This paper traces the historical development of frequentist sample size estimation from its philosophical origins to its present-day complexity. Preliminary concepts were identified by Christiaan Huygens' work on expected value and Jacob Bernoulli's law of large numbers, which first linked sample size and estimation accuracy. The 18th and 19th centuries brought major advances in probability theory through the work of Pierre-Simon de Laplace, Carl Friedrich Gauss and Siméon-Denis Poisson, yet explicit sample size planning remained uncommon. The early 20th century saw the emergence of methods for sample size calculations based on Jerzy Neyman and Egon Pearson's hypothesis testing framework and Sir Ronald Aylmer Fisher's experimental design principles. While Donald Mainland and Austin Bradford Hill referred indirectly to these as early as the 1930s, it took many decades before their explicit use became common. After the Second World War, contributions from figures such as Abraham Wald further embedded sample size planning with sequential methodologies. From the 1970s onward, standardised formulas, regulatory requirements, reporting standards such as CONSORT and statistical software consolidated frequentist sample size estimation as a routine component in applied research. In the 21st century, simulation-based, adaptive and Bayesian approaches, together with open-source computational ecosystems, have expanded the scope and accessibility of sample size methods. In contemporary research, sample size estimation has evolved into a multifaceted discipline; its methodological sophistication is contingent upon the underlying objective, illustrating the persistent divergence between explanatory inference and decision-oriented design.
OBJECTIVES:Avoidable harm and variations in quality have remained persistent features of health systems, but the track record of financial incentives in driving improvement is mixed. Based on an evaluation of NHS Resolution's Maternity Incentive Scheme (MIS), which focuses on safety of maternity care in English NHS trusts, we identify generalisable principles to inform design of financial incentive schemes in healthcare. DESIGN:Qualitative process evaluation based on interviews with those involved in the design and delivery of MIS. SETTING:Organisations involved in running MIS and organisations participating in the scheme. PARTICIPANTS:Thirty-five individuals were interviewed, including 17 involved in the national-level administration of MIS and 18 with experience of MIS at local level. MAIN OUTCOME MEASURES:Not applicable. RESULTS:We identified strengths, weaknesses and unintended consequences of the Scheme from the perspective of participants. MIS was seen by national-level stakeholders as having succeeded in elevating maternity safety in organisations' priorities and consolidating disparate safety requirements into a unified framework. They saw MIS as a clinically credible and system-owned mechanism for prioritisation. However, local-level participants reported significant administrative burdens, opportunity costs and challenges in interpreting and implementing its requirements. The Scheme's all-or-nothing reimbursement model, while reinforcing parity across the areas it covered, sometimes led to disproportionate focus on marginal issues and created perverse incentives when full compliance seemed unattainable. We identify seven key lessons for the design of incentive systems that might optimise their impact from the findings. CONCLUSIONS:Careful design of incentive schemes is vital to minimise unintended consequences. Lessons from MIS are relevant to broader healthcare system reform efforts and initiatives aiming to harness financial levers for quality improvement, such as those in the 10-Year Health Plan for England.
OBJECTIVE:To compare healthcare utilisation and costs for Long COVID (LC) in England and Wales. DESIGN:Case-control cohort analysis with multiple age-, sex-, ethnicity-, deprivation-, region- and comorbidity-matched control groups: (1) COVID-only, no LC; (2) pre-pandemic; (3) contemporary non-COVID and (4) pre-LC (self-controlled, pre-COVID pandemic). SETTING:National, population-based, linked UK electronic health records (British Heart Foundation/NHS England Secure Data Environment). PARTICIPANTS:Adults aged ⩾18 years with LC between January 2020 and December 2023. MAIN OUTCOME MEASURES:Healthcare utilisation (number of consultations/visits per person): primary care (general practitioner (GP)), secondary care (outpatient, inpatient and emergency department, investigations and procedures) and inflation-adjusted cost (£) for LC and control populations. RESULTS:In England (n = 295,180) and Wales (n = 7925), LC was associated with higher utilisation and costs across primary and secondary care. Mean annual total cost for LC versus contemporary controls was £6681.6 versus £2039.9 in Wales (3.27-fold) and £3378.3 versus £1355.8 in England (2.49-fold). GP consultations averaged 26.76 (SD 22.07) per person-year in the Welsh LC cohort versus 14.63 (SD 14.34) in England (absolute difference 12.13 visits/year). Cross-national multiplicative difference-in-differences estimates indicated a 25% greater relative LC-related cost increase in Wales compared with England (ratio 1.25, 95% CI 1.09-1.42), corresponding to an absolute excess of £2501 per person-year (95% CI £1707-£3270). CONCLUSIONS:LC is associated with sustained increases in healthcare utilisation and costs in England and Wales. Our findings suggest that system-level service design may influence healthcare use and costs following COVID-19, warranting further evaluation of post-viral care models.
OBJECTIVES:To evaluate recruitment equity for NHS specialty training posts between 2021-2024, characterising demographics, quantifying appointment disparities by protected characteristics and assessing temporal trends. DESIGN:Longitudinal cohort study using national recruitment data via annual Freedom of Information requests. SETTING:National Health Service, UK. PARTICIPANTS:All medical and surgical specialty training applications to NHS England (2021-2024). MAIN OUTCOME MEASURES:Application success by protected characteristics. RESULTS:Of 214,893 applications, 52,998 (24.7%) were appointed. Annual success rates fell from 12,419/37,971 (32.7%) in 2021 to 13,929/81,189 (17.2%) in 2024. Competitiveness increased but non-UK graduate applications did not reduce successful UK graduate numbers. Gender segregation persisted: surgical specialties had the highest proportion of male applicants, whereas for females this was observed in obstetrics and gynaecology. Female applicants had higher success rates than males (27.5% vs 22.2%; Δ5.3%, 95% CI 4.95-5.70, p < 0.001). Pregnant/maternity-leave candidates had lower success (21.3% vs 25.8%, Δ4.5%, 95% CI 3.15-5.82, p < 0.001), most markedly in paediatrics (Δ14.8%, 95% CI 8.95-20.58, p < 0.001) and surgery (Δ13.7%, 95% CI 7.60-19.82, p = 0.008). UK graduates outperformed non-UK graduates (40.7% vs 15.5%; Δ25.2%, 95% CI 24.8-25.6, p < 0.001). Adjusted for country of graduation, 15/15 minority ethnic groups had lower odds of success versus White-British, with steepest declines among Black Caribbean and Bangladeshi graduates. CONCLUSIONS:Inequities persist in NHS specialty recruitment. Gender segregation remains and disparities disadvantage pregnant/maternity-leave applicants. Disparities impacting minority ethnic UK graduates have widened. While data constraints preclude adjusting for confounders, these consistent trends require continuous monitoring and targeted interventions to ensure equitable access.
ABSTRACT Background: The increasing incidence of Candida glabrata complex infections in hospitalized patients and their association with high mortality rates prompted the determination of cryptic species among clinical isolates from a tertiary hospital and the evaluation of their susceptibility profiles to commonly prescribed antifungal agents. Methods: This study evaluated 80 C. glabrata isolates obtained from patients admitted to a Brazilian public tertiary hospital. The isolates were recovered from different clinical specimens, predominantly urine and blood, across various medical units. Results: MALDI-TOF MS analysis revealed that all isolates were Candida glabrata sensu stricto. Minimum inhibitory concentrations (MICs), determined via broth microdilution and according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines, showed high susceptibility to amphotericin B (AmB), voriconazole (VRC), and echinocandins (ECNs) [caspofungin (CSF), anidulafungin (ANF), and micafungin (MCF)], as well as uniform susceptibility within the "I" category (susceptible, increased exposure) to fluconazole (FLC). Comparisons of resistance profiles revealed higher prevalences of resistance to AmB and VRC than to ECNs, both overall and in urine isolates, with a similar trend observed in blood isolates. Comparative analysis with reference EUCAST C. glabrata data highlighted higher localized MIC values for AmB, ANF, and MCF, lower MICs for FLC, and equivalent distributions for VRC. Conclusion: All recovered isolates were confirmed as Candida glabrata sensu stricto and exhibited different susceptibility profiles from reference EUCAST isolates. These findings establish a strong regional baseline, serving as a useful guide for monitoring therapeutic measures and supporting antimicrobial stewardship.
OBJECTIVES:Between December 2022 and July 2024, the English National Health Service (NHS) experienced 27 periods of industrial action spanning 78 days, involving hospital and ambulance staff. We examined the direct and indirect impacts of these strikes on emergency department (ED) performanceDesign:A retrospective causal mediation analysis. Effects were estimated using mixed effects accelerated failure time, linear and generalised linear regression models with patient- and hospital-level covariates within a causal mediation framework. SETTING:20 major (Type 1) EDs in England with high-quality linkage across ED, inpatient, and imaging data. PARTICIPANTS:Patients attending these EDs between August 2022 and July 2024. MAIN OUTCOME MEASURES:A patient's time in ED analysed in relation to strike activity at the mid-point of attendance by one or more staff groups: (1) resident/junior doctors, (2) consultants, (3) both resident and consultant doctors, (4) paramedics and (5) nurses. RESULTS:Average duration of ED attendances reduced on days affected by residents' strikes (-12.6%, 95% CI -10.4% to -14.8%), consultant strikes (-5.6%, 95% CI -2.7% to -8.4%), paramedic strikes (-4.5%, 95% CI -2.0% to -6.8%), but increased when residents and consultants were on strike simultaneously (+7.2%, 95% CI 3.8%-10.7%). There were no significant changes to ED durations during nurse strikes (-1.7%, 95% CI -1.5% to 4.7%). Changes in emergency inpatient occupancy explained a proportion of the change in average ED durations (resident doctor 10.4%, consultants 53.3%, combined doctors 5.4% and paramedics 14.3%). The impact of strikes on ED attendance volumes was mixed. The net effect of these changes explained 1.5%, 16.8% and 28.8% of the change in average ED durations observed during residents, combined doctor and paramedic strikes, respectively. During the residents' strikes, patients were more likely to receive treatments in ED (adjusted incident risk ratio 1.013, 95% CI 1.008-1.018), but less likely to be admitted (adjusted odds ratio 0.963, 95% CI 0.946-0.980). Efforts to meet the 4-h target intensified during the resident, consultant and combined doctors strike, but reduced during the nurse and paramedic strikes. This explained 2.7% and 17.1% of the changes in average ED durations observed during the resident and consultant strikes, respectively. There were substantial reductions in many forms of planned hospital care during the resident, consultant and combined doctor strikes, but these did not contribute to the observed reductions in ED durations. CONCLUSION:Industrial action - particularly by resident and consultant doctors - was associated with shorter ED stays, partly mediated by greater emergency bed availability, lower demand and intensified throughput efforts. However, much of the reduction during resident strikes remained unexplained, suggesting unmeasured operational or behavioural adaptations. Substantial reductions in planned care did not significantly affect ED performance.
Abstract Background: Although bone tissue possesses inherent regenerative capacity, critical-sized defects require grafts for complete functional repair. This in vivo study evaluated the bone repair process using laser photobiomodulation therapy (PBM) in defects filled with a combination of hydroxyapatite, β-tricalcium phosphate and heterologous fibrin biopolymer (HFB). Methods: Thirty male rats were divided into three groups: biomaterial alone (BG), biomaterial + HFB (BBG), and biomaterial + HFB + PBM (BBPG). A 5-mm circular calvarial osteotomy was performed and filled according to each protocol. In BBPG, an 830-nm laser was applied immediately post-surgery and three times weekly until euthanasia at 14 or 42 days. Analyses included micro-CT, histomorphology, histomorphometry, and polarized light microscopy of collagen fibers. Results: Micro-CT showed centripetal bone regeneration restricted to defect margins, with biomaterial particles persisting centrally. Histologically, new bone progressed from immature trabecular architecture at day 14 to a mature lamellar conformation by day 42, notably in BBPG. All groups showed a significant temporal increase in new bone percentage. BBPG demonstrated superior bone growth at 42 days (26.64 ± 2.15%) compared to BG (14.85 ± 1.63%) and BBG (20.05 ± 1.70%). The birefringence of the collagen fibers showed a color transition from red to yellowish-green during the analyzed periods. Conclusion: The combination of the biomaterial, fibrin biopolymer and photobiomodulation significantly enhanced bone defect repair and matrix maturation without barrier membranes, presenting high translational potential for cost-effective clinical applications in regenerative medicine.
Abstract Background: In the Brazilian Amazon, most snakebites are caused by Bothrops atrox. Although pediatric cases are less frequent, children are more vulnerable to severe complications and long-term disabilities. This study aims to describe the clinical profile of B. atrox envenomation in children treated at a tertiary hospital in Manaus, in Western Brazilian Amazon, and to characterize the resulting long-term musculoskeletal impairments in a subgroup of these patients. Methods: We retrospectively analyzed sociodemographic and clinical data from patients up to 12 years and 11 months of age treated between January 2010 and December 2023. A total of 258 children who were victims of B. atrox envenoming were eligible; however, a subgroup of 27 children underwent in-person musculoskeletal evaluations starting three months after hospital discharge. Results: In the subgroup of children evaluated, the majority were male (63%), were aged over ten years (59.3%), and were from rural areas (96.3%). Over half (51.8%) received medical care within six hours after the bite. The lower limbs were most frequently affected (96.3%). Common local symptoms included pain (100%), edema (96.3%), bleeding (37%), and bruising (29.6%). Secondary infections occurred in 18.5% of cases. Most envenomations were classified as moderate in severity (44.4%). In this subgroup, long-term disabilities were identified in 21 children (77.7%), who presented primarily with intermittent chronic pain (55.5%). Physical examination revealed scars (59.3%), edema (22.2%), and deformities (3.7%). Sensory alterations were noted in tactile (11.1%), pain (25.9%), thermal (22.2%), and vibratory (29.6%) sensitivity. Range of motion was impaired in 37% of cases, and one child exhibited abnormal posture and reflexes. Conclusions: This study highlights a broad spectrum of persistent musculoskeletal sequelae following Bothrops envenomation in children. Our findings underscore the urgent need for comprehensive care, follow-up, and rehabilitation programs for pediatric snakebite victims in the Amazon region.
