Randomised comparison of intravenous and subcutaneous routes of glucagon-like peptide-1 administration for lowering plasma glucose in hyperglycaemic subjects with type 2 diabetes.

AIM: To perform a direct, double-blind, randomised, crossover comparison of subcutaneous and intravenous glucagon-like peptide-1 (GLP-1) in hyperglycaemic subjects with type 2 diabetes naïve to GLP-1-based therapy. MATERIALS AND METHODS: Ten fasted, hyperglycaemic subjects (1 female, age 63 ± 10 years [mean ± SD], glycated haemoglobin 73.5 ± 22.0 mmol/mol [8.9% ± 2.0%], both mean ± SD) received subcutaneous GLP-1 and intravenous saline, or intravenous GLP-1 and subcutaneous saline. Infusion rates were doubled every 120 min (1.2, 2.4, 4.8 and 9.6 pmol·kg-1·min-1 for subcutaneous, and 0.3, 0.6, 1.2 and 2.4 pmol·kg-1·min-1 for intravenous). Plasma glucose, total and intact GLP-1, insulin, C-peptide, glucagon and gastrointestinal symptoms were evaluated over 8 h. The results are presented as mean ± SEM. RESULTS: Plasma glucose decreased more with intravenous (by ~8.0 mmol/L [144 mg/dL]) than subcutaneous GLP-1 (by ~5.6 mmol/L [100 mg/dL]; p < 0.001). Plasma GLP-1 increased dose-dependently, but more with intravenous than subcutaneous for both total (∆max 154.2 ± 3.9 pmol/L vs. 85.1 ± 3.8 pmol/L; p < 0.001), and intact GLP-1 (∆max 44.2 ± 2.2 pmol/L vs. 12.8 ± 2.2 pmol/L; p < 0.001). Total and intact GLP-1 clearance was higher for subcutaneous than intravenous GLP-1 (p < 0.001 and p = 0.002, respectively). The increase in insulin secretion was greater, and glucagon was suppressed more with intravenous GLP-1 (p < 0.05 each). Gastrointestinal symptoms did not differ (p > 0.05 each). CONCLUSIONS: Subcutaneous GLP-1 administration is much less efficient than intravenous GLP-1 in lowering fasting plasma glucose, with less stimulation of insulin and suppression of glucagon, and much less bioavailability, even at fourfold higher infusion rates.

Efficacy and safety of intraoperative controlled hypotension: a systematic review and meta-analysis of randomised trials.

BACKGROUND: Intraoperative controlled hypotension improves surgical field visibility by reducing blood loss (efficacy) but poses potential risks linked to organ hypoperfusion (safety). The use of controlled hypotension persists despite increasing evidence of associations between intraoperative inadvertent hypotension and adverse outcomes. Therefore, we tested the hypothesis that the focus and results of intraoperative controlled hypertension research differ across anaesthesia and surgery investigators because of differing priorities. METHODS: We systematically reviewed randomised trials comparing controlled hypotension with usual care with trials categorised by investigators' affiliation. RESULTS: We identified 48 eligible trials, of which 37 were conducted by anaesthesia investigators and 11 by surgery investigators. For the primary outcome, 54% of the anaesthesia-led trials focused on safety, whereas all (100%) surgery-led trials focused on efficacy (P=0.004). Compared with usual care, mean arterial pressure in controlled hypotension was 23% (95% confidence interval [CI] 17-29%) lower in anaesthesia trials and 30% (95% CI 14-37%) lower in surgery trials; estimated blood loss was 44% (95% CI 30-55%) less in anaesthesia trials and 38% (95% CI 30-49%) less in surgery trials. Overall, blood loss was reduced by 43% (95% CI 32-53%), and trial sequential analysis supported an efficacy conclusion. Mean arterial pressure and estimated blood loss reductions were associated (R2=0.41, P=0.002). All trials were underpowered for safety outcomes, and none adequately evaluated myocardial or renal injury. CONCLUSIONS: Anaesthesia researchers prioritised safety outcomes, whereas surgery researchers emphasised efficacy in controlled hypotension trials. Controlled hypotension significantly reduces blood loss. In contrast, safety outcomes were poorly studied. Given increasing observational evidence linking inadvertent hypotension to myocardial and renal injury, the safety of controlled hypotension remains to be addressed. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023450397).

Comparing the effectiveness, safety and tolerability of interventions for depressive symptoms in people with multiple sclerosis: A systematic review.

BACKGROUND: Depression is more common in people with multiple sclerosis (MS) compared to the general population. While many interventions are available for treating depressive symptoms in people with MS, it is unclear how different intervention modalities compare. This systematic review aimed to compare the reported effectiveness, safety, and tolerability of interventions for treating depressive symptoms in people with MS. METHODS: We systematically searched 7 databases for randomised controlled trials (RCTs) of pharmaceutical, psychological, physical, and electromagnetic stimulation interventions which aimed to reduce depressive symptoms amongst adults with MS. Screening, data extraction and risk of bias assessment were completed by at least two independent researchers. We planned to synthesise the data using network meta-analysis, however the high risk of bias of the included trials resulted in synthesis without meta-analysis. RESULTS: Of 1,949 citations, 31 trials (21 psychological, seven physical activity, two pharmaceutical, and one combination) were included, comprising 2,289 participants. Of the 31 eligible trials 24 were at high and six at moderate risk of bias, which precluded meta-analysis. Twenty-six trials reported on efficacy and only 16/31 reported safety and/or tolerability, using inconsistent methods. CONCLUSIONS: The current strength of the evidence for treating depressive symptoms in MS is low, therefore, we are not able to summarise or make comparisons between the treatment modalities. There is an urgent need for high-quality and diverse trials investigating treatment options for depression in people with MS. This can only be achieved if the conduct and reporting of RCTs are improved.

Key results from observational studies and real-world evidence of sodium-glucose cotransporter-2 inhibitor effectiveness and safety in reducing cardio-renal risk.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio-renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio-renal diseases and SGLT2 inhibitors has been explored through landmark trials and real-world evidence (RWE) studies, demonstrating significant reductions in cardio-renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real-world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio-renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower-limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio-renal protective effects in real-world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long-term effects and safety profiles.

LLIN Evaluation in Uganda Project (LLINEUP)-effects of a vector control trial on Plasmodium infection prevalence and genotypic markers of insecticide resistance in Anopheles vectors from 48 districts of Uganda.

Pyrethroid bednets treated with the synergist piperonyl butoxide (PBO) offer the possibility of improved vector control in mosquito populations with metabolic resistance. In 2017-2019, we conducted a large-scale, cluster-randomised trial (LLINEUP) to evaluate long-lasting insecticidal nets (LLINs) treated with a pyrethroid insecticide plus PBO (PBO LLINs), as compared to conventional, pyrethroid-only LLINs across 104 health sub-districts (HSDs) in Uganda. In LLINEUP, and similar trials in Tanzania, PBO LLINs were found to provide greater protection against malaria than conventional LLINs, reducing parasitaemia and vector density. In the LLINEUP trial, we conducted cross-sectional household entomological surveys at baseline and then every 6 months for two years, which we use here to investigate longitudinal changes in mosquito infection rate and genetic markers of resistance. Overall, 5395 female Anopheles mosquitoes were collected from 5046 households. The proportion of mosquitoes infected (PCR-positive) with Plasmodium falciparum did not change significantly over time, while infection with non-falciparum malaria decreased in An. gambiae s.s., but not An. funestus. The frequency of genetic markers associated with pyrethroid resistance increased significantly over time, but the rate of change was not different between the two LLIN types. The knock-down resistance (kdr) mutation Vgsc-995S declined over time as Vgsc-995F, the alternative resistance mutation at this codon, increased. Vgsc-995F appears to be spreading into Uganda. Distribution of LLINs in Uganda was previously found to be associated with reductions in parasite prevalence and vector density, but here we show that the proportion of infective mosquitoes remained stable across both PBO and non-PBO LLINs, suggesting that the potential for transmission persisted. The increased frequency of markers of pyrethroid resistance indicates that LLIN distribution favoured the evolution of resistance within local vectors and highlights the potential benefits of resistance management strategies.Trial registration: This study is registered with ISRCTN, ISRCTN17516395. Registered 14 February 2017, http://www.isrctn.com/ISRCTN17516395 .

Minimisation of dialysis risk in hospital patients with chronic kidney disease (MinDial): study protocol for a multicentre, stepped-wedge, cluster-randomised controlled trial.

BACKGROUND: Early identification of patients with chronic kidney disease (CKD) and advancing kidney insufficiency, followed by specialist care, can decelerate the progression of the disease. However, awareness of the importance and possible consequences of kidney insufficiency is low among doctors and patients. Since kidney insufficiency can be asymptomatic even in higher stages, it is often not even known to those belonging to risk groups. This study aims to clarify whether, for hospitalised patients with advanced chronic kidney disease, a risk-based appointment with a nephrology specialist reduces disease progression. METHODS: The target population of the study is hospitalised CKD patients with an increased risk of end-stage renal disease (ESRD), more specifically with an ESRD risk of at least 9% in the next 5 years. This risk is estimated by the internationally validated Kidney Failure Risk Equation (KFRE). The intervention consists of a specific appointment with a nephrology specialist after the hospital stay, while control patients are discharged from the hospital as usual. Eight medical centres include participants according to a stepped-wedge design, with randomised sequential centre-wise crossover from recruiting patients into the control group to recruitment to the intervention. The estimated glomerular filtration rate (eGFR) is measured for each patient during the hospital stay and after 12 months within the regular care by the general practitioner. The difference in the change of the eGFR over this period is compared between the intervention and control groups and considered the primary endpoint. DISCUSSION: This study is designed to evaluate the effect of risk-based appointments with nephrology specialists for hospitalised CKD patients with an increased risk of end-stage renal disease. If the intervention is proven to be beneficial, it may be implemented in routine care. Limitations will be examined and discussed. The evaluation will include further endpoints such as non-guideline-compliant medication, economic considerations and interviews with contributing physicians to assess the acceptance and feasibility of the intervention. TRIAL REGISTRATION: German Clinical Trials Register DRKS00029691 . Registered on 12 September 2022.

Early specialised treatment for bipolar disorder: Long-term follow-up from the early intervention in affective disorders (EIA) randomised controlled trial.

BACKGROUND: It is unclear whether treatment early after onset in bipolar disorder may improve the long-term illness course. The early intervention in affective disorders (EIA) randomised controlled trial found that 2-years treatment in a specialised mood disorder clinic combining evidence-based pharmacological treatment with group psychoeducation improved clinical outcomes compared with standard treatment in patients with bipolar disorder discharged after their 1st, 2nd, or 3rd hospital admission. We aimed to assess the 16 years long-term outcomes after randomisation of the participants in the EIA trial. METHODS: Data were obtained by linking nation-wide Danish population-based registers. All 158 participants of the EIA trial (Trial Registration Number NCT00253071) were followed from time of randomisation (2005-2009) to end of study (31 December 2021). The primary outcome was risk of psychiatric readmission. Secondary outcomes were total admissions and costs, medication use, intentional self-harm or suicide attempt or suicide, and socio-economic measures. RESULTS: The absolute mean risk of psychiatric readmission was 49.3% in the intervention group and 59.8% in the control group, with no statistically significant difference between the groups (b = -0.10, 95% CI: -0.26 to 0.047, p = 0.18). Compared with the control group, patients in the intervention group had numerically fewer total admission days (mean (SD) 44 (77) versus 62 (109)), lower total cost of psychiatric hospital admissions and hospital-based outpatient visits (mean (SD) 22,001 (36793) euros versus 29,822 (52671) euros) and higher use of lithium and antipsychotics, but the differences were not statistically significant. Fewer patients in the intervention group had an event of intentional self-harm or suicide attempt or suicide during follow-up (OR 0.25, 95% CI: 0.15-0.40, p < 0.001) compared with the control group and more patients in the intervention group used antiepileptics (OR 2.21, 95% CI: 1.08-4.60, p = 0.031). CONCLUSION: Analyses of very long-term outcomes of the EIA trial may potentially indicate a beneficial effect of the intervention at the long term but were likely underpowered to detect a more subtle effect and for most outcomes the differences between groups were not statistically significant.

Randomized Trial of Postoperative Radiation Therapy After Wide Excision of Neurotropic Melanoma of the Head and Neck (RTN2 Trial 01.09).

BACKGROUND: Cutaneous neurotropic melanoma (NM) of the head and neck (H&N) is prone to local relapse, possibly due to difficulties widely excising the tumor. This trial assessed radiation therapy (RT) to the primary site after local excision. METHODS: Participants from 15 international centers were randomized to observation or RT. The participants were required to have microscopically negative excision margins 5 mm wide or wider and no evidence of disease elsewhere. The primary outcome was time to local relapse. The secondary outcomes included time to any recurrence, overall survival (OS), and toxicity. RESULTS: The trial ceased prematurely due to slow recruitment and the COVID-19 pandemic. During 2009-2020, 50 participants were randomized: 23 to observation and 27 to RT. The most common NM subsites were scalp (32%), midface (22%), and lip (20%). The median depth of invasion was 5 mm, and desmoplasia observed in 69%. The median duration from randomization to last contact was 4.8 years. Four participants (8%) experienced local relapse as a first recurrence during the study period: 3 in the observation arm and 1 in the RT arm (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.03-2.76; p = 0.279). No statistically significant difference in time to any relapse or OS was observed. More than 6 months after randomization, grade 3 or greater toxicity was experienced by 10% of the participants in the observation arm and 12.5% of the participants in the RT arm of the study. CONCLUSION: Due to low accrual, the role of adjuvant RT for cutaneous NM of the H&N excised with microscopically negative margins 5 mm wide or wider remains undefined. Its routine use cannot be recommended. Local relapse might be less common than previously anticipated based on retrospective reports.

Oral misoprostol alone, compared with oral misoprostol followed by oxytocin, in women induced for hypertension of pregnancy: A multicentre randomised trial.

OBJECTIVE: To assess whether, in those requiring continuing uterine stimulation after cervical ripening with oral misoprostol and membrane rupture, augmentation with low-dose oral misoprostol is superior to intravenous oxytocin. DESIGN: Open-label, superiority randomised trial. SETTING: Government hospitals in India. POPULATION: Women who were induced for hypertensive disease in pregnancy and had undergone cervical ripening with oral misoprostol, but required continuing stimulation after artificial membrane rupture. METHODS: Participants received misoprostol (25 micrograms, orally, 2-hourly) or titrated oxytocin through an infusion pump. All women had one-to-one care; fetal monitoring was conducted using a mixture of intermittent and continuous electronic fetal monitoring. MAIN OUTCOME MEASURES: Caesarean birth. RESULTS: A total of 520 women were randomised and the baseline characteristics were comparable between the groups. The caesarean section rate was not reduced with the use of misoprostol (misoprostol, 84/260, 32.3%, vs oxytocin, 71/260, 27.3%; aOR 1.23; 95% CI 0.81-1.85; P = 0.33). The interval from randomisation to birth was somewhat longer with misoprostol (225 min, 207-244 min, vs 194 min, 179-210 min; aOR 1.137; 95% CI 1.023-1.264; P = 0.017). There were no cases of hyperstimulation in either arm. The rates of fetal heart rate abnormalities and maternal side effects were similar. Fewer babies in the misoprostol arm were admitted to the special care unit (10 vs 21 in the oxytocin group; aOR 0.463; 95% CI 0.203-1.058; P = 0.068) and there were no neonatal deaths in the misoprostol group, compared with three neonatal deaths in the oxytocin arm. Women's acceptability ratings were high in both study groups. CONCLUSIONS: Following cervical preparation with oral misoprostol and membrane rupture, the use of continuing oral misoprostol for augmentation did not significantly reduce caesarean rates, compared with the use of oxytocin. There were no hyperstimulation or significant adverse events in either arm of the trial.

Evaluation of lived experience Peer Support intervention for mental health service consumers in Primary Care (PS-PC): study protocol for a stepped-wedge cluster randomised controlled trial.

BACKGROUND: The demand for mental health services in Australia is substantial and has grown beyond the capacity of the current workforce. As a result, it is currently difficult for many to access secondary healthcare providers. Within the secondary healthcare sector, however, peer workers who have lived experience of managing mental health conditions have been increasingly employed to intentionally use their journey of recovery in supporting others living with mental health conditions and their communities. Currently, the presence of peer workers in primary care has been limited, despite the potential benefits of providing supports in conjunction with GPs and secondary healthcare providers. METHODS: This stepped-wedge cluster randomised controlled trial (RCT) aims to evaluate a lived experience peer support intervention for accessing mental health care in primary care (PS-PC). Four medical practices across Australia will be randomly allocated to switch from control to intervention, until all practices are delivering the PS-PC intervention. The study will enrol 66 patients at each practice (total sample size of 264). Over a period of 3-4 months, 12 h of practical and emotional support provided by lived experience peer workers will be available to participants. Scale-based questionnaires will inform intervention efficacy in terms of mental health outcomes (e.g., self-efficacy) and other health outcomes (e.g., healthcare-related costs) over four time points. Other perspectives will be explored through scales completed by approximately 150 family members or carers (carer burden) and 16 peer workers (self-efficacy) pre- and post-intervention, and 20 medical practice staff members (attitudes toward peer workers) at the end of each study site's involvement in the intervention. Interviews (n = 60) and six focus groups held toward the end of each study site's involvement will further explore the views of participants, family members or carers, peer workers, and practice staff to better understand the efficacy and acceptability of the intervention. DISCUSSION: This mixed-methods, multi-centre, stepped-wedge controlled study will be the first to evaluate the implementation of peer workers in the primary care mental health care sector. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12623001189617. Registered on 17 November 2023, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=386715.

Demystifying estimands in cluster-randomised trials.

Estimands can help clarify the interpretation of treatment effects and ensure that estimators are aligned with the study's objectives. Cluster-randomised trials require additional attributes to be defined within the estimand compared to individually randomised trials, including whether treatment effects are marginal or cluster-specific, and whether they are participant- or cluster-average. In this paper, we provide formal definitions of estimands encompassing both these attributes using potential outcomes notation and describe differences between them. We then provide an overview of estimators for each estimand, describe their assumptions, and show consistency (i.e. asymptotically unbiased estimation) for a series of analyses based on cluster-level summaries. Then, through a re-analysis of a published cluster-randomised trial, we demonstrate that the choice of both estimand and estimator can affect interpretation. For instance, the estimated odds ratio ranged from 1.38 (p = 0.17) to 1.83 (p = 0.03) depending on the target estimand, and for some estimands, the choice of estimator affected the conclusions by leading to smaller treatment effect estimates. We conclude that careful specification of the estimand, along with an appropriate choice of estimator, is essential to ensuring that cluster-randomised trials address the right question.

Equivalent immunogenicity across three RSVpreF vaccine lots in healthy adults 18-49 years of age: Results of a randomized phase 3 study.

BACKGROUND: Bivalent RSV prefusion F subunit vaccine (RSVpreF), comprised of equal quantities of stabilized prefusion F antigens from the major circulating subgroups (RSV A, RSV B), is licensed for prevention of RSV-associated lower respiratory tract illness (LRTI) in older adults and for maternal vaccination for prevention of RSV-associated LRTI in infants. To support licensure and large-scale manufacturing, this lot consistency study was conducted to demonstrate equivalence in immunogenicity across 3 RSVpreF lots. METHODS: This phase 3, multicenter, parallel-group, placebo-controlled, randomized (1:1:1:1), double-blind study evaluated immunogenicity, safety, and tolerability of RSVpreF in healthy 18-49-year-old adults. Participants received a single 120-µg injection of 1 of 3RSVpreF lots or placebo. Geometric mean ratio (GMR) of RSV serum 50 % neutralizing geometric mean titers obtained 1 month after vaccination were compared between each vaccine lot for RSV A and RSV B, separately. Equivalence between lots was defined using a 1.5-fold criterion (GMR 95 % CIs for every lot pair within the 0.667-1.5 interval). Safety and tolerability were assessed. RESULTS: Of 992participants vaccinated, 948 were included in the evaluable immunogenicity population. All 3 RSVpreF lots elicited strong immune responses, meeting the 1.5-fold equivalence criterion for all between-lot comparisons for both RSV A and RSV B. Across the 3 lots, RSV A and RSV B 50 % neutralizing geometric mean titers substantially increased from baseline (RSV A, 1671-1795; RSV B 1358-1429) to 1 month after RSVpreF vaccination (RSV A, 24,131-25,238; RSV B, 19,238-21,702), corresponding to ≥14-fold increases in 50 % neutralizing titers for both RSV A and RSV B from before to 1 month after vaccination. Single doses of RSVpreF were safe and well tolerated, with similar safety profiles across the 3 RSVpreF lots. CONCLUSIONS: These findings support the reproducibility of RSVpreF vaccine manufacturing with similar safety and reactogenicity profiles (NCT05096208).

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY.

BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Comparison of sequential and mixture injections of opioids and hyperbaric bupivacaine for subarachnoid block for lower segment caesarean section: a randomised controlled study.

INTRODUCTION: Opioids are commonly added to local anaesthetic for subarachnoid block for caesarean section due to their synergistic effects. The physiochemical characteristics of opioids suggest premixing with hyperbaric bupivacaine may limit their distribution within the CSF. We studied the effect of a separate injection with a combination of bupivacaine, morphine and fentanyl on block characteristics, haemodynamic changes, postoperative pain and patient satisfaction. METHOD: Following ethical approval and informed consent, a prospective double-blinded randomised controlled trial was performed in a university hospital. A total of 126 patients undergoing caesarean section were randomised to two groups. In group M, the premixed group, patients received 12 mg of hyperbaric bupivacaine, 20 mcg of fentanyl and 100 mcg of morphine injected as a single mixture. In group S, the separate injection group, patients received the same drugs in separate injections. Measurements included haemodynamics, block distribution, intra- and postoperative pain, as well as patient satisfaction. RESULTS: Patients in both groups had similar block height, time to maximum sensory block, time to block regression and motor block. However, haemodynamics were different between the groups. The proportion of systolic hypotension episodes was greater in group S [159/1320 (12.05%)] than group M [113/1452 (7.78%)], with P = 0.0002. Moreover, a greater amount of ephedrine was administered in group S than group M, with values 12.09 (8.1) and 9.09 (8.5) mg respectively (P = 0.001). Additionally, postoperative pain, as measured by the Visual Analogue Scale (VAS), was greater in group M, with a VAS of 4.6 (1.7), vs. group S, which recorded a VAS of 3.8 (2.0) (P = 0.017). CONCLUSION: Sequential injection of intrathecal opioids and hyperbaric bupivacaine resulted in greater early haemodynamic instability and slightly better postoperative analgesia without any difference in block height or patient satisfaction. CLINICAL TRIAL REGISTRATION: NCT04403724.

Categorisation of continuous covariates for stratified randomisation: How should we adjust?

To obtain valid inference following stratified randomisation, treatment effects should be estimated with adjustment for stratification variables. Stratification sometimes requires categorisation of a continuous prognostic variable (eg, age), which raises the question: should adjustment be based on randomisation categories or underlying continuous values? In practice, adjustment for randomisation categories is more common. We reviewed trials published in general medical journals and found none of the 32 trials that stratified randomisation based on a continuous variable adjusted for continuous values in the primary analysis. Using data simulation, this article evaluates the performance of different adjustment strategies for continuous and binary outcomes where the covariate-outcome relationship (via the link function) was either linear or non-linear. Given the utility of covariate adjustment for addressing missing data, we also considered settings with complete or missing outcome data. Analysis methods included linear or logistic regression with no adjustment for the stratification variable, adjustment for randomisation categories, or adjustment for continuous values assuming a linear covariate-outcome relationship or allowing for non-linearity using fractional polynomials or restricted cubic splines. Unadjusted analysis performed poorly throughout. Adjustment approaches that misspecified the underlying covariate-outcome relationship were less powerful and, alarmingly, biased in settings where the stratification variable predicted missing outcome data. Adjustment for randomisation categories tends to involve the highest degree of misspecification, and so should be avoided in practice. To guard against misspecification, we recommend use of flexible approaches such as fractional polynomials and restricted cubic splines when adjusting for continuous stratification variables in randomised trials.

A Randomised Phase II Trial to Evaluate the Feasibility of Radiotherapy Dose Escalation, Facilitated by Intensity-Modulated Arc Radiotherapy Techniques, in High-Risk Neuroblastoma.

BACKGROUND AND PURPOSE: For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. MATERIALS AND METHODS: Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. RESULTS: Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0-36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7-35.9 Gy). CONCLUSION: IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial.

Prostatic Artery Embolisation Versus Transurethral Resection of the Prostate for Benign Prostatic Obstruction: 5-year Outcomes of a Randomised, Open-label, Noninferiority Trial.

BACKGROUND AND OBJECTIVE: Prostatic artery embolisation (PAE) and transurethral resection of the prostate (TURP) are two of the surgical options for treatment of lower urinary tract symptoms/benign prostatic obstruction (LUTS/BPO). Our aim was to compare the efficacy and safety of PAE and TURP for LUTS/BPO treatment at long-term follow-up. METHODS: We conducted a randomised, open-label, single-centre trial at a Swiss tertiary care centre. The main outcome was the change in International Prostate Symptom Score (IPSS) after PAE versus TURP. Secondary outcomes included patient-reported outcomes, functional measures, and adverse events assessed at baseline and at 3, 6, 12, 24, and 60 mo. Between-group differences in the change from baseline to 5 yr were tested using two-sided Mann-Whitney and t tests. KEY FINDINGS AND LIMITATIONS: Of the 103 patients with refractory LUTS/BPO who were randomised between 2014 and 2017, 18/48 who underwent PAE and 38/51 who underwent TURP reached the 60-mo follow-up visit. The mean reduction in IPSS from baseline to 5 yr was -7.78 points after PAE and -11.57 points after TURP (difference 3.79 points, 95% confidence interval [CI] -0.66 to 8.24; p = 0.092). TURP was superior for most patient-reported secondary outcomes except for erectile function. At 5 yr, PAE was less effective than TURP regarding objective parameters, such as the improvement in maximum urinary flow rate (3.59 vs 9.30 ml/s, difference -5.71, 95% CI -10.72 to -0.70; p = 0. 027) and reduction in postvoid residual volume (27.81 vs 219.97 ml; difference 192.15, 95% CI 83.79-300.51; p = 0.001). CONCLUSIONS AND CLINICAL IMPLICATIONS: The improvement in LUTS/BPO at 5 yr after PAE was inferior to that achieved with TURP. The limitations of PAE should be considered during patient selection and counselling. PATIENT SUMMARY: In this study, we show the long-term results of prostate artery embolisation (PAE) in comparison to transurethral resection of the prostate (TURP) for the treatment of benign prostate enlargement causing urinary symptoms. PAE shows good long-term results in properly selected patients, although the improvements are less pronounced than with TURP. This trial is registered on ClinicalTrials.gov as NCT02054013.

Implementing Enhanced Recovery After Surgery for hysterectomy in a hospital network with audit and feedback: A stepped-wedge cluster randomised trial.

OBJECTIVE: To evaluate the effectiveness of implementing the Enhanced Recovery After Surgery (ERAS) protocol in patients undergoing elective hysterectomy in a network of regional hospitals, supported by an intensive audit-and-feedback (A&F) approach. DESIGN: A multi-centre, stepped-wedge cluster randomised trial (ClinicalTrials.gov NCT04063072). SETTING: Gynaecological units in the Piemonte region, Italy. POPULATION: Patients undergoing elective hysterectomy, either for cancer or for benign conditions. METHODS: Twenty-three units (clusters), stratified by surgical volume, were randomised into four sequences. At baseline (first 3 months), standard care was continued in all units. Subsequently, the four sequences implemented the ERAS protocol successively every 3 months, after specific training. By the end of the study, each unit had a period in which standard care was maintained (control) and a period in which the protocol, supported by feedback, was applied (experimental). MAIN OUTCOME MEASURES: Length of hospital stay (LOS), without outliers (>98th percentile). RESULTS: Between September 2019 and May 2021, 2086 patients were included in the main analysis with an intention-to-treat approach: 1104 (53%) in the control period and 982 (47%) in the ERAS period. Compliance with the ERAS protocol increased from 60% in the control period to 76% in the experimental period, with an adjusted absolute difference of +13.3% (95% CI 11.6% to 15.0%). LOS, moving from 3.5 to 3.2 days, did not show a significant reduction (-0.12 days; 95% CI -0.30 to 0.07 days). No difference was observed in the occurrence of complications. CONCLUSIONS: Implementation of the ERAS protocol for hysterectomy at the regional level, supported by an A&F approach, resulted in a substantial improvement in compliance, but without meaningful effects on LOS and complications. This study confirms the effectiveness of A&F in promoting important innovations in an entire hospital network and suggests the need of a higher compliance with the ERAS protocol to obtain valuable improvements in clinical outcomes.

A web-enabled, school-based intervention for bullying prevention (LINKlusive): a cluster randomised trial.

Background: There is a need for more sustainable interventions and for assessing the effectiveness of school-based universal anti-bullying programmes in vulnerable populations. We assessed the efficacy of a multicomponent, web-enabled, school-based intervention that aims to improve school climate and reduce bullying (LINKlusive) relative to conventional practices (control condition). Methods: We conducted a cluster randomised controlled trial in primary and secondary schools in Madrid, Spain. The primary outcome measure was peer-reported bullying victimisation after the 12-week intervention (study endpoint). We analysed data using longitudinal mixed-effects models. The trial was registered with the ISRCTN registry (15719015). Findings: We included 20 schools (10 in each group); 6542 students participated at baseline; 6403 were assessed at study endpoint. After the intervention, there was a statistically significant reduction in bullying victimisation in both the intervention (OR 0.61, 95% CI [0.41, 0.90]) and control groups (OR 0.69, 95% CI [0.51, 0.92]), with no evidence of differences in the whole sample (OR 0.89, 95% CI [0.58, 1.36]; aOR 0.89, 95% CI [0.58, 1.37]). Subgroup analyses showed a statistically significant effect of LINKlusive on bullying victimisation in primary education (aOR 0.68, 95% CI [0.47, 0.98]). In students with peer-reported bullying victimisation at baseline, LINKlusive showed a statistically significant effect on depression (-1.43, 95% CI [-2.46, -0.40], adjusted standardised mean difference (SMD) -0.41) and quality of life (2.18, 95% CI [0.80, 3.56], adjusted SMD 0.45). Interpretation: LINKlusive could be effective in reducing bullying victimisation in primary school students. Sustainable whole-school interventions to promote mental health and reduce risk factors are warranted to improve outcomes in young people, especially in the early years of education. Funding: Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation.

Design, recruitment and baseline characteristics of the LENS trial.

BACKGROUND: Findings from cardiovascular outcome trials suggest that treatment with fenofibrate may reduce the progression of diabetic retinopathy. However, no dedicated large-scale randomised trials have yet investigated this hypothesis. METHODS: LENS is a streamlined randomised double-masked placebo-controlled trial, based in Scotland, assessing whether treatment with fenofibrate (145 mg tablet daily or, in the context of impaired renal function, on alternate days) in people with early retinopathy reduces progression to referable diabetic retinopathy (defined in NHS Scotland's Diabetic Eye Screening grading scheme as referable background or proliferative retinopathy, or referable maculopathy in either eye) or treatment with retinal laser, intravitreal injections or vitrectomy. Adults with diabetes mellitus and non-referable retinopathy (mild background retinopathy in both eyes or observable background retinopathy in one/both eyes at the most recent NHS retinal screening assessment; or observable maculopathy in one/both eyes in the previous 3 years) were eligible. Potential participants were identified from routinely collected healthcare data and followed up using regular contact from the research team and linkage to national electronic morbidity, mortality, biochemistry and retinal screening records. Study treatment was mailed to participants. RESULTS: Between 18 September 2018 and 27 July 2021, 1151 participants were randomised. Their mean age was 61 (SD 12) years, 312 (27%) were female and 305 (26%) had type 1 diabetes. 96% had bilateral mild background retinopathy and 10% had observable maculopathy. CONCLUSIONS: LENS will provide a robust evaluation of the efficacy of treating people at risk of progression of diabetic retinopathy with fenofibrate. Results are anticipated in mid-2024. TRIAL REGISTRATIONS: NCT03439345; ISRCTN15073006; EuDRACT 2016-002656-24.