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Celebrating 20 years of excellence with Doug Altman and welcoming the future.
Challenges to fracture service availability and readiness provided by allopathic and traditional health providers: national surveys across The Gambia and Zimbabwe.
BACKGROUND: Populations in Africa are ageing, hence the number of age-related fragility fractures, including hip fractures, is rising. Hip fractures are an indicator condition for older adult health provision, as they require a multifaceted pathway of care. To enable health service planning, detailed national-level understanding of current fracture service provision is needed. METHODS: The WHO Service Availability & Readiness Assessment survey was modified to evaluate fracture service availability, and readiness. All health care facilities to which a patient with a hip fracture could present in The Gambia and Zimbabwe were invited to participate between October 2021 and January 2023. A further traditional bone-setter (TBS)-specific survey assessed TBS care in The Gambia. Availability of services per 100 000 adults ≥ 18 years, and general, fracture-specific, and hip fracture-specific care readiness were determined. RESULTS: All invited facilities in Zimbabwe (n = 186), 98% in The Gambia (n = 150), and 35 of 42 (83%) TBS participated in the survey. General availability of hospital facilities was low in both Zimbabwe and The Gambia and many facilities lacked regular electricity, reliable oxygen supplies, and sharp/infectious waste disposal. In The Gambia, 78.6% public hospitals and 53.8% other facility types (e.g. NGO/mission) had no doctors. Fracture care readiness:
Benefits and harms of placebo in surgical randomised clinical trials: a systematic review
Objective: To investigate whether placebo controls should be used in the evaluation of surgical interventions. Design: Systematic review. Data sources: We searched Medline, Embase, and the Cochrane Controlled Trials Register from their inception to November 2013. Study selection: Randomised clinical trials comparing any surgical intervention with placebo. Surgery was defined as any procedure that both changes the anatomy and requires a skin incision or use of endoscopic techniques. Data extraction: Three reviewers (KW, BJFD, IR) independently identified the relevant trials and extracted data on study details, outcomes, and harms from included studies. Results: In 39 out of 53 (74%) trials there was improvement in the placebo arm and in 27 (51%) trials the effect of placebo did not differ from that of surgery. In 26 (49%) trials, surgery was superior to placebo but the magnitude of the effect of the surgical intervention over that of the placebo was generally small. Serious adverse events were reported in the placebo arm in 18 trials (34%) and in the surgical arm in 22 trials (41.5%); in four trials authors did not specify in which arm the events occurred. However, in many studies adverse events were unrelated to the intervention or associated with the severity of the condition. The existing placebo controlled trials investigated only less invasive procedures that did not involve laparotomy, thoracotomy, craniotomy, or extensive tissue dissection. Conclusions: Placebo controlled trial is a powerful, feasible way of showing the efficacy of surgical procedures. The risks of adverse effects associated with the placebo are small. In half of the studies, the results provide evidence against continued use of the investigated surgical procedures. Without well designed placebo controlled trials of surgery, ineffective treatment may continue unchallenged.
Development of a topic‐specific bibliographic database supporting the updates of SPIRIT 2013 and CONSORT 2010
Introduction: An important mechanism of research waste is inadequate incorporation of, and references to, previous relevant research. Identifying references for a research manuscript can be challenging, in part due to the exponential rise in potentially relevant literature to consider. For large research projects, such as developing or updating reporting guidelines, it may be helpful to construct a supportive topic‐specific bibliographic database. Methods: In support of updating the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and the CONsolidated Standards Of Reporting Trials (CONSORT) 2010, we developed the SPIRIT‐CONSORT Evidence Bibliographic database (SCEBdb): a freely available topic‐specific bibliographic database of publications providing an evidence foundation for the updates. We searched multiple sources of potential publications and tagged included ones with database‐specific keywords. For context, we also formulated 10 core considerations for constructing topic‐specific bibliographic databases and identified and described 5 illustrative other databases. Results: As of April 2024, the SCEBdb included 846 publications. The database proved useful as a supplementary information source for our scoping review of published comments on SPIRIT 2013 and CONSORT 2010, for a supplementary Delphi process, and in the writing phase of the guidance documents. We expect that the database will be useful for future projects within the fields of clinical research methodology, bias, evidence synthesis, and randomized trials. Conclusion: The methods involved in constructing the SCEBdb, and our suggested core considerations for topic‐specific bibliographic databases, could be helpful for researchers reflecting on whether, and how, to develop a topic‐specific bibliographic database.
The Impact of Body Mass Index (BMI) on Clinical Outcomes for Patients Receiving Systemic Anti-Cancer Therapies for Advanced Clear Cell Renal Carcinoma.
IntroductionObesity is a risk factor for the development of renal cell carcinoma (RCC), however observational studies have suggested patients with RCC receiving systemic anti-cancer therapy (SACT) and BMI ≥25 kg/m2 may have a better prognosis than patients with a normal or low BMI, a phenomenon often referred to as the obesity paradox.MethodsThe impact of BMI on survival outcomes in patients with advanced clear cell RCC receiving SACT within the National Health Service (NHS) in England between 2010 and 2018 was investigated. A retrospective analysis was performed using the SACT dataset from NHS-England.ResultsA total of 1034 patients were included. The majority of patients commenced treatment with oral SACT, pazopanib (53.3%) and sunitinib (43.7%). Median overall survival for patients with BMI ≤25 kg/m2 was 12.6 months (95% CI; 10.1-14.4) and 17.9 months (15.4-20.0) for patients with BMI ≥25 kg/m2 (P < .001). The association between BMI and improved survival was greatest in the first year of commencing SACT with the adjusted mortality rate of 68.9% for patients with BMI less than 25 kg/m2 compared to 48.6% for patients with BMI greater than 25 kg/m2 (rate ratio .77, .63 to .93).ConclusionA high BMI compared to a normal or low BMI was associated with improved survival in patients with metastatic RCC who were predominantly treated with oral SACT. Improved survival in obese patients with advanced RCC may be associated with improved response to systemic targeted therapies.
Erratum to: Methods for evaluating medical tests and biomarkers.
[This corrects the article DOI: 10.1186/s41512-016-0001-y.].
A comparative study of shoulder replacement outcomes using linked national registry and hospital data from England and Denmark.
BACKGROUND: The incidence of shoulder replacement surgery continues to rise internationally. The aim of this study was to compare revision surgery, reoperations and serious adverse events after shoulder replacement surgery in England and Denmark. METHODS: Linked National Joint Registry and NHS Hospital Episode Statistics of England, and linked Danish Shoulder Arthroplasty Registry and Danish National Patient Registry data were available from 1 April 2012 to 31 December 2020. All primary shoulder replacements in adult patients were included. Revision surgery, reoperations and serious adverse events were compared between the two countries, and stratified by procedure type and surgical indication. The risk of revision and serious adverse events were adjusted for age, sex and comorbidities, using flexible parametric survival models and logistic regression models, respectively. RESULTS: A total of 41,471 and 9,268 primary shoulder replacement procedures were analysed from England and Denmark, respectively. The mean patient age in Denmark was 70.6 years (SD 10.1) and in England 72.6 years (SD 9.9). Danish patients had a lower risk of serious adverse events (4.5%) compared to patients in England (5.6%), but a slightly higher risk of re-operations by 1 year (Denmark 2.3% [95% CI 2.0% to 2.6%], England 1.7% [95% CI 1.6% to 1.8%]). There was a slightly lower risk of revision joint replacement surgery by 8 years in Denmark (5.1% [95% CI 4.5% to 5.8%]) compared to England (5.7% [95% CI 5.4% to 6.1%]). The reverse total shoulder replacement had a higher revision rate in Denmark, but the anatomical total shoulder replacement and humeral hemiarthroplasty had lower revision rates. Denmark had a considerably higher revision rate for patients having surgery for acute trauma. These results remained the same after adjusting for age, sex, and the Charlson Comorbidity Index. CONCLUSIONS: While there was variation in the demographics of patients having shoulder replacement surgery in England and Denmark, differences in serious adverse events and revision rates were observed despite case-mix adjustment. Some of this variation might be attributed to the differences seen in the use of different procedures for different surgical indications between the two countries.
Incidence and survival of colorectal cancer in the United Kingdom from 2000-2021: a population-based cohort study.
BACKGROUND: The management of colorectal cancer (CRC) is evolving, with advances in screening and treatment. OBJECTIVE: To leverage population-based data to generate up-to-date UK estimates of age and sex-specific incidence and overall survival for the period 2000-2021. DESIGN: We analysed nationally representative primary care records from Clinical Practice Research Datalink (CPRD) GOLD and replicated in CPRD Aurum. We calculated incidence rates, and short- and long-term survival stratified by age, sex, and diagnosis year. RESULTS: Overall incidence was 67.4/100,000 person years, increasing in 2000-2011 to drop slightly in 2011-2014, and then plateauing. In contrast, early-onset CRC raised uninterruptedly throughout the study period, from 8.33 to 19.07/100,000 person-years.Overall survival was 78.3%, 51.4% and 38.5% at 1-, 5-, and 10-years respectively, lower in men compared to women. Modest improvements in survival were observed over the study period, particularly for 60-69-year-old patients. CONCLUSION: Although the overall incidence in the population has plateaued, a worrying increasing trend of early-onset CRC was observed. Moreover, the slight improvement in overall survival suggests that significant progress is still needed. These findings highlight the urgent need for continued research and resource allocation to improve the diagnosis and management of colorectal cancer.
Invasive group A streptococcal infections in North West England: epidemiology, risk factors and fatal infection.
OBJECTIVES: In England, notifications of invasive group A streptococcal (iGAS) infections have increased since 2015. We describe time trends, risk factors, as well as clinical and infection characteristics amongst iGAS cases in North West England, focussing on people who inject drugs (PWIDs), prisoners and homeless populations (referred to as risk groups), and analyse factors for fatal infection. STUDY DESIGN: The study design used was a cross-sectional study. METHODS: Data for all iGAS cases notified to Public Health England North West between January 2016 and May 2019 were used. Analysis consisted of time trend analysis, descriptive statistics, hypothesis testing to investigate differences in clinical and infection characteristics between risk and non-risk groups and binary logistic regression to identify factors associated with fatal infection. RESULTS: There were 1353 cases. Two hundred and two were amongst risk groups, who were predominantly PWIDs in Greater Manchester. Soft tissue risk factors were widespread. There were differences in strain-type between risk and non-risk groups. Female gender, cancer, emm1.0 and emm5.23 were associated with increased odds of death, whilst cellulitis was associated with reduced odds. The relationship between age and death was U-shaped. CONCLUSIONS: iGAS has increased in North West England since 2016, including amongst PWIDs. This may be due to emm-type replacement, barriers to good hygiene and increasing colonisation.
A 5-transcript signature for discriminating viral and bacterial etiology in pediatric pneumonia.
Pneumonia stands as the primary cause of death among children under five, yet current diagnosis methods often result in inadequate or unnecessary treatments. Our research seeks to address this gap by identifying host transcriptomic biomarkers in the blood of children with definitive viral and bacterial pneumonia. We performed RNA sequencing on 192 prospectively collected whole blood samples, including 38 controls and 154 pneumonia cases, uncovering a 5-transcript signature (genes FAM20A, BAG3, TDRD9, MXRA7, and KLF14) that effectively distinguishes bacterial from viral pneumonia (area under the curve (AUC): 0.95 [0.88-1.00]). Initial validation using combined definitive and probable cases yielded an AUC of 0.87 [0.77-0.97], while full validation in a new prospective cohort of 32 patients achieved an AUC of 0.92 [0.83-1.00]. This robust signature holds significant potential to enhance diagnostics accuracy for pediatric pneumonia, reducing diagnostic delays and unnecessary treatments and potentially transforming clinical practice.
A diagnostic host-specific transcriptome response for Mycoplasma pneumoniae pneumonia to guide pediatric patient treatment.
Mycoplasma pneumoniae causes atypical pneumonia in children and young adults. Its lack of a cell wall makes it resistant to beta-lactams, which are the first-line treatment for typical pneumonia. Current diagnostic tests are time-consuming and have low specificity, leading clinicians to administer empirical antibiotics. Using a LASSO regression simulation approach and blood microarray data from 107 children with pneumonia (including 30 M. pneumoniae) we identify eight different transcriptomic signatures, ranging from 3-10 transcripts, that differentiate mycoplasma pneumonia from other bacterial/viral pneumonias with high accuracy (AUC: 0.84-0.95). Additionally, we demonstrate that existing signatures for broadly distinguishing viral/bacterial infections and viral/bacterial pneumonias are ineffective in distinguishing M. pneumoniae from viral pneumonia. The new signatures are successfully validated in an independent RNAseq cohort of children with pneumonia, demonstrating their robustness. The high sensibility of these signatures presents a valuable opportunity to guide the treatment and management of M. pneumoniae pneumonia patients.
Local anaesthetic transperineal biopsy versus transrectal prostate biopsy in prostate cancer detection (TRANSLATE): a multicentre, randomised, controlled trial.
BACKGROUND: Prostate cancer diagnosis requires biopsy, traditionally performed under local anaesthetic with ultrasound guidance via a transrectal approach (TRUS). Local anaesthetic ultrasound-guided transperineal biopsy (LATP) is gaining popularity in this setting; however, there is uncertainty regarding prostate sampling, infection rates, tolerability, side-effects, and cost-effectiveness. TRANSLATE was a randomised clinical trial that aimed to compare detection of Gleason Grade Group (GGG) 2 or higher prostate cancer, side-effects, tolerability, and patient-reported outcomes, after LATP versus TRUS biopsy. METHODS: In this randomised clinical trial which was done at ten hospitals in the UK, patients aged 18 years or older were eligible if investigated for suspected prostate cancer based on elevated age-specific prostate-specific antigen or abnormal digital rectal examination, and if biopsy-naive having received pre-biopsy MRI on a 1·5 or higher Tesla scanner. Individuals were excluded if they had any previous prostate biopsy, extensive local disease easily detectable by any biopsy (prostate-specific antigen >50 ng/mL or entire gland replaced by tumour on MRI), symptoms of concurrent or recent urinary tract infection, history of immunocompromise, need for enhanced antibiotic prophylaxis, absent rectum, or inability to position in lithotomy. Participants were randomly assigned in a 1:1 ratio to receive LATP or TRUS biopsy, using web-based software with a randomisation sequence using a minimisation algorithm to ensure balanced allocation across biopsy groups for minimisation factors (recruitment site, and location of the MRI lesion). The primary outcome was detection of GGG 2 or higher prostate cancer, analysed in the modified intention-to-treat population (all randomly assigned to treatment who had a biopsy result available). Key secondary endpoints assessing post-biopsy adverse events were infection, bleeding, urinary and sexual function, tolerability, and patient-reported outcomes. This trial is registered with ClinicalTrials.gov (NCT05179694) and at ISRCTN (ISRCTN98159689), and is complete. FINDINGS: Between Dec 3, 2021, and Sept 26, 2023, 2078 (76%) of 2727 assessed individuals were eligible, and 1126 (41%) of 2727 agreed to participate. 1044 (93%) of the 1126 participants were White British. Participants were allocated to TRUS (n=564) or LATP (n=562) biopsy, and were followed up at time of biopsy, and at 7 days, 35 days, and 4 months post-biopsy. We found GGG 2 or higher prostate cancer in 329 (60%) of 547 participants with biopsy results randomly assigned to LATP compared with 294 (54%) of 540 participants with biopsy results randomly assigned to TRUS biopsy (odds ratio [OR] 1·32 [95% CI 1·03-1·70]; p=0·031). Infection requiring admission to hospital within 35 days post-biopsy occurred in 2 (<1%) of 562 participants in the LATP group compared with 9 (2%) of 564 in the TRUS group. No statistically significant difference was observed in the reporting of overall biopsy-related complications (LATP 454 [81%] of 562 vs TRUS 436 [77%] of 564, OR 1·23 [95% CI 0·93 to 1·65]), urinary retention requiring catheterisation (LATP 35 [6%] of 562 vs TRUS 27 [5%] of 564), urinary symptoms (median International Prostate Symptom Score: LATP 8 [IQR 4-14] vs TRUS 8 [4-13], OR 0·36 [95% CI -0·38 to 1·10]), nor sexual function (median International Index of Erectile Function score: LATP 5 [2-25] vs TRUS 8 [3-24], OR -0·60 [-1·79 to 0·58]) at 4 months after biopsy. Trial participants more commonly reported LATP biopsy to be immediately painful and embarrassing compared with TRUS (LATP 216 [38%] of 562 vs TRUS 153 [27%] of 564; OR 1·84 [95% CI 1·40 to 2·43]). Serious adverse events occurred in 14 (2%) of 562 participants in the LATP group and 25 (4%) of 564 in the TRUS group. INTERPRETATION: Among biopsy-naive individuals being investigated for possible prostate cancer, biopsy with LATP led to greater detection of GGG 2 or higher disease compared with TRUS. These findings will help to inform patients, clinicians, clinical guidelines, and policy makers regarding the important trade-offs between LATP and TRUS prostate biopsy. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment.
Achilles tendinopathy.
Achilles tendon pathologies are prevalent, impacting ~6% of the general population and up to 50% of elite endurance runners over their lifetimes. These conditions substantially affect quality of life and work productivity, leading to substantial societal costs. Achilles tendinopathy (AT) is a condition marked by localized pain and functional impairment related to mechanical loading. AT can considerably impair participation and potentially also performance in sports and daily activities. The aetiology of AT is multifactorial and repetitive overloading of the tendon is often observed as the inciting factor by health professionals. However, AT can also be associated with adverse effects of certain medication, ageing and various comorbidities. Characteristic tendon changes include proteoglycan accumulation, fluid accumulation with swelling and hypervascularization. Tissue disorganization advances as pathological changes in matrix structure are driven by altered cellular function and makeup, often accompanied by persistent inflammation. Treatment strategies include various interventions, although these can be protracted and challenging for both patients and health-care providers, often with high failure rates. Current research focuses on understanding the pathological processes at the cellular and molecular levels to distinguish between disease categories and to investigate the role of inflammation, metabolic maladaptation and mechanical stress. Emerging therapeutic approaches need to be developed to address these underlying mechanisms. These approaches focus on optimizing rehabilitation protocols and advancing the development of adjunct therapies, such as advanced therapy medicinal products, alongside the integration of precision medicine to improve treatment outcomes.
