Objective:To compare the efficacy and safety of glucagon-like peptide 1 (GLP-1) based drug treatments for weight loss in adults with overweight or obesity without diabetes. Design:Network meta-analysis of randomised controlled trials. Data sources:Embase, PubMed (Medline), and Web of Science, 1 January 2000 to 6 March 2026. Eligibility criteria for selecting studies:Randomised controlled trials that enrolled adults with overweight or obesity, comparing GLP-1 receptor agonists or related co-agonists with placebo or active comparators, with a minimum intervention duration of 12 weeks. Excluded were trials that enrolled participants with diabetes, or where diabetes status could not be clearly determined. Results:58 trials of 24 214 participants were analysed. Compared with placebo, weight loss was greatest with retatrutide (-22.10%, 95% confidence interval -25.60% to -18.60%), followed by tirzepatide (-19.28%, -20.39% to -18.16%), and CagriSema (a combination of cagrilintide and semaglutide, -17.32%, -19.32% to -15.32%). Conventional GLP-1 receptor agonists showed more modest effects. Similar patterns were seen for waist circumference and lipid outcomes. Treatment rankings suggested a probabilistic hierarchy favouring next generation incretin based treatments, although confidence intervals overlapped for several comparisons. Low certainty evidence suggested higher rates for discontinuing treatment with danuglipron and retatrutide, whereas mazdutide showed better tolerability. Conclusions:In adults with overweight or obesity without diabetes, next generation incretin based treatments achieved greater weight loss than conventional GLP-1 receptor agonists. Differences in tolerability, limited head-to-head evidence, and residual uncertainty, however, should be considered when interpreting comparative treatment effects. Study registration:PROSPERO CRD420261279841.
High altitude pulmonary hypertension occurs in a subset of the 80-140 million people who live at altitudes ≥2500 m. This type of pulmonary hypertension is generally defined by a mean pulmonary artery pressure >30 mm Hg and is associated with symptoms of exercise intolerance, with possible progression to right heart failure. High altitude pulmonary hypertension can be difficult to distinguish from other forms of pulmonary hypertension, including pulmonary arterial hypertension and pulmonary hypertension caused by lung disease. In theory, removal from high altitude effectively treats high altitude pulmonary hypertension but not pulmonary arterial hypertension and pulmonary hypertension caused by lung disease. In reality, mechanistic overlap between the diseases exists, and the clinical phenotypes may likewise overlap. Limited evidence exists for other treatments for high altitude pulmonary hypertension, with the greatest rationale currently for pulmonary vasodilators. Future research should revisit the diagnostic threshold for high altitude pulmonary hypertension and for other forms of pulmonary hypertension at high altitude. Also, more research is needed to better differentiate between patients living at high altitude with high altitude pulmonary hypertension and those with other forms of pulmonary hypertension, and to define which treatments can be extrapolated from other types of pulmonary hypertension to high altitude pulmonary hypertension.
Objectives To quantify the incidence of gestational diabetes mellitus in England, determine inequalities in diagnoses and pregnancy outcomes, and assess the indirect effects of the covid-19 pandemic. Design Contemporary, cross sectional observational study. Setting Primary and secondary care data from NHS England, based on the Hospital Episode Statistics Admitted Patient Care dataset, 1 January 2018 to 31 December 2022. Participants 2 314 365 women, aged 16-50 years, who gave birth to 2 758 170 babies in 184 hospitals. Main outcome measures Rates of gestational diabetes, infants born small for gestational age or large for gestational age, and emergency caesarean births, summarised yearly and monthly, based on socioeconomic deprivation and ethnic group. Results Diagnoses of gestational diabetes increased from about 8% in 2018 to >12% in 2022. The increase was greatest for individuals from non-white ethnic groups (23% for Asian women) or those living in deprivation (14%). Mothers from these backgrounds were also at greater risk of adverse pregnancy outcomes, such as emergency caesarean birth (odds ratio for black mothers 1.36, 95% confidence interval 1.34 to 1.38), preterm birth (odds ratio for deprived mothers 1.29, 1.27 to 1.31), or having an infant small for gestational age (odds ratio for Asian mothers 2.42, 2.39 to 2.45). Also, a diagnosis of gestational diabetes for these women was associated with an increase in the odds of preterm birth. Changes to screening methodology for gestational diabetes during the covid-19 pandemic had no significant effect on the number of diagnoses. Conclusions The study found that one in eight mothers in England had a diagnosis of gestational diabetes, and that profound health inequalities exist in their outcomes. Strategies are urgently needed to provide and improve care for this high risk group, given the implications of gestational diabetes on the short and long term health outcomes for mothers and babies.
Objectives To evaluate the use of postmarketing requirements under the FDA Amendments Act (FDAAA) and postmarketing commitments issued by the US Food and Drug Administration (FDA), for new drugs approved from 2016 to 2024, and to determine rates of study completion and changes in drug labelling resulting from these studies. Design Cross sectional evaluation of postmarketing studies. Setting All new drugs and their associated indications approved by the FDA's Center for Drug Evaluation and Research, 1 January 2016 to 31 December 2024. Population 420 drugs approved by the FDA for 567 indications, associated with 913 FDAAA postmarketing requirements and 434 postmarketing commitments. Main outcome measures Drug characteristics associated with issuance of FDAAA postmarketing requirements and issuance of postmarketing commitments, rates of study completion and on-time completion, and proportion of studies leading to changes in drug labelling. Results More than two thirds of drugs (n=287, 68.3%) had at least one FDAAA postmarketing requirement and 42.9% (n=180) had at least one postmarketing commitment. Indications with an orphan designation were more likely to have an FDAAA postmarketing requirement (63.3% v 48.6%; absolute difference 14.7%, 95% confidence interval (CI) 6.7% to 22.8%), as were indications approved with an expedited programme (59.6% v 48.1%; absolute difference 11.5%, 2.7% to 20.3%). Similarly, postmarketing commitments were more likely to be issued for indications with an orphan designation (47.0% v 33.6%; absolute difference 13.4%, 5.4% to 21.4%) and those using expedited approval programmes (47.9% v 23.8%; absolute difference 24.1%, 16.2% to 32.1%). Among studies due by the end of 2024, 73.4% (95% CI 69.2% to 77.3%; n=345) of FDAAA postmarketing requirements and 81.5% (76.3% to 86.1%; n=212) of postmarketing commitments were completed, although only 33.4% (29.1% to 37.9%) (n=157) and 36.2% (30.3% to 42.3%) (n=94), respectively, were completed on time. Of the 311 fulfilled FDAAA postmarketing requirement studies, 63.3% (n=197) resulted in at least one labelling change, most often in the section on use in specific populations and clinical pharmacology. Fewer postmarketing commitment studies (n=94, 49.7%) resulted in changes in drug labelling, with most changes found in the clinical pharmacology and clinical studies sections. Conclusions FDAAA postmarketing requirements and postmarketing commitments are important regulatory tools for generating postapproval evidence, particularly for drugs approved with orphan designation or under expedited programmes. Although a large proportion of studies resulted in changes in drug labelling, delays in completion were common, highlighting the need to ensure effective oversight and timely study completion and reporting.
Objective:To estimate the associations between gestational weight gain and maternal immediate perinatal and postpartum outcomes by pooling data from low and middle income countries. Design:Individual participant data meta-analyses. Data sources:PubMed, Embase, Web of Science, and Cochrane Library, based on three searches (Search 1: all prospective studies published from January 2000 to May 2021; Search 2: randomized controlled trials of balanced energy and protein supplementation published until June 2021; Search 3: randomized controlled trials of anti-infectious agents published until August 2021). Eligibility criteria for selecting studies:Prospective studies (randomised controlled trials or observational cohort studies) with measured maternal weight during pregnancy and data available on maternal height, based in populations from low and middle income countries with no underlying conditions. Results:The analyses included 156 300 women from 61 studies and 23 countries, with most participants based in South Asia (n=78 454, 50.2%) and sub-Saharan Africa (n=36 327, 23.2%). Compared with women with adequate (90-125%) gestational weight gain, women with excessive (>125%) gestational weight gain had a higher risk of caesarean delivery (risk ratio 1.10, 95% confidence interval 1.06 to 1.13, τ2=0.000) and emergency caesarean delivery (risk ratio 1.22, 1.03 to 1.43, τ2=0.000). Women with moderately (70% to <90%) or severely inadequate (<70%) versus adequate gestational weight gain had lower risks for caesarean delivery (risk ratio in women with moderately inadequate gestational weight gain 0.88, 95% confidence interval 0.84 to 0.92, τ2=0.004; risk ratio in women with severely inadequate gestational weight gain 0.82, 0.77 to 0.88, τ2=0.010) and emergency caesarean delivery (risk ratio in moderately inadequate gestational weight gain 0.82, 0.71 to 0.95, τ2=0.004; risk ratio in severely inadequate gestational weight gain 0.73, 0.56 to 0.96, τ2=0.103). Excessive versus adequate gestational weight gain was associated with higher postpartum weight retained at any time point (mean difference 2.00 kg, 95% confidence interval 1.49 to 2.50, τ2=1.317), whereas moderately and severely inadequate gestational weight gain were associated with lower retained weight compared with adequate gestational weight gain. Similar trends were found for postpartum body mass index. Severely inadequate gestational weight gain was associated with lower systolic and diastolic blood pressure at any time point post partum than adequate gestational weight gain. No associations were observed for other outcomes including postpartum depressive symptoms or breastfeeding. Evidence indicating an interaction between gestational weight gain and body mass index before pregnancy was found when examining the risk of caesarean delivery and postpartum weight retention, body mass index, and systolic blood pressure as outcomes. Conclusions:These findings support the association between suboptimal gestational weight gain and adverse maternal outcomes in the immediate perinatal and postpartum periods. Further research examining the consequences of suboptimal gestational weight gain in low and middle income countries would be valuable to inform potential strategies to improve long term maternal health. Review registration:PROSPERO CRD42023432836.
Objective To examine the efficacy of conservative (non-surgical) treatments, usual care, and no treatment for chronic radicular and non-specific back pain.Design Time course network meta-analysis.Data sources Six electronic databases (Medline, SPORTDiscus, CINAHL, PsycINFO, Embase, and CENTRAL), searched from inception to 24 July 2020, and 302 previous systematic reviews.Eligibility criteria for selecting studies Full peer reviewed publications in English or German of randomised controlled trials, randomised clinical trials, randomised controlled cluster trials, or randomised crossover trials in adults (aged ≥18 years) receiving common conservative treatments for non-specific and radicular chronic low back pain. Treatments examined were acupuncture, education or advice, electrotherapy (including heat and ice electrotherapeutic modalities applied non-invasively), exercise training, manual treatments or manipulation, massage, the McKenzie method, pharmacotherapy, psychological treatments, traction, physical therapy (otherwise not falling into specific treatment combinations), placebo, multidisciplinary pain management, usual care (eg, management by a doctor), and no treatment (true control).Results Back pain intensity, leg pain intensity, disability, and mental health outcomes were reported immediately (<1 day), and at short term (≥1 day and ≤3 months), intermediate term (>3 and <12 months), and long term (≥12 months) time points. 581 reports of 551 studies (71 126 patients) were included. 510 trials included people with non-specific chronic low back pain and 41 trials included those with radicular chronic low back pain. For back pain (0-100 scale), acupuncture (mean difference −20.91, 95% credible interval −24.00 to −11.95), electrotherapy (−18.98, −21.84 to−10.95), exercise (−15.59, −17.51 to −10.05), manual treatment (−19.48, −22.17 to −11.74), massage (−25.61, −30.42 to −10.91), and multidisciplinary pain management (−18.96, −22.26 to −9.58) exceeded the minimal clinically important difference (set at 0.5 standard deviation) in the short term. For disability (0-100 scale), acupuncture (mean difference −10.52, 95% credible intervals −11.84 to −6.59), massage (−9.95, −11.45 to −5.50), and multidisciplinary pain management (−12.56, −13.91 to −8.55) were clinically effective in the short term. In the immediate and intermediate term only, the McKenzie method and massage, respectively, exceeded the minimal clinically important difference. In the long term, although two of the 14 treatments for back pain and nine of 14 treatments for disability had statistically significant benefits compared with no treatment, the effects were not clinically significant. The certainty of the evidence based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework was low (1.4%) to very low (98.6%) across interventions and time points. Findings for massage and the McKenzie method were not stable in the sensitivity analyses. Treatment effects for radicular chronic low back pain did not seem to differ from those for non-specific chronic low back pain.Conclusions Some treatments were effective for pain and function in non-specific chronic low back pain, but improvements did not persist long term. Most of the evidence was for non-specific chronic low back pain; the evidence base for radicular chronic low back pain was limited. Although sensitivity analyses did not provide evidence for a different response in radicular chronic low back pain, an evidence gap remains for this subpopulation. Future work should explore strategies to establish the long term efficacy of modifications to lifestyle and behaviour.Systematic review registration PROSPERO CRD42020182039
Prehabilitation transforms the preoperative waiting period into an opportunity for patients to actively improve their health before surgery. With surgical populations ageing and presenting with increasing frailty, patient prioritised outcomes, such as postoperative complications and disability, affect >20% of patients undergoing major surgery, resulting in substantial healthcare costs. This review combines the current evidence for prehabilitation components, including exercise, and respiratory, nutritional, cognitive, and psychosocial interventions. Although respiratory prehabilitation showed high certainty evidence for reducing postoperative pulmonary complications after major surgery, other components showed promising but lower certainty benefits. Multimodal prehabilitation, especially when exercise and nutrition are combined, seems to be most effective for improving clinical and patient centred outcomes. Significant knowledge gaps remain, however, about optimal programme design, delivery models, target populations, and strategies to maximise adherence. Patient perspectives emphasise the importance of individualised coaching or support from healthcare professionals, or both, home based accessibility, and collaborative care. Future research should include a focus on pragmatic multicentre trials with robust cost effectiveness analyses to support implementation in the health system of effective, scalable prehabilitation programmes that can meaningfully improve outcomes for surgical patients. Opportunities to enhance the effectiveness and reach of prehabilitation include exploiting existing and emerging technologies, as well as optimising participant support to maximise adherence.
Objective To summarise the evidence so far from all randomised controlled trials on the efficacy of communication of polygenic risk scores in changing health outcomes.Design Systematic review and meta-analysis.Data sources Cochrane Central Register of Controlled Trials (CENTRAL) and Pubmed, from inception to 1 March 2025.Eligibility criteria for selecting studies Randomised controlled trials in human participants; articles published or accepted for publication in peer reviewed journals, or with available results on ClinicalTrials.gov, without time restriction in any language; and randomised controlled trials comparing the disclosure of inherited genetic risk obtained through the polygenic risk score for any phenotype (intervention group) with scenarios where no genetic information was provided (comparator group).Results Of 7830 articles retrieved, 27 randomised controlled trials were eligible for inclusion in the analysis. Polygenic risk scores mainly predicted risks for cancer (n=9 randomised controlled trials), cardiovascular diseases (n=8), and diabetes (n=6). 21 randomised controlled trials targeted mainly healthy populations, three targeted at-risk populations, and three trials targeted individuals who had already developed a disease and the polygenic risk score predicted complications. Most randomised controlled trials (15/27) concluded in their abstracts with favourable claims about the polygenic risk score, with only 5/15 trials justifying the score with any significant results. Nine of the 27 randomised controlled trials had a high risk of bias. Meta-analysis showed no significant effects on any of the 22 outcomes tested in two or more trials. Standardised mean differences for dietary outcomes were −0.11 (95% confidence interval (CI) −0.22 to 0.01) for daily energy intake, 0.03 (−0.18 to 0.25) for daily fat intake, and −0.11 (−0.28 to 0.06) for alcohol consumption. For physical activity, standardised mean difference was −0.01 (95% CI −0.13 to 0.11). Relative risks were 1.12 (95% CI 0.77 to 1.61) for screening attendance, 1.50 (0.98 to 2.29) for use of statins, and 0.95 (0.32 to 2.79) for incidence of disease. For psychological outcomes, standardised mean differences were −0.02 (95% CI −0.13 to 0.08) for anxiety, −0.06 (−0.23 to 0.10) for worry, −0.04 (−0.21 to 0.13) for perceived risk, and −0.05 (−0.23 to 0.13) for depression. For clinical outcomes, mean differences were −2.01 (95% CI −8.27 to 4.26) for total cholesterol, −3.64 (−7.88 to 0.60) for low density lipoprotein cholesterol, −0.21 (−2.65 to 2.23) for high density lipoprotein cholesterol, −1.88 (−4.17 to 0.42) for diastolic blood pressure, −1.26 (−4.44 to 1.92) for systolic blood pressure, −0.12 (−0.63 to 0.39) for body mass index, and −0.33 (−0.87 to 0.20) for weight. 80 outcomes were reported across multiple studies, with each outcome reported in a single trial only. 19 of 80 were primary outcomes, and of these two had significant results (P<0.05), as did three secondary outcomes.Conclusions Overall, despite frequent promising claims, disclosure of polygenic risk scores did not result in meaningful changes in behavioural, psychological, or clinical measures for the outcomes examined. Although when interpreting the findings the heterogeneity and methodological limitations of the available trials should be considered, communication of polygenic risk scores did not show consistent improvements in preventive behaviours or risk factor modification.Systematic review registration Open Science Framework doi.org/10.17605/OSF.IO/28V6J
Postpartum haemorrhage is the leading cause of maternal mortality worldwide, accounting for a substantial proportion of preventable deaths, particularly in settings with limited resources. Despite its clinical significance, understanding the haemostatic changes underpinning postpartum haemorrhage has historically been limited, with management strategies largely extrapolated from trauma related bleeding. Important physiological differences exist between these conditions, however, which has implications for diagnosis and treatment. Normal pregnancy is characterised by increased coagulation factors and reduced fibrinolysis, resulting in a hypercoagulable state. These adaptations are protective but influence the haemostatic response to bleeding. Recent evidence has refined our understanding of coagulopathy in postpartum haemorrhage. In most cases, haemostasis is preserved despite major blood loss, but fibrinogen depletion is an early and important predictor of severe haemorrhage. A distinct and rare entity, acute obstetric coagulopathy, has been described, characterised by hyperfibrinolysis, hypofibrinogenaemia, dysfibrinogenaemia, and depletion of selective coagulation factors, and is associated with poor maternal and neonatal outcomes. Traditional laboratory coagulation tests are limited by turnaround time and insensitivity to key abnormalities, such as fibrinolysis. Viscoelastic haemostatic assays (eg, thromboelastography (TEG) and rotational thromboelastometry (ROTEM)) offer rapid, point-of-care assessment of clot formation and stability, allowing earlier identification of coagulopathy and more targeted transfusion strategies. Evidence suggests that their use may reduce unnecessary administration of blood products without compromising outcomes. Management strategies are evolving. Tranexamic acid has shown a clear benefit in terms of mortality when given early, and is now widely recommended. In contrast, routine empiric use of fresh frozen plasma is increasingly questioned, given the relative preservation of coagulation factors in most patients with postpartum haemorrhage and the potential risks of over-transfusion. Instead, targeted correction of coagulopathy, especially hypofibrinogenaemia, and judicious use of blood components is gaining interest, guided by clinical and laboratory findings. In summary, advances in the understanding of haemostatic changes in postpartum haemorrhage support a shift towards individualised targeted transfusion strategies. Wider adoption of point-of-care testing and further high quality research are needed to optimise transfusion approaches and improve maternal outcomes globally.
Current treatment for pulmonary fibrosis is limited to nintedanib and pirfenidone, which slow but do not halt or reverse the progression of the disease. These treatments are widely used globally. Emerging agents, such as nerandomilast, showed positive results in phase 3 trials and was approved in the US in 2025 for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis, but is not yet licensed for clinical use in the UK. As our understanding of the pathogenesis of pulmonary fibrosis advances, so does the potential to develop treatments that more effectively target underlying mechanisms while being safe and well tolerated. Insights into key pathogenic pathways, including epithelial injury, fibroblast activation, extracellular matrix deposition, B and T cell involvement, and dysregulated cytokine signalling pathways, have enabled various therapeutic targets to be explored. Despite the extensive efforts behind each study, many questions remain unanswered. Negative trials are equally important, in providing insights into how future clinical trials can be better designed and targeted. Meanwhile, positive studies show encouraging results and identify potential treatments, all contributing to the overarching goal of not just slowing, but ultimately reversing, fibrosis.
Objective To perform comprehensive validations of the integrative Box (iBox) system, a prediction model for long term risk of kidney allograft failure, for extension of its context of use in clinical trials as well as for its wider implementation in clinical practice.Design Extended validation study.Setting Paris Transplant Group database (comprising kidney recipients with transplantations between 1 January 2005 and 1 January 2014) and European, North American, and South American hospitals (comprising recipients of kidneys transplanted beween 1 January 2000 and 1 January 2022). Patients were followed until 1 November 2024.Participants 12 683 kidney tranplant recipients from 21 academic centres in Europe, North America, and South America; 4000 patients in the derivation cohort and 8683 in the validation cohorts.Main outcome measures Performance of the iBox, including flexible iBox versions in specific clinical contexts (race-free estimated glomerular filtration rate (eGFR) equations (ie, without including race as a factor in the calculation), in specific clinical contexts (initial nephropathy recurrence, BK virus associated nephropathy, and different immunosuppressive strategies), and over-extended follow-up periods. Predictive performance was assessed by discrimination, calibration, overall fit, and clinical utility.Results 12 683 kidney transplant recipients were included in the study (n=4000 in the derivation cohort and n=8683 in the validation cohorts). Median follow-up time after risk evaluation was 5.78 years (interquartile range (IQR) 3.51-7.00) in the derivation cohort and 4.68 years (2.48-7.00) in the validation cohorts. 549 (13.7%) and 991 (11.4%) patients had graft loss in the derivation and validation cohorts, respectively. All versions of the iBox algorithm maintained good discrimination and overall fit performance in the derivation and validation cohorts (C index range 0.79-0.87, Brier scores 0.08-0.11). Calibration was adequate in some but not all external validation cohorts, with trends toward overestimation or underestimation of predicted risks. Decision curve analysis showed positive and comparable net benefit for all iBox algorithms across decision thresholds up to 40% in the derivation cohort (net benefit 0.07-0.08 at 20% threshold) and validation cohorts (net benefit 0.03-0.11 at 20% threshold). Accounting for the competing risk of death with a functioning graft resulted in similar performance, except for calibration which varied across cohorts, without any model consistently outperforming any other model. The model performed well with different race-free eGFR equations (C index 0.81), in various clinical scenarios, including disease recurrence and BK virus nephropathy, with different immunosuppressive strategies, such as calcineurin inhibitors and mTOR (mechanistic target of rapamycin) inhibitors (C index range 0.74-0.87), and when extending the prediction period to 10 years after risk evaluation (C index 0.79). The iBox predictive performance was not modified when various histological indices were used. The iBox was also superior to eGFR slope (C index 0.81 v 0.62) and circulating anti-HLA donor specific antibodies (C index 0.81 v 0.57) in its predictive ability.Conclusions In this study, the robust predictive performance of the iBox system across diverse real world settings and clinical scenarios was shown. These results highlight the versatility and reliability of the iBox system, and support its use for risk stratification in routine clinical practice and as a surrogate endpoint for clinical trials.
Objective To assess whether procalcitonin-guided decision making can safely reduce the duration of antibiotic treatment in neonatal late onset sepsis.Design Prospective multicentre, randomised open label trial.Setting 33 level 3 and level 2B neonatology departments in France.Participants Newborn babies born after 24 weeks’ gestation, of postconceptional age 24-45 weeks and after 4 days of life, weighing more than 700 g, with suspected or proven late onset sepsis, requiring antibiotics for more than 48 hours, and without meningitis, septic shock, and deep-seated infection.Interventions Participants were randomly assigned to procalcitonin-guided or usual care antibiotic treatment. In the procalcitonin-guided group, procalcitonin concentration was measured at randomisation and then every two days. A non-binding recommendation to discontinue antibiotics was given if the procalcitonin concentration was 0.5 µg/L or lower. In the usual care group, treatment was provided according to local protocols.Main outcome measures The primary outcome was the duration of antibiotic treatment (under the superiority hypothesis). The key secondary outcome was non-inferiority for mortality (margin 3%) at day 28 after randomisation.Results Between February 2019 and February 2023, 248 newborns were randomised to the procalcitonin-guided group and 256 to the usual care group. In the intention-to-treat analysis, the median duration of antibiotic treatment was eight days (interquartile range (IQR) 5.0-12.0) in the procalcitonin-guided group versus 10 days (8.0-13.0) in the usual care group (absolute difference between groups −2.0 (IQR −3.8 to −1.0), P<0.001). At day 28, the proportion of death was six of 248 newborns (2.4%) in the procalcitonin-guided group versus 10 of 256 (3.9%) in the usual care group (absolute difference between groups −1.5% (95% confidence interval (CI) −5.0 to 1.8). The proportion of recurrence was seven of 248 (2.8%) newborns in the procalcitonin-guided group versus 10 (3.9%) of 256 in the usual care group (absolute difference between groups −1.1% (95% CI −4.6 to 2.3).Conclusion In this study population, the use of procalcitonin significantly reduced the duration of antibiotic treatment in neonatal late onset sepsis, without increasing mortality or serious adverse events.Trial registration NCT03730636.
Objectives:To evaluate the association between fragility fracture and interruption of bisphosphonate prescription after three and five years of initial prescription, and to explore the incidence of atypical femoral fracture and osteonecrosis of jaw after three and five years of continued prescription of bisphosphonates. Design:Nested case-control and cohort studies. Setting:Clinical Practice Research Datalink Aurum, an anonymised longitudinal database of NHS primary care electronic health records, linked to hospital admission and mortality records from Hospital Episode Statistics and Office for National Statistics databases, respectively, 1 January 1997 to 31 December 2022. Participants:Adults aged ≥18 years on the date of the first prescription of alendronate or risedronate, and with primary care data linked to Hospital Episode Statistics and Office for National Statistics databases. Participants with a medication possession ratio of ≥67% in each of the first three and five years were followed up from the three or five year time points to the earliest of fragility fracture, death, end of study, two years, or last data availability. Cases were those who had a fragility fracture and were matched with up to four control participants. Main outcome measures:Incidence of fragility fracture, atypical femoral fracture, and osteonecrosis of jaw were main outcomes. Results:Data for 26 809 and 13 408 participants prescribed bisphosphonates for three and five years, respectively, were included. Fragility fracture was not associated with interruption of bisphosphonate prescription or intermittent prescription compared with continuous prescription in those previously prescribed bisphosphonates for three years (adjusted odds ratio 1.02, 95% confidence interval (CI) 0.85 to 1.24 and 1.13, 0.93 to 1.38, respectively) or five years (adjusted odds ratio 0.92, 0.75 to 1.13 and 0.87, 0.67 to 1.13, respectively). Time since last prescription was not associated with fragility fracture. After three and five years of bisphosphonate prescription, the incidence of atypical femoral fractures was 1.93 (95% CI 1.55 to 2.41) and 2.50 (1.92 to 3.26) per 1000 person years, respectively, and the incidence of osteonecrosis of jaw was 0.07 (0.02 to 0.21) and 0.00 per 1000 person years, respectively, within two years. Conclusion:Fragility fracture was not associated with interruption of bisphosphonate prescription for up to two years, after either three or five years of prescription. The incidence of atypical femoral fracture or osteonecrosis of jaw was uncommon and rare respectively.
Objective To compare a non-operative treatment strategy with appendectomy for children with simple appendicitis, in terms of complications, avoidance of appendectomy, health related quality of life, and costs, after one year of follow-up.Design Non-inferiority randomised controlled trial.Setting 15 academic or general teaching hospitals, Netherlands, 1 January 2017 to 19 October 2023.Participants 302 children, aged 7-17 years with imaging confirmed simple appendicitis, excluding those with a faecolith.Interventions Participants were randomised to the non-operative treatment strategy group (n=151) or the appendectomy group (n=151). The non-operative treatment strategy group received 48 hours of intravenous amoxicillin-clavulanic acid and gentamicin, followed by five days of oral amoxicillin-clavulanic acid.Main outcome measures The primary outcome was the proportion of participants with a complication within one year (non-inferiority margin of 5%). Secondary outcomes were the number of participants not requiring appendectomy, health related quality of life, and costs.Results In the intention-to-treat population, 14/151 (9.3%) participants in the non-operative treatment strategy group versus 13/151 (8.6%) in the appendectomy group had a complication during the one year follow-up period (absolute risk difference 0.7%, upper limit of 95% confidence interval (CI) 7.1%). Appendectomy was avoided in 105/151 (69.5%) participants in the non-operative treatment strategy group. No difference was found in health related quality of life between the treatment groups. Costs (both direct and societal) were lower in the non-operative treatment strategy group (mean difference €767 (£668; US$902), 95% CI 320 to 1214 for direct costs and €874, 118 to 1631 for societal costs). In the non-operative treatment strategy group, length of hospital stay was significantly longer (3.3±2.4 v 1.9±1.2 days, mean difference 1.5, 95% CI 1.1 to 1.9) and more unscheduled healthcare visits occurred. Patient satisfaction measured by the Net Promoter Score was significantly lower in the non-operative treatment strategy group (18.9±4.6% v 48.0±5.8%, mean difference −29.1, 95% CI−30.8 to −27.4) at the one year follow-up.Conclusions Non-inferiority of a non-operative treatment strategy for acute simple appendicitis in children could not be proven significantly. Most of the 95% CI was within the 5% non-inferiority margin, however, with a probability of 90.7% that a non-operative treatment strategy resulted in an increase in complications of ≤5%. Absolute risk difference in the proportion of participants with complications was marginal. Surgery was avoided in about 70% of participants in the non-operative treatment strategy group. Health related quality of life was comparable between the treatment strategies. A non-operative treatment strategy was associated with lower costs, but longer time in hospital, more unscheduled healthcare visits, and lower patient satisfaction at the one year follow-up, measured by the Net Promoter Score.Trial registration NCT02848820; NTR5977.
Objectives To assess whether initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) rather than sulfonylureas is associated with all cause acute pancreatitis and cause specific acute pancreatitis and to characterise temporal risk patterns of the various causes of acute pancreatitis associated with GLP-1RA use.Design Target trial using the electronic healthcare databases of the US Department of Veterans Affairs healthcare system.Setting US Department of Veterans Affairs.Participants 333 687 users of the Veterans Affairs healthcare system with type 2 diabetes initiating GLP-1RA (n=132 551) or sulfonylureas (n=201 136) between 1 January 2017 and 31 December 2023.Exposure Initiation of GLP-1RA or sulfonylureas, and separately, continued use of GLP-1RA or sulfonylureas during follow-up.Main outcome measures Risks of acute pancreatitis during 12 months’ follow-up including all cause acute pancreatitis and cause specific acute pancreatitis (eg, pancreatitis that is suspected drug induced, alcohol induced, hypertriglyceridaemia associated, biliary, and idiopathic or other cause). The risks were measured through discrete time survival models after application of inverse probability weighting.Results In intention-to-treat analyses, participants who initiated GLP-1RAs had similar rates of all cause pancreatitis at one year compared with participants who initiated sulfonylureas (rate difference −3.64, 95% confidence interval (CI) −30.76 to 23.48 per 100 000 persons at one year). However, the overall null finding was the net result of countervailing effects across various causes of acute pancreatitis. GLP-1RA was associated with an increased risk of suspected drug induced acute pancreatitis (23.45 (14.27 to 33.85)) and decreased risks of hypertriglyceridaemia associated (−16.96 (−27.41 to −7.34)) and alcohol induced pancreatitis (−10.32 (−18.12 to −3.17)). Similar rates of biliary and idiopathic or other causes of acute pancreatitis were observed in the two groups. In per protocol analyses, drug induced acute pancreatitis attributable to GLP-1RA clustered early (42% of GLP-1RA attributable events over one year of follow-up occurred in the first three months), whereas reductions in alcohol related acute pancreatitis concentrated between months four and six and hypertriglyceridaemia associated acute pancreatitis concentrated between months 10 and 12. Cumulatively, these divergent temporal trends resulted in a net increase in risk of all cause pancreatitis during the first two months of treatment, with similar monthly risk observed for the remainder of follow-up.Conclusions In this nationwide cohort, similar rates of all cause acute pancreatitis in GLP-1RA and sulfonylurea users were observed at one year. Increased risk of suspected drug induced pancreatitis during the early period was offset by later reductions in alcohol induced and hypertriglyceridaemia associated acute pancreatitis. Clinicians should counsel patients on early risk while recognising the overall neutral long term effect.
Objective To identify and characterise primary care or community based interventions for patients with multimorbidity involving depression or anxiety, and to determine their effectiveness for improving patients’ mental health, physical health, and quality of life.Design Systematic review with meta-analysis.Data sources Medline, Embase, Cochrane Library, CINAHL, PsycInfo, and Web of Science databases, from inception to 11 November 2024.Eligibility criteria for selecting studies Included studies were randomised controlled trials of primary care or community based interventions targeting adults with depression or anxiety disorders and one or more long term physical conditions. Risk of bias assessment used the Cochrane risk of bias tool. Interventions were categorised as organisational or patient oriented, and were subgrouped by intervention type. Intervention components were systematically categorised, and effects on mental health and quality of life outcomes were meta-analysed in groups defined by intervention type and assessment time point. Physical health outcomes were too heterogenous to meta-analyse and were synthesised without meta-analysis with Fisher's method for combining P values.Results 29 randomised controlled trials comprising 9487 participants were included. High quality evidence was found for organisational interventions (n=10, including collaborative care, stepped care, and post-discharge interventions) which resulted in small improvements in symptoms of depression (standardised mean difference −0.25, 95% confidence interval (CI) −0.43 to −0.06) and quality of life (0.21, 0.01 to 0.41), but had no effect on symptoms of anxiety at the end of the intervention. No effect on depression or anxiety symptoms was observed, and no data for quality of life were found from organisational interventions at the late follow-up period (18-24 months). In the subgroup analysis, collaborative care resulted in sustained improvements in symptoms of depression at 18-24 months. Synthesis without meta-analysis showed evidence of benefit from organisational interventions (specifically collaborative care) on physiological (eg, haemoglobin A1c levels), but not on functional (eg, disability) or global physical health outcomes. Low to moderate quality evidence was found for patient oriented interventions (n=19; interventions including exercise, psychotherapy, and psychoeducation) which led to small improvements in symptoms of depression (standardised mean difference −0.46, 95% CI −0.71 to −0.21) and quality of life (0.22, 0.14 to 0.29) at the end of the intervention. These effects were diminished at the late follow-up period (≥12 months). In the subgroup analysis, no reported data for the long term effects of exercise, psychotherapy, or psychoeducation (18-24 months after randomisation) were found. Synthesis without meta-analysis showed evidence of benefit from patient oriented interventions (primarily psychotherapy) on physiological, functional, and global physical health outcomes.Conclusions The study showed that interventions improved mental health, physical health, and quality of life outcomes in people with multimorbidity involving depression or anxiety, but the effects were small and, for patient oriented interventions in particular, diminished over time.Systematic review registration PROSPERO CRD420251004355.
Vaccines have saved an estimated 154 million lives in the past 50 years and support 15 of the 17 United Nations sustainable development goals. Vaccines are also an important tool in the control of new outbreaks of infectious diseases. The vaccine cold chain, however, is key in enabling and empowering implementation of vaccine policy and societal protection from all vaccine preventable diseases, and is especially relevant in low and middle income countries in sub-Saharan Africa. The vaccine cold chain is a complex, highly specialised, temperature controlled supply chain network that extends from the point of vaccine manufacture to dose administration, and has multiple points of vulnerability. Large quantities of vaccines are lost because of excess heat or accidental freezing, resulting in missed opportunities for vaccination. Disruption to the provision of routine vaccines during the covid-19 pandemic resulted in millions of children not being vaccinated. The vaccine cold chain needs strategic prioritisation for investment and innovation so that the next generation of vaccine cold chains for low and middle income countries can be designed towards providing reliable and sustainable vaccine security in an uncertain world of climate change, managing the advent of new vaccine technologies, and narrowing inequalities in global health for resource poor communities. This review focuses on the vaccine cold chain in African low and middle income countries, and how new and emerging advances in vaccine science and challenges will affect the readiness to control the burden of vaccine preventable disease on the continent.
Metabolic dysfunction associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease globally and a major cause of liver related and cardiometabolic morbidity. MASLD is defined by the presence of hepatic steatosis and at least one of five cardiometabolic features in the absence of secondary causes of liver disease and substantial alcohol consumption (>20 g/day for women and 30 g/day for men). The recent reclassification of non-alcoholic fatty liver disease to MASLD represents a paradigm shift towards recognising the central role of systemic metabolic dysfunction and cardiometabolic risk factors in the pathogenesis of the disease and development of complications. The pathophysiology of MASLD is complex, multifaceted, and interconnected, involving adipose tissue dysfunction, altered hepatic lipid metabolism, mitochondrial and endoplasmic reticulum stress, dysregulation of the gut-liver axis, and genetic predisposition. The severity of liver fibrosis remains the strongest predictor of all cause mortality and liver specific morbidity and mortality, and the burden of cardiometabolic dysfunction affects the risk of complications in MASLD. Non-invasive serum based and imaging based biomarkers are crucial in identifying advanced liver fibrosis and guiding risk stratification. This narrative review summarises the current understanding of the pathogenesis of MASLD, the clinical use of non-invasive diagnostics, and compares international guidelines for disease management. This review also discusses approved and emerging treatment options for MASLD, recognising the current need for developing strategies for monitoring the efficacy of treatment.
Objective To determine whether antihypertensive treatment of blood pressure levels of <140/90 mm Hg can reduce the incidence of pre-eclampsia.Design Secondary analysis of data from prospective cohort studies.Setting Three prospective screening studies of women who attended routine hospital maternity visits at 11-13 weeks' gestation, 1 February 2010 to 31 December 2016. Participants were from seven secondary care institutions in England.Participants 54 422 pregnancies screened at 11-13 weeks' gestation for pre-eclampsia and with blood pressure values available, that resulted in a liveborn or stillborn infant at ≥24 weeks' gestation.Main outcome measures Incidence of pre-eclampsia (overall, and at preterm or term gestational ages), according to modelled blood pressure lowering.Results The study population was ethnically diverse (17.3% black participants, 7.8% from South or East Asia, and 2.6% self-identified with more than one ethnic group). The Fetal Medicine Foundation competing risks model was used to calculate the expected risk of pre-eclampsia, based on maternal characteristics, mean arterial pressure, uterine artery pulsatility index, and placental growth factor. The expected risk of pre-eclampsia was used to calculate the expected incidence of pre-eclampsia. Reducing diastolic blood pressure from >85 mm Hg to a target of 85 mm Hg would mean that 4.8% of women would be offered antihypertensive drugs, with a potential relative risk reduction of 21.4% (absolute reduction of 2.9%) in any pre-eclampsia and 28.3% (absolute reduction of 1.4%) reduction in preterm pre-eclampsia. By reducing diastolic blood pressure from >80 mm Hg to a target of 80 mm Hg, 13.2% of women would receive antihypertensive drugs, with a potential relative risk reduction of 26.0% (absolute reduction of 2.3%) in any pre-eclampsia and 33.8% (absolute reduction of 1.0%) reduction in preterm pre-eclampsia. By reducing diastolic blood pressure from >75 mm Hg to a target of 75 mm Hg, 29.5% of women would receive antihypertensive drugs, with a potential relative risk reduction of 32.8% (absolute reduction of 2.1%) in any pre-eclampsia and 41.6% (absolute reduction of 0.8%) in preterm pre-eclampsia.Conclusions Lowering blood pressure from early pregnancy may reduce preterm and term pre-eclampsia. This finding requires evaluation in a definitive randomised trial.
Objectives To characterise patterns of use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) and assess the associations between various GLP-1RA treatment scenarios and the risk of major adverse cardiovascular events.Design Target trial emulation.Setting Electronic healthcare databases of US Department of Veterans Affairs, 1 January 2017 to 31 December 2023. Data obtained from domains in the Veterans Affairs Corporate Data Warehouse.Participants Veterans Affairs users with type 2 diabetes who started treatment with GLP-1RAs (n=132 551) or sulfonylureas (n=201 136), followed up for three years. Veterans Affairs users were defined as having at least two visits to Veterans Affairs and having used the Veterans Affairs outpatient pharmacy within a year before receiving treatment with GLP-1RAs or sulfonylureas.Interventions GLP-1RAs or sulfonylureas. In the GLP-1RA arm, treatment status was reassigned every six months, generating 16 prespecified treatment strategies that varied in length of continued use, discontinuation, or interruption.Main outcome measures Three year cumulative incidence of major adverse cardiovascular events (myocardial infarction, stroke, or all cause death).Results The cohort included 132 551 incident users of GLP-1RAs and 201 136 incident users of sulfonylureas (defined as no prescription for GLP-1RAs or sulfonylureas within a year of the first prescription). A duration dependent association was found between the use of GLP-1RAs and the cumulative three year risk of major adverse cardiovascular events. Compared with the sulfonylurea reference group, participants who used GLP-1RAs for 0.5, 1, or 1.5 years, before discontinuing for the remainder of the three years, showed incidence risk ratios close to 1.0, with no significant reduction in the risk of major adverse cardiovascular events at three years. Compared with the sulfonylurea group, the reduction in the risk of major adverse cardiovascular events was significant in people who continued to use GLP-1RAs for 2 and 2.5 years, before discontinuing for the remainder of the three years (incidence risk ratio 0.93, 95% confidence interval (CI) 0.88 to 0.98 and 0.85, 0.81 to 0.90, respectively). Participants who continued to use GLP-1RAs for the whole three year follow-up period had the most pronounced risk reduction (incidence risk ratio 0.82, 95% CI 0.78 to 0.85) compared with the sulfonylurea group. Compared with continued use of GLP-1RA, discontinuing treatment for 0.5 years was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio 1.04, 95% CI 1.01 to 1.08); the risk increased progressively with a longer duration of discontinuation, with an incidence risk ratio of 1.14 (1.09 to 1.18) and 1.22 (1.16 to 1.27) for one and two years of discontinuation, respectively. Compared with continued use of GLP-1RA, 0.5 years of interruption was associated with an increased risk of major adverse cardiovascular events; longer durations of interruption were progressively associated with a higher risk of major adverse cardiovascular events, with an incidence risk ratio of 1.12 (95% CI 1.06 to 1.19) and 1.16 (1.11 to 1.22) for one and two years of interrupted use, respectively.Conclusions The cardiovascular benefit of GLP-1RAs accumulated with continuous use, but even brief periods of discontinuations or interruptions might progressively erode and could ultimately reverse this protection, increasing the risk of cardiovascular events.
