trauma-care survivability under threat is now the central problem.
To assess uptake of nirsevimab, a long-acting monoclonal antibody for respiratory syncytial virus (RSV) prevention, during the first season of Ireland's Pathfinder pilot universal newborn immunisation programme and to identify socio-demographic and perinatal predictors of uptake. Cross-sectional analysis of routinely collected programme data. Ireland's Mid-West region, served by University Maternity Hospital Limerick, the sole maternity and neonatal hospital for the region. Infants born 1 September 2024 to 28 February 2025. Uptake of nirsevimab before hospital discharge. Overall uptake was 89.4% (1600/1790) and did not vary by month (p=0.119); it was similar by sex (male 89.5%, female 89.2%; p=0.838). Preterm infants had higher uptake than term (96.9% vs 88.7%; p=0.001), and those admitted to the neonatal unit also had higher uptake (93.0% vs 88.4%; p=0.009). In adjusted analyses, maternal age (adjusted OR (aOR) 1.06 per year, 95% CI 1.03 to 1.09, p<0.001) and preterm birth (aOR 3.08 (95% CI 1.14 to 8.37), p=0.027) were associated with uptake. Uptake varied by maternal ethnicity: 91.5% in white Irish, 53.6% in Irish Traveller (aOR 0.13 (95% CI 0.08 to 0.23)), 79.7% in other white background (aOR 0.39 (95% CI 0.24 to 0.61)), 90.0% in black or black Irish, 98.3% in Asian or Asian Irish and 84.2% in other/mixed or prefer not to say. Although uptake among white Irish was high, they accounted for the largest absolute number of infants who did not receive nirsevimab, reflecting their predominance in the birth cohort. During the first season of Ireland's Pathfinder RSV pilot programme in the Mid-West region, nearly 90% of newborns received nirsevimab before discharge. Uptake was consistently high across months, indicating effective implementation but lower among infants of Irish Traveller and other white background mothers, highlighting the need for targeted, culturally adaptable equity strategies within a high-uptake programme. These findings may inform national and international policies and offer practical lessons for universal RSV immunisation.
To construct and validate prediction models for zonisamide (ZNS) concentration in pediatric patients with epilepsy based on 12 machine learning algorithms, to screen for the optimal algorithm, and to provide a scientific basis for the formulation of individualized ZNS dosing regimens in children. Clinical data of patients who underwent ZNS therapeutic drug monitoring at Kunming Children's Hospital from May 2022 to January 2026 were retrospectively collected and randomly divided into a training set and a test set at a ratio of 7:3. Key predictive variables were determined through a multi-stage feature screening strategy (covering correlation analysis, collinearity diagnosis, univariate analysis, Lasso regression, and random forest algorithm). Based on the selected variables, 12 machine learning regression models were constructed to predict ZNS concentration, and grid search combined with 5-fold cross-validation was employed for parameter optimization and performance evaluation. The coefficient of determination (R2), mean squared error (MSE), root mean squared error (RMSE), and mean absolute error (MAE) were used as primary evaluation metrics. Finally, the SHAP method was adopted to interpret the feature contribution and decision logic of the optimal model. The modeling cohort of this study enrolled 532 pediatric patients who received zonisamide treatment at the Department of Neurology, Kunming Children's Hospital from May 2022 to May 2024. These patients were randomly divided into a training set (375 cases) and an internal validation set (157 cases) at a ratio of 7:3. Additionally, 436 pediatric patients from the same department of the same hospital from June 2024 to January 2026 were included as an external validation cohort. Comparisons of general clinical data, laboratory indicators, and medication-related data among the groups showed no statistically significant differences (all p > 0.05), indicating that the baseline data were balanced and comparable. The median (interquartile range) ZNS concentrations in the training set, internal validation set, and external validation cohort were 9.65 (8.11, 11.98) μg/mL, 9.93 (8.23, 12.06) μg/mL, and 10.77 (7.67, 13.69) μg/mL, respectively. Through multi-stage feature screening, gender, dosage, age, red blood cell count, concomitant medication status, total protein, uric acid, and platelets were identified as key factors influencing ZNS concentration. Among the 12 constructed machine learning models, the Random Forest (RF) algorithm demonstrated the optimal performance: in the training set, R2 was 0.97%, RMSE was 0.83%, MAE was 0.57%, and Err20 was 7.40%; in the internal validation set, R2 was 0.78%, RMSE was 1.99%, MAE was 1.48%, and Err20 was 31.20%; and in the external validation set, R2 was 0.89%, RMSE was 1.31%, MAE was 0.86%, and Err20 was 16.50%. SHAP method combined with representative decision tree analysis revealed that dosage and gender were the primary factors influencing ZNS concentration, followed by total protein and uric acid; among them, dosage showed a positive contribution, gender exhibited a bidirectional effect, and laboratory indicators mostly showed nonlinear associations. Decision tree analysis indicated that the model used gender as the primary splitting feature and incorporated multi-indicator interactions; its decision logic aligned with pharmacokinetic theory, providing strong support for the interpretability of the model's clinical application. This study successfully constructed and validated a ZNS concentration prediction model for pediatric patients with epilepsy based on the random forest algorithm. The model demonstrated high precision, strong stability, and good generalization ability. Gender, dose, uric acid, and total protein are core variables influencing ZNS concentration. The findings can provide a reference for the formulation of individualized ZNS dosing regimens in children.
Current evidence supports the role of Immunonutrition Support (IMNS) to improve surgical outcomes in gastrointestinal (GI) cancer, but the optimal formula and prescription timing remain unclear. This systematic review and meta-analysis aimed to evaluate the efficacy of IMNS on postoperative outcomes in patients with GI cancer. The systematic search was conducted in three databases (PubMed, Embase, Cochrane Library) in March 2024. The protocol was registered at PROSPERO under registration number CRD42024524537. Studies were selected based on the PICOS framework. Population: GI cancer patients; Intervention: immunonutrition support; Comparator: isonitrogenous and isocaloric supplementation, or standard care; Outcome: mortality, length of hospital stay, and postoperative complications; Study design: randomized controlled trial (RCT). Random-effects models were used to calculate pooled odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI). A total of 90 RCTs were included in the systematic review, with 55 eligible for meta-analysis. Data from 7,462 patients were analyzed. IMNS formula based on arginine, nucleotides, and omega-3 fatty acids, administered perioperatively, orally or enterally, significantly reduced the odds of anastomotic leak (OR 0.62; 95% CI 0.50-0.76), infectious complications (e.g., respiratory (OR 0.46; 95% CI 0.33-0.64), urinary (OR 0.58; 95% CI 0.38-0.89), wound (OR 0.67; 95% CI 0.46-0.98), and sepsis (OR 0.45; 95% CI 0.28-0.70), and shortened hospital stay by a mean of 2.47 days (95% CI -4.13 to -0.80). In contrast, omega-3 fatty acids alone did not improve postoperative morbidity. IMNS with arginine, nucleotides, and omega-3 fatty acids improves infection odds and hospital stay without a significant effect on overall survival, while omega-3 fatty acids alone did not decrease morbidity odds in GI cancer patients undergoing surgery.
Diabetic foot ulcer (DFU) is one of the reasons for hospitalization among diabetic patients. The objective is to study the impact of pharmaceutical care on quality-adjusted life years (QALY) in DFU patients. The eligible DFUs patients were randomized into the General Care (GC) and Pharmaceutical Care (PC) Group in a 1:1 ratio using the block design method. The study was carried out for 2 years at a tertiary care teaching hospital. The PC group received pharmaceutical care from the clinical pharmacist along with general care. The sociodemographics, health-related quality of life (HRQoL), and economic data were collected from the both groups at baseline, 6th month, and 12thmonth. The changes in the outcomes within groups were analyzed using repeated measures of ANOVA. Out of 174 DFU patients, 87 each were allocated to PC and GC groups. At baseline, there was no statistically significant difference in HRQoL scores; in contrast, during 6th and 12thmonth, follow-ups showed a statistically significant improvement in domains like dependence/daily life (P = 0.006), negative emotions (P = 0.030) and bothered by ulcer care (P = 0.024) in the PC group compared to the GC group. The PC group gained (-) Rs. 9984.3 and (-) US$.119.83 QALY at less cost when compared with the GC group DFU patients. The clinical pharmacist who provided structured pharmaceutical care services had significant positive impact on the HRQoL and economic outcomes in the PC group compared to the GC group. The study intervention was cost effective based on India's GDP per capita of 2022.
To compare postpartum trajectories in body weight and cardiometabolic biomarkers between women with and without GDM, and to explore the moderating effect of progression to type 2 diabetes (T2DM). We used electronic primary care healthcare records and linked hospital episode records of women who gave birth between 2001 and 2021. Each woman with GDM was matched to four women without GDM based on age at delivery and delivery date (±3 months). We fitted mixed-effects multivariate linear models to map biomarker trajectories and extracted coefficients and 95% confidence intervals (CIs) for each year postpartum. A total of 43 572 women diagnosed with GDM were matched with 174 288 women without GDM in pregnancy. Across the 15-year follow-up, women with GDM weighed more (difference of 5.5 kg [95% CI: 5.3 to 5.7]), had higher HbA1c concentrations (4.4 mmol/mol [95% CI: 4.3 to 4.5]), systolic and diastolic blood pressure (2.6 mmHg [95% CI: 2.4 to 2.7] and 1.7 mmHg [1.6 to 1.8] higher, respectively), and low-density lipoprotein cholesterol (0.08 [95% CI: 0.06 to 0.10]). However, biomarkers increased at a slower rate during the follow-up period among women with GDM, except for HbA1c (increase of 9.3 mmol/mol [95% CI: 8.8 to 9.7] and 2.3 mmol/mol [95% CI: 1.9 to 2.6] in the GDM and non-GDM groups, respectively). Future Progression to type 2 diabetes moderated biomarker trajectories. Differences in biomarker trajectories in the early postpartum present an opportunity for early risk stratification and targeted prevention among women with previous GDM.
Concomitant rhinoplasty and breast augmentation are not rare these days because of high aesthetic demands. Costal cartilage harvested through breast surgery incision could be a convenient choice for rhinoplasty, which possibly prevents scarring from multiple incisions. A modified procedure of costal cartilage harvested using simple surgical tools for the concurrence of rhinoplasty and breast augmentation was applied in our hospital. This study aims to share our experience with this approach and its efficacy and safety profile. This is a retrospective cohort study that collected data on healthy patients who underwent breast augmentation and rhinoplasty simultaneously using autologous costal cartilage from January 2019 to January 2024. Varied incisions, including inframammary fold, peri-areolar incision, or trans-areolar incision, were conducted to harvest costal cartilage for rhinoplasty. Data relating to patients, surgery, aesthetic assessments, and postoperative complications were retrieved. A total of 114 female patients (31.4 ± 0.65 years) were included in this study. IMF incision approach made up the majority. Time for costal cartilage harvest was about 15 min, and total surgical time was 290-370 min (312.6 ± 1.71 min). Four cases (3.5%) developed keloids postoperatively. Three cases (2.63%) required revision surgery due to postoperative nasal deformity. No complication of pneumothorax, pericardial rupture, hematoma, or infection occurred postoperatively. A low rate of complications and acceptable scarring suggested that the combination procedure applied simple tools for cartilage harvest, which was relatively safe to apply for patients who desired to perform these procedures at the same time. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
In Saudi Arabia, where healthcare modernization is a key priority under Vision 2030, Lean Six Sigma (LSS) is being increasingly adopted to address healthcare challenges. This systematic review aimed to evaluate the impact of LSS methodology on healthcare quality. A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Specific databases were searched (PubMed, ScienceDirect, Google Scholar, and the Saudi Digital Library) for studies published between January 2016 and December 2023. The inclusion criteria were peer-reviewed English-language studies assessing LSS interventions in Saudi healthcare settings, with measurable outcomes related to quality improvement. Studies focusing solely on Lean or Six Sigma, outside the healthcare sector, or lacking empirical data were excluded. Two reviewers independently screened studies, extracted data, and assessed methodological quality and risk of bias using the Quality Assessment of Diverse Research (QuADS) tool. Data were synthesized qualitatively. This review included 13 studies from diverse Saudi healthcare settings. The methodological quality of included studies was generally high, exceeding the 70% quality threshold. LSS interventions consistently improved operational efficiency (e.g., reduced wait times and streamlined workflows), patient safety (e.g., fewer medication errors and hospital-acquired infections), medication management (e.g., reduced prescription errors), and resource utilization (e.g., cost savings and resource allocation). However, limited workforce expertise, resistance to change, and insufficient organizational support are the challenges to LSS implementation. LSS positively impacts healthcare quality in Saudi Arabia. Targeted training and robust support structures are essential for sustaining LSS-driven improvements as a valuable tool for healthcare transformation.
Cryptococcosis is a severe invasive fungal infection with limited therapeutic options beyond fluconazole-based regimens. Isavuconazole, a broad-spectrum triazole antifungal, has emerged as a potential alternative, although clinical data supporting its use remain scarce. We aimed to evaluate the real-world effectiveness and safety of isavuconazole in patients with different forms of cryptococcosis. A retrospective observational study was conducted at a tertiary-care hospital, including patients with cryptococcosis who received isavuconazole at any treatment phase. Standard microbiological methods were used for pathogen identification and susceptibility testing. Demographic, clinical, and microbiological data were collected. Clinical and microbiological responses and tolerability were assessed at end of treatment or until death. Eight patients with cryptococcosis received isavuconazole, most of whom were immunocompromised. Clinical presentations included pulmonary and disseminated disease, with Cryptococcus neoformans as the predominant species. Isavuconazole was primarily used during the consolidation and maintenance phases, after induction therapy with amphotericin B and flucytosine for 2 weeks in most cases, and as salvage therapy in two patients. It was well tolerated during prolonged treatment (6-12 months). In the two patients with isavuconazole therapeutic drug monitoring, plasma total trough concentrations were within the therapeutic range (5 and 3.5 µg/mL, respectively), whereas cerebrospinal fluid total concentration levels were undetectable. A favorable clinical response was observed in four patients, while three remain on treatment with ongoing clinical improvement; one patient died early. Microbiological clearance was achieved in all culture-positive cases. Isavuconazole demonstrated clinical effectiveness in this cohort of patients across different presentations of cryptococcosis. Treatment was safe and well tolerated, supporting its role as an alternative antifungal option against Cryptococcus, particularly when fluconazole is limited by adverse effects or drug-drug interactions. However, data on central nervous system penetration were limited, and further studies are needed to better define its role in cryptococcal meningitis management.
Neovascular age-related macular degeneration (nAMD) is a chronic sight-threatening disease requiring repeated intravitreal antivascular endothelial growth factor (anti-VEGF) injections. Although established anti-VEGF agents have transformed the prognosis of nAMD, a proportion of patients demonstrate persistent exudation, limited durability, or inability to extend beyond short treatment intervals. Faricimab is a bispecific intravitreal antibody targeting both vascular endothelial growth factor A and angiopoietin-2, designed to improve vascular stability, reduce exudation, and increase treatment durability. This clinical audit evaluates 24-month real-world outcomes following switching to faricimab in suboptimal responders with nAMD in an NHS medical retina service. A retrospective clinical audit was conducted of 274 eyes with nAMD switched to faricimab at Sherwood Forest Hospitals NHS Foundation Trust between January 2023 and January 2025. All eyes had previously received at least one anti-VEGF agent and were switched because of persistent disease activity, inadequate anatomical response, or high treatment burden. Data were extracted from the Medisight electronic patient record and cross-checked against pharmacy records. Primary outcomes were best corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study letters and central macular thickness (CMT) on optical coherence tomography. Secondary outcomes included injection interval extension, number of injections, and safety events. Baseline mean BCVA was 58.1 letters. Mean BCVA improved to 59.7 letters at less than six months, representing a gain of +1.6 letters. At 12 months, mean BCVA was 56.9 letters, a change of -1.2 letters from baseline. At 24 months, mean BCVA was 54.4 letters, a change of -3.7 letters from baseline. Anatomical response was more consistent, with mean CMT reductions of -29.1 µm at less than six months, -34.7 µm at 12 months, and -45.7 µm at 24 months. The mean injection interval increased from 7.88 weeks before switching to 10.67 weeks after switching, representing an extension of +2.79 weeks. No cases of intraocular inflammation, retinal vasculitis, or endophthalmitis were recorded. In this real-world NHS audit, faricimab achieved meaningful anatomical improvement and reduced treatment burden in treatment-experienced nAMD eyes switched because of suboptimal response or limited durability on previous anti-VEGF therapy. Visual acuity improved modestly during early follow-up but declined slightly over 24 months, despite progressive anatomical drying. This functional-anatomical dissociation likely reflects the chronicity of disease and irreversible macular damage in a switch population. Faricimab appears to be a safe and effective second-line option for reducing exudation and extending treatment intervals, although expectations regarding long-term visual gain should be realistic.
The cost-effectiveness of liposome irinotecan (II) (HR070803) in combination with 5-fluorouracil and leucovorin as a treatment for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma offering a potential new standard of care has not been established. Considering the high cost of liposome irinotecan (II), the aim of this study was to evaluate the economic value of liposome irinotecan (II) combined with 5-fluorouracil and leucovorin（5-FU/LV） versus placebo combined with 5-FU/LV for this indication from the perspective of the Chinese healthcare system. We developed a three-state Markov model based on the trial: NCT05074589 to estimate lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effect ratios (ICERs) in terms of cost per QALY gained. The utility of health status and the disutility of adverse events were obtained from the published literature. Costs were obtained from local hospitals and published literature. Costs and outcomes were discounted at a discount rate of 5% per year. To assess the robustness of the model, univariate and probabilistic sensitivity analysis was performed. In the base-case analysis, liposome irinotecan (II) regimen provided an additional 0.08 QALYs compared to the placebo regimen with an ICER of $310,418.81/ QALY gained, which indicates that the liposome irinotecan (II) regimen is not cost-effective at the $39,221.95/ QALY threshold. One-way sensitivity analyses showed that the model was most sensitive to the utility of PFS, the cost of liposome irinotecan (II), and the utility of PD. Probabilistic sensitivity analyses showed that the liposome irinotecan (II) regimen had a probability of 0 for having a cost effect at $39,221.95/ QALY. Price simulations show that the liposome irinotecan (II) option is cost-effective at a willingness-to-pay (WTP) of $39,221.95/QALY if the price of liposome irinotecan (II) is reduced to $2.93/mg (88.6% reduction). From the perspective of the Chinese healthcare system, liposome irinotecan (II) in combination with 5-FU/LV was less cost-effective than placebo in combination with 5-FU/LV for locally advanced or metastatic pancreatic ductal adenocarcinoma.
The accumulation of N-desethylamiodarone (DEA), an active metabolite of amiodarone, is a recognized risk factor for interstitial pneumonia. However, predictors of DEA accumulation, particularly during the initiation phase of amiodarone therapy, remain unclear. We aimed to identify predictors of DEA accumulation using classification and regression tree analysis and to verify their association with interstitial pneumonia in patients receiving amiodarone. We conducted a retrospective analysis of 80 patients who underwent therapeutic drug monitoring of amiodarone and DEA levels at Kitasato University Hospital. Potential risk factors for elevated DEA levels (≥ 0.6 mg/L) were identified using classification and regression tree analysis with 20 variables. To prevent overfitting, strict pruning parameters were implemented (minimum bucket size = 7, maximum depth = 2). N-desethylamiodarone levels were compared between patients with and without interstitial pneumonia, and the findings were validated through Monte Carlo simulations based on published pharmacokinetic models. Elevated DEA levels (≥ 0.6 mg/L) were observed in 23 patients (29%). Classification and regression tree analysis identified treatment duration (cutoff: 47 days) and weight-adjusted dose (cutoff: 2.15 mg/kg/day) as primary determinants of DEA accumulation (accuracy: 0.88; area under the curve: 0.90 [95% confidence interval 0.84-0.95]). Among the five patients who developed interstitial pneumonia, four (80%) exhibited elevated DEA levels, compared to 19 of 75 (25%) patients without interstitial pneumonia (p = 0.022). Pharmacokinetic simulations confirmed that the probability of toxic DEA accumulation increases substantially at doses exceeding 150 mg/day. Treatment duration (≥ 47 days) and weight-adjusted dose (≥ 2.15 mg/kg/day) are significant predictors of DEA accumulation in this cohort of Japanese patients. Elevated DEA levels are significantly associated with the onset of interstitial pneumonia. To minimize the risk of toxicity, taking a maintenance dose of ≤ 100 mg/day (or < 2.15 mg/kg/day, which corresponds to ≤ 100 mg/day for a standard 50-kg patient) and monitoring DEA levels are recommended.
To develop phenotype algorithms for the detection of adverse events (AEs) or AE-proxies in electronic health records (EHRs), accounting for varying data availability. Multicentre study conducted as part of the Use Case POLAR_MI (POLypharmacy, drug interActions, Risks) of the German Medical Informatics Initiative (MII). Germany. Multidisciplinary teams from 10 German university sites within the MII. Not applicable. Literature- and consensus-based development and operationalisation of AE algorithms using structured EHR data, including a standardised, multicentre expert review process. Data categories used: International Classification of Diseases, 10th Revision (ICD-10) codes for diagnoses; Anatomical Therapeutic Chemical (ATC) codes and 'Pharmazentralnummern' (PZN; German eight-digit identification code for pharmaceutical products) for medications (used in the treatment of AEs); Logical Observation Identifiers Names and Codes (LOINC) for laboratory values and medical findings; and 'Operationen- und Prozedurenschlüssel' (OPS; German procedure classification) codes for medical and surgical procedures. We developed 82 algorithms for 48 AEs. Algorithms for the same AE varied by data categories or code selections. At the AE level, 31 AEs were covered exclusively by newly developed algorithms, and 17 AEs by at least one modified algorithm.Overall, 52 algorithms were based on a single data category, while 30 required multiple categories. ICD-10 codes were most commonly used (n=65 AE algorithms), followed by LOINC (n=27), ATC codes (n=18), OPS codes (n=11) and PZN (n=2). All phenotype algorithms were semantically modelled and can be executed using the publicly available Terminology- and Ontology-based Phenotyping (TOP) Framework, which supports export in various formats. We present a peer-reviewed set of algorithms for a large number of AEs, which can be implemented in structured routine electronic data sources and (pending validation studies) may support pharmacoepidemiologic research. The algorithms will be implementable across all 39 participating sites of the German MII. As a next step, we will empirically validate the algorithms against all information (including free text) contained in EHRs. Not applicable.
This study aims to estimate the rate of recruitment of participants. This is a pilot, multicentre, double-blind, placebo-controlled, randomised controlled trial of oral oxycodone and sublingual placebo vs sublingual buprenorphine and oral placebo for postoperative pain management for 7 days after pelvic exenteration. Patients will be recruited from three metropolitan quaternary referral centres that offer advanced gastrointestinal surgery in Australia. The inclusion criteria will be patients over the age of 18 years undergoing pelvic exenteration surgery and exclusion criteria are previous adverse events related to the study drugs, currently requiring monoamine oxidase inhibitor medications and if epidural analgesia is planned in the perioperative period. Enrolled patients will undergo pelvic exenteration surgery and be initiated postoperatively on patient-controlled analgesia. In the postoperative period, when clinically appropriate to take oral medications, patients will be commenced on trial analgesia for 7 days. Participants will be randomised to receive either oral active oxycodone 5-10 mg up to 3 hourly as required (with sublingual placebo) or sublingual active buprenorphine 200-400 mcg 3 hourly as required (with oral placebo). The primary outcome measure is the rate of recruitment over a 6-month period. Secondary outcomes include an assessment of missing data, protocol adherence and acceptability of the trial to participants. The trial received ethics approval from Sydney Local Health District, Royal Prince Alfred Hospital Human Research Ethics Committee (No: X25-0128 & 2025/ETH01058). The results of the study will be disseminated by publication and presentation at local annual scientific meetings in Australia. The study protocol is prospectively registered at the Australian New Zealand Clinical Trials Registry (ANZCTR) (www.anzctr.org.au; ACTRN12625000901404).
Residual cardiovascular risk remains high after acute coronary syndrome (ACS) despite intensive LDL-cholesterol lowering. Elevated triglycerides may contribute to this risk. Although icosapent ethyl (IPE) has shown cardiovascular benefit in high-risk statin-treated patients, access in Italy is limited by Italian Medicines Agency (AIFA) reimbursement criteria, which are more restrictive than the European Medicines Agency (EMA) indications. We compared EMA and AIFA eligibility for IPE in a real-world post-ACS cohort, assessed the association of triglyceride levels and variability with 12-month ischemic recurrence, and explored the potential economic impact of broader IPE use. This retrospective observational study included 430 consecutive adults admitted for ACS to a tertiary hospital in Italy in 2024, with 12-month follow-up. During follow-up, 48 patients (11.2%) experienced recurrent ACS. Diabetes mellitus was independently associated with recurrence (OR 2.90, 95% CI 1.41-5.97; p = 0.004), whereas male sex was protective (OR 0.46, 95% CI 0.23-0.93; p = 0.030). Absolute triglyceride levels were not significantly associated with recurrence, whereas triglyceride variability was: the coefficient of variation remained independently associated with recurrent events (OR 1.04, 95% CI 1.00-1.09; p = 0.029). According to EMA criteria, 35 patients (8.1%) were eligible at discharge and 15 (3.5%) at first follow-up; under AIFA criteria, only one patient was eligible. A marked discrepancy exists between EMA indications and AIFA reimbursement criteria for IPE, resulting in restricted access for high-risk post-ACS patients. Broader access, aligned with current evidence, may improve secondary prevention and represent a cost-effective strategy.
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The combined creatinine (SCr)- and cystatin C (CysC)-based estimated glomerular filtration rate (eGFR) provides a more accurate assessment of kidney function. Given that precise estimation of kidney function is important for optimal vancomycin dosing, few studies have evaluated whether a combined estimate better predicts vancomycin clearance and improves clinical outcomes. In this retrospective study, 4 kidney function estimation methods, Cockcroft-Gault (CG), SCr-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), CysC-based CKD-EPI, and the combined SCr and CysC CKD-EPI equations, were assessed in 66 adult inpatients to determine which method most accurately predicts vancomycin clearance (CL vanco). Although the CG- and SCr-based CKD-EPI estimates were comparable, substantial differences were observed among the methods. The combined SCr and CysC estimate showed the highest correlation [ρ = 0.854; 95% confidence interval (CI): 0.76-0.91], the most linear relationship (R2 = 0.75), the best precision (root mean square error = 0.92 L/h; 95% CI: 0.76-1.05), and the least bias (mean predicted error = 0.16 L/h; 95% CI: -0.07 to 0.38), indicating the best overall performance among the 4 methods. These results suggest that combined SCr and CysC estimates may be associated with more accurate and precise vancomycin dosing than the other methods. This finding implies that other medications cleared by the kidneys, especially those with narrow therapeutic windows, may be appropriately administered using the combined estimate. Further studies are required to determine whether these findings lead to improved clinical outcomes.
Low success rates in clinical drug development can be largely attributed to the poor predictive power of existing preclinical models. Microphysiological systems (MPS) have greatly advanced in vitro modeling; however, current platforms do not adequately support long-term sampling and often fail to recapitulate nutrient and drug exposure dynamics. To address these limitations, we established a machine vision-guided MPS with real-time fluidic control that enables fully automated periodic sampling with high temporal resolution, media replenishment, and programmable dosing, allowing for the simulation of dynamic nutritional or pharmacological exposure scenarios. We showcase the system's capability by emulating physiological insulin profiles and repeated-dose pharmacokinetic exposures over multiple weeks. Furthermore, pharmacokinetically accurate acetaminophen exposure in 3D primary human liver spheroids mimicking an acute overdose rapidly induced liver toxicity, as evidenced by aminotransferase release, cytokine secretion and a drop in cellular ATP. In contrast, dose-equivalent constant exposure patterns did not elicit detectable hepatotoxicity. Mechanistically, targeted proteomics of sampled supernatants and Cell Painting revealed that toxicity was paralleled by disrupted lipid homeostasis, loss of tight junctions and extracellular matrix remodeling. These results demonstrate the robustness and versatility of the machine vision-guided automated microphysiological platform and underscore the importance of incorporating drug exposure dynamics for mechanistic toxicology.
Vitiligo is a chronic autoimmune depigmenting disorder affecting 0.5%-2% of the global population, characterized by bidirectional interplay between psychological stress and disease progression, with accumulating evidence highlighting the central role and translational relevance of the neuro-endocrine-immune-cutaneous axis in its pathogenesis. Epidemiological data indicate over half of patients experience significant psychological stress prior to disease onset, while visible depigmentation markedly elevates the burden of depression and anxiety, establishing a self-amplifying pathogenic loop. Mechanistically, neural crest-derived melanocytes form functional "neuro-pigment units" with intraepidermal nerve endings, enabling bidirectional communication via neuropeptides including calcitonin gene-related peptide (CGRP) and substance P. Dynamic crosstalk among keratinocytes, sensory neurons, and melanocytes integrates neurotrophic and inflammatory signals to tightly regulate melanocyte survival and biological function. Sympathetic activation drives melanocyte injury via norepinephrine-mediated β2-adrenergic receptor signaling, while dopamine metabolites exacerbate apoptosis via the oxidative stress-Akt-Bad axis; context-dependent hypothalamic-pituitary-adrenal axis effects and light-melatonin-circadian clock disruption further promote immune dysregulation and melanocyte loss. Notably, neuromodulatory approaches like transcutaneous auricular vagus nerve stimulation show therapeutic promise by attenuating oxidative stress and limiting pathogenic CD8⁺ T-cell infiltration. These insights have fostered targeted strategies including CGRP receptor antagonists and dual antioxidant-neuroprotective natural compounds. Integrating neuroimmunological modulation with psychological and circadian interventions represents a promising precision medicine framework for vitiligo management.
We present the case of a 60-year-old non-smoking woman previously treated for luminal B human epidermal growth factor receptor 2 (HER2)-positive invasive breast carcinoma with surgery, AC60 chemotherapy, trastuzumab, breast radiotherapy, and hormone therapy at the Mohammed VI Oncology Center in Casablanca, Morocco. Four years after completing treatment, she presented with respiratory symptoms and was diagnosed with a well-differentiated, lepidic-type mucinous primary lung adenocarcinoma, staged IIIA (pT2bN1M0). Molecular analysis showed the absence of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) and ROS1 rearrangements, rearranged during transfection (RET) fusions, and MET exon 14 skipping, with intermediate programmed death-ligand 1 (PD-L1) expression, assessed by tumor proportion score (TPS) of 10%. The patient received neoadjuvant vinorelbine-cisplatin chemotherapy followed by volumetric modulated arc therapy (VMAT) thoracic radiotherapy at 66 Gy, achieving clinical and radiological stabilization. This case highlights the occurrence of a second driver-negative primary lung adenocarcinoma in a non-smoker and underscores the importance of integrated histopathological, immunohisto chemical, and targeted molecular evaluation in distinguishing primary tumors from metastases, as well as the potential role of post-therapeutic carcinogenesis.