Household Air Pollution Interventions to Improve Health in Low- and Middle-Income Countries: An Official American Thoracic Society Research Statement.

Background: An estimated 3 billion people, largely in low- and middle-income countries, rely on unclean fuels for cooking, heating, and lighting to meet household energy needs. The resulting exposure to household air pollution (HAP) is a leading cause of pneumonia, chronic lung disease, and other adverse health effects. In the last decade, randomized controlled trials of clean cooking interventions to reduce HAP have been conducted. We aim to provide guidance on how to interpret the findings of these trials and how they should inform policy makers and practitioners.Methods: We assembled a multidisciplinary working group of international researchers, public health practitioners, and policymakers with expertise in household air pollution from within academia, the American Thoracic Society, funders, nongovernmental organizations, and global organizations, including the World Bank and the World Health Organization. We performed a literature search, convened four sessions via web conference, and developed consensus conclusions and recommendations via the Delphi method.Results: The committee reached consensus on 14 conclusions and recommendations. Although some trials using cleaner-burning biomass stoves or cleaner-cooking fuels have reduced HAP exposure, the committee was divided (with 55% saying no and 45% saying yes) on whether the studied interventions improved measured health outcomes.Conclusions: HAP is associated with adverse health effects in observational studies. However, it remains unclear which household energy interventions reduce exposure, improve health, can be scaled, and are sustainable. Researchers should engage with policy makers and practitioners working to scale cleaner energy solutions to understand and address their information needs.

Twenty years of participation of racialised groups in type 2 diabetes randomised clinical trials: a meta-epidemiological review.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus prevalence is increasing globally and the greatest burden is borne by racialised people. However, there are concerns that the enrolment of racialised people into RCTs is limited, resulting in a lack of ethnic and racial diversity. This may differ depending whether an RCT is government funded or industry funded. The aim of this study was to review the proportions of racialised and white participants included in large RCTs of type 2 diabetes pharmacotherapies relative to the disease burden of type 2 diabetes in these groups. METHODS: The Ovid MEDLINE database was searched from 1 January 2000 to 31 December 2020. English language reports of RCTs of type 2 diabetes pharmacotherapies published in select medical journals were included. Studies were included in this review if they had a sample size of at least 100 participants and all participants were adults with type 2 diabetes. Industry-funded trials must have recruited participants from at least two countries. Government-funded trials were not held to the same standard because they are typically conducted in a single country. Data including the numbers and proportions of participants by ethnicity and race were extracted from trial reports. The participation-to-prevalence ratio (PPR) was calculated for each trial by dividing the percentage of white and racialised participants in each trial by the percentage of white and racialised participants with type 2 diabetes, respectively, for the regions of recruitment. A random-effects meta-analysis was used to generate the pooled PPRs and 95% CIs across study types. A PPR <0.80 indicates under-representation and a PPR >1.20 indicates over-representation. Risk of bias assessments were not conducted for this study as the objective was to examine recruitment of racialised and white participants rather than evaluate the trustworthiness of clinical trial outcomes. RESULTS: A total of 83 trials were included, involving 283,122 participants, of which 15 were government-funded and 68 were industry-funded trials. In government-funded trials, the PPR for white participants was 1.11 (95% CI 0.99, 1.24) and the PPR for racialised participants was 0.72 (95% CI 0.60, 0.86). In industry-funded trials, the PPR for white participants was 1.95 (95% CI 1.74, 2.18) and the PPR for racialised participants was 0.36 (95% CI 0.32, 0.42). The limitations of this study include the reliance on investigator-reported ethnicity and race to classify participants as 'white' or 'racialised', the use of estimates for type 2 diabetes prevalence and demographic data, and the high levels of heterogeneity of pooled estimates. However, despite these limitations, the results were consistent with respect to direction. CONCLUSIONS/INTERPRETATION: Racialised participants are under-represented in government- and industry-funded type 2 diabetes trials. Strategies to improve recruitment and enrolment of racialised participants into RCTs should be developed. REGISTRATION: Open Science Framework registration no. f59mk ( https://osf.io/f59mk ) FUNDING: The authors received no financial support for this research or authorship of the article.

Efficacy and Safety of Drugs for Gastroparesis: Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: Although there have been multiple drugs tested in gastroparesis, their relative efficacy and safety are unknown. We evaluated this in a network meta-analysis of randomized controlled trials (RCTs). METHODS: We searched the literature to September 7, 2022. We judged the efficacy of drugs based on global symptoms of gastroparesis; individual symptoms, including nausea, vomiting, abdominal pain, bloating, or fullness; and safety according to total adverse events and adverse events leading to withdrawal. We extracted data as intention-to-treat analyses, assuming dropouts to be treatment failures and reporting pooled relative risks (RRs) of not improving with 95% confidence intervals (CIs), ranking drugs according to P-score. RESULTS: We identified 29 RCTs (3772 patients). Based on global symptoms, clebopride ranked first for efficacy (RR, 0.30; 95% CI, 0.16-0.57; P-score = .99) followed by domperidone (RR, 0.68; 95% CI, 0.48-0.98; P-score = .76). No other drug was superior to placebo. Only 2 drug classes were efficacious: in rank order, oral dopamine antagonists (RR, 0.58; 95% CI, 0.44-0.77; P-score = .96) and tachykinin-1 antagonists (RR, 0.69; 95% CI, 0.52-0.93; P-score = .83). For individual symptoms, oral metoclopramide ranked first for nausea (RR 0.46; 95% CI, 0.21-1.00; P-score = .95), fullness (RR 0.67; 95% CI, 0.35-1.28; P-score = .86), and bloating (RR 0.53; 95% CI, 0.30-0.93; P-score = .97), based on only 1 small trial. Only prucalopride was more likely to be associated with adverse events than placebo. CONCLUSIONS: In a network meta-analysis, oral dopamine antagonists and tachykinin-1 antagonists were more efficacious than placebo for gastroparesis, but confidence in the evidence was low to moderate for most comparisons. There is an unmet need for efficacious therapies for gastroparesis.

Systematic Review and Meta-analysis: Efficacy of Mesalamine in Irritable Bowel Syndrome.

BACKGROUND & AIMS: Some patients with irritable bowel syndrome (IBS) demonstrate low-grade inflammation in the intestine. Mesalamine, which has anti-inflammatory effects, may be an efficacious treatment for IBS, but studies are conflicting. We conducted a systematic review and meta-analysis to assess efficacy and safety of mesalamine in IBS. METHODS: We searched the medical literature up to September 14, 2022, to identify randomized controlled trials (RCTs) of mesalamine in IBS. We judged efficacy and safety using dichotomous assessments of effect on global IBS symptoms, abdominal pain, bowel habit or stool frequency, and occurrence of any adverse event. We pooled data using a random effects model, with efficacy and safety reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 8 eligible RCTs (820 patients). Mesalamine was more efficacious than placebo for global IBS symptoms (RR of global symptoms not improving, 0.86; 95% CI, 0.79-0.95; number needed to treat = 10; 95% CI, 6-27), but not for abdominal pain or bowel habit or stool frequency. Subgroup analyses demonstrated efficacy of mesalamine in IBS with diarrhea for global IBS symptoms (RR, 0.88; 95% CI, 0.79-0.99), but not patients with other predominant bowel habits or those with post-infection IBS. Adverse event rates were no higher with mesalamine (RR, 1.20; 95% CI, 0.89-1.63) but were reported in only 5 trials. CONCLUSIONS: Mesalamine may be modestly efficacious for global symptoms in IBS, particularly IBS with diarrhea, but quality of evidence was low. Adequately powered high quality RCTs of mesalamine in IBS are needed.

The Efficacy of Tradipitant in Patients With Diabetic and Idiopathic Gastroparesis in a Phase 3 Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Neurokinin receptor 1 antagonists are effective in reducing nausea and vomiting in chemotherapy-induced emesis. We investigated the safety and efficacy of tradipitant, a neurokinin receptor 1 antagonist, in patients with idiopathic and diabetic gastroparesis. METHODS: A total of 201 adults with gastroparesis were randomly assigned to oral tradipitant 85 mg (n = 102) or placebo (n = 99) twice daily for 12 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. Blood levels were monitored for an exposure-response analysis. The primary outcome was change from baseline to week 12 in average nausea severity, measured by daily symptom diary. RESULTS: The intention-to-treat (ITT) population did not meet the prespecified primary endpoint at week 12 (difference in nausea severity change drug vs placebo; P = .741) or prespecified secondary endpoints. Post hoc analyses were performed to control for drug exposure, rescue medications, and baseline severity inflation. Subjects with high blood levels of tradipitant significantly improved average nausea severity beginning at early time points (weeks 2-4). In post hoc sensitivity analyses, tradipitant treatment demonstrated strengthened effects, with statistically significant improvements in nausea at week 12. CONCLUSIONS: Although tradipitant did not reach significance in the ITT population, a pharmacokinetic exposure-response analysis demonstrated significant effects with adequate tradipitant exposure. When accounting for confounding factors such as baseline severity inflation and rescue medication, a statistically significant effect was also observed. These findings suggest that tradipitant has potential as a treatment for the symptom of nausea in gastroparesis. (ClincialTrials.gov, Number: NCT04028492).

Healthy Tendon Stem Cell-Derived Exosomes Promote Tendon-To-Bone Healing of Aged Chronic Rotator Cuff Tears by Breaking the Positive-Feedback Cross-Talk between Senescent Tendon Stem Cells and Macrophages through the Modulation of Macrophage Polarization.

The re-tear rate of rotator cuff tears (RCT) after surgical repair is high, especially in aged patients with chronic tears. Senescent tendon stem cells (s-TSCs) generally exist in aged and chronically torn rotator cuff tendons and are closely associated with impaired tendon-to-bone healing results. The present study found a positive feedback cross-talk between s-TSCs and macrophages. The conditioned medium (CM) from s-STCs can promote macrophage polarization mainly toward the M1 phenotype, whose CM reciprocally accelerated further s-TSC senescence. Additional healthy tendon stem-cells derived exosomes (h-TSC-Exos) can break this positive feedback cross-talk by skewing macrophage polarization from the M1 phenotype to the M2 phenotype, attenuating s-TSCs senescence. S-TSC senescence acceleration or attenuation effects induced by M1 or M2 macrophages are associated with the inhibition or activation of the bone morphogenetic protein 4 signaling pathway following RNA sequencing analysis. Using an aged-chronic rotator cuff tear rat model, it is found that h-TSC-Exos can shift the microenvironment in the tendon-to-bone interface from a pro-inflammatory to an anti-inflammatory type at the acute postoperative stage and improve the tendon-to-bone healing results, which are associated with the rejuvenated s-TSCs. Therefore, this study proposed a potential strategy to improve the healing of aged chronic RCT.

The clinical efficacy and safety of berberine in the treatment of non-alcoholic fatty liver disease: a meta-analysis and systematic review.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, emerging as a significant health issue on a global scale. Berberine exhibits potential for treating NAFLD, but clinical evidence remains inconclusive. This meta-analysis was conducted to assess the efficacy and safety of berberine for treating NAFLD. METHODS: This study was registered with PROSPERO (No. CRD42023462338). Identification of randomized controlled trials (RCTs) involved searching 6 databases covering the period from their initiation to 9 September 2023. The primary outcomes comprised liver function markers such as glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), lipid indices including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment for insulin resistance (HOMA-IR) and body mass index (BMI). Review Manager 5.4 and STATA 17.0 were applied for analysis. RESULTS: Among 10 RCTs involving 811 patients, berberine demonstrated significant reductions in various parameters: ALT (standardized mean difference (SMD) = - 0.72), 95% confidence interval (Cl) [- 1.01, - 0.44], P < 0.00001), AST (SMD = - 0.79, 95% CI [- 1.17, - 0.40], P < 0.0001), GGT (SMD = - 0.62, 95% CI [- 0.95, - 0.29], P = 0.0002), TG (SMD = - 0.59, 95% CI [- 0.86, - 0.31], P < 0.0001), TC(SMD = - 0.74, 95% CI [- 1.00, - 0.49], P < 0.00001), LDL-C (SMD = - 0.53, 95% CI [- 0.88, - 0.18], P = 0.003), HDL-C (SMD = - 0.51, 95% CI [- 0.12, 1.15], P = 0.11), HOMA-IR (SMD = - 1.56, 95% CI [- 2.54, - 0.58], P = 0.002), and BMI (SMD = - 0.58, 95% CI [- 0.77, - 0.38], P < 0.00001). Importantly, Berberine exhibited a favorable safety profile, with only mild gastrointestinal adverse events reported. CONCLUSION: This meta-analysis demonstrates berberine's efficacy in improving liver enzymes, lipid profile, and insulin sensitivity in NAFLD patients. These results indicate that berberine shows promise as an adjunct therapy for NAFLD. Trial registration The protocol was registered with PROSPERO (No. CRD42023462338). Registered on September 27, 2023.

Secular Trend in GFR Decline in Non-Dialysis CKD Based on Observational Data From Standard of Care Arms of Trials.

RATIONALE & OBJECTIVE: The standard of care (SoC) group of randomized controlled trials (RCTs) is a useful setting to explore the secular trends in kidney disease progression because implementation of best clinical practices is pursued for all patients enrolled in trials. This meta-analysis evaluated the secular trend in the change of glomerular filtration rate (GFR) decline in the SoC arm of RCTs in chronic kidney disease (CKD) published in the last 30 years. STUDY DESIGN: Systematic review and meta-analysis of the SoC arms of RCTs analyzed as an observational study. SETTING & STUDY POPULATIONS: Adult patients with CKD enrolled in the SoC arm of RCTs. SELECTION CRITERIA FOR STUDIES: Phase 3 RCTs evaluating GFR decline as an outcome in SoC arms. DATA EXTRACTION: Two independent reviewers evaluated RCTs for eligibility and extracted relevant data. ANALYTICAL APPROACH: The mean of GFR declines extracted in the SoC arm of selected RCTs were pooled by using a random effects model. Meta-regression analyses were performed to identify factors that may explain heterogeneity. RESULTS: The SoC arms from 92 RCTs were included in the meta-analysis with a total of 32,202 patients. The overall mean GFR decline was-4.00 (95% CI, -4.55 to-3.44) mL/min/1.73m2 per year in the SoC arms with a high level of heterogeneity (I2, 98.4% [95% CI, 98.2-98.5], P<0.001). Meta-regression analysis showed an association between publication year (ß estimate, 0.09 [95% CI, 0.032-0.148], P=0.003) and reduction in GFR over time. When evaluating publication decade categorically, GFR decline was-5.44 (95% CI, -7.15 to-3.73), -3.92 (95% CI, -4.82 to-3.02), and -3.20 (95% CI, -3.75 to -2.64) mL/min/1.73m2 per year during 1991-2000, 2001-2010, and 2011-2023, respectively. Using meta-regression, the heterogeneity of GFR decline was mainly explained by age and proteinuria. LIMITATIONS: Different methods assessing GFR in selected trials and observational design of the study. CONCLUSIONS: In the last 3 decades, GFR decline has decreased over time in patients enrolled in RCTs who received the standard of care. TRIAL REGISTRATION: Registered at PROSPERO with record number CRD42022357704. PLAIN-LANGUAGE SUMMARY: This study evaluated the secular trend in the change in glomerular filtration rate (GFR) decline in the placebo arms of randomized controlled trials (RCTs) that were studying approaches to protect the kidneys in the setting of chronic kidney disease. The placebo groups of RCTs are useful for examining whether the rate of progression of kidney disease has changed over time. We found an improvement in the slope of change in GFR over time. These findings suggest that adherence to standards of kidney care as implemented in clinical trials may be associated with improved clinical outcomes, and these data may inform the design of future RCTs in nephrology.

Assessing the robustness of positive vascular surgery randomized controlled trials using their fragility index.

OBJECTIVE: The fragility index (FI) measures the robustness of statistically significant findings in randomized controlled trials (RCTs) by quantifying the minimum number of event conversions required to reverse a dichotomous outcome's statistical significance. In vascular surgery, many clinical guidelines and critical decision-making points are informed by a handful of key RCTs, especially regarding open surgical versus endovascular treatment. The objective of this study is to evaluate the FI of RCTs with statistically significant primary outcomes that compared open vs endovascular surgery in vascular surgery. METHODS: In this meta-epidemiological study and systematic review, MEDLINE, Embase, and CENTRAL were searched for RCTs comparing open versus endovascular treatments for abdominal aortic aneurysms, carotid artery stenosis, and peripheral arterial disease to December 2022. RCTs with statistically significant primary outcomes were included. Data screening and extraction were conducted in duplicate. The FI was calculated by adding an event to the group with the smaller number of events while subtracting a nonevent to the same group until Fisher's exact test produced a nonstatistically significant result. The primary outcome was the FI and proportion of outcomes where the loss to follow-up was greater than the FI. The secondary outcomes assessed the relationship of the FI to disease state, presence of commercial funding, and study design. RESULTS: Overall, 5133 articles were captured in the initial search with 21 RCTs reporting 23 different primary outcomes being included in the final analysis. The median FI (first quartile, third quartile) was 3 (3, 20) with 16 outcomes (70%) reporting a loss to follow-up greater than its FI. Mann-Whitney U test revealed that commercially funded RCTs and composite outcomes had greater FIs (median, 20.0 [5.5, 24.5] vs median, 3.0 [2.0, 5.5], P = .035; median, 21 [8, 38] vs median, 3.0 [2.0, 8.5], P = .01, respectively). The FI did not vary between disease states (P = .285) or between index and follow-up trials (P = .147). There were significant correlations between the FI and P values (Pearson r = 0.90; 95% confidence interval, 0.77-0.96), and the number of events (r = 0.82; 95% confidence interval, 0.48-0.97). CONCLUSIONS: A small number of event conversions (median, 3) are needed to alter the statistical significance of primary outcomes in vascular surgery RCTs evaluating open surgical and endovascular treatments. Most studies had loss to follow-up greater than its FI, which can call into question trial results, and commercially funded studies had a greater FI. The FI and these findings should be considered in future trial design in vascular surgery.

BEYOND: a randomized controlled trial comparing efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus antagonist protocol during the first ovarian stimulation cycle.

STUDY QUESTION: How does a gonadotrophin-releasing hormone (GnRH) agonist versus a GnRH antagonist protocol affect ovarian response when using an individualized fixed daily dose of follitropin delta for ovarian stimulation? SUMMARY ANSWER: The BEYOND trial data demonstrate thatindividualized fixed-dose follitropin delta is effective when used in a GnRH agonist protocol, compared with a GnRH antagonist protocol, in women with anti-Müllerian hormone (AMH) ≤35 pmol/l and no increased risk of ovarian hyperstimulation syndrome (OHSS). WHAT IS KNOWN ALREADY: The efficacy and safety of an individualized fixed daily dose of follitropin delta (based on body weight and AMH) have been established in randomized controlled trials (RCTs) using a GnRH antagonist protocol. Preliminary study data indicate that individualized follitropin delta is also efficacious in a GnRH agonist protocol (RAINBOW trial, NCT03564509). There are no prospective comparative data using individualized follitropin delta for ovarian stimulation in a GnRH agonist versus a GnRH antagonist protocol. STUDY DESIGN, SIZE, DURATION: This is the first randomized, controlled, open-label, multi-centre trial exploring efficacy and safety of individualized follitropin delta dosing in a GnRH agonist versus a GnRH antagonist protocol in participants undergoing their first ovarian stimulation cycle for IVF/ICSI. A total of 437 participants were randomized centrally and stratified by centre and age. The primary endpoint was the number of oocytes retrieved. Secondary endpoints included ongoing pregnancy rates, adverse drug reactions (including OHSS), live births, and neonatal outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants (18-40 years; AMH ≤35 pmol/l) were enrolled at specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway, and Switzerland. The mean number of oocytes retrieved was compared between the GnRH agonist and antagonist protocols using a negative binomial regression model with age and AMH at screening as factors. Analyses were based on all randomized subjects, using a multiple imputation method for randomized subjects withdrawing before the start of stimulation. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 437 randomized subjects, 221 were randomized to the GnRH agonist, and 216 were randomized to the GnRH antagonist protocol. The participants had a mean age of 32.3 ± 4.3 years and a mean serum AMH of 16.6 ± 7.8 pmol/l. A total of 202 and 204 participants started ovarian stimulation with follitropin delta in the GnRH agonist and antagonist groups, respectively. The mean number of oocytes retrieved was statistically significantly higher in the agonist group (11.1 ± 5.9) versus the antagonist group (9.6 ± 5.5), with an estimated mean difference of 1.31 oocytes (95% CI: 0.22; 2.40, P = 0.0185). The difference in number of oocytes retrieved was influenced by the patients' age and ovarian reserve, with a greater difference observed in patients aged <35 years and in patients with high ovarian reserve (AMH >15 pmol/l). Both the GnRH agonist and antagonist groups had a similar proportion of cycle cancellations (2.0% [4/202] versus 3.4% [7/204]) and fresh blastocyst transfer cancellations (13.4% [27/202] versus 14.7% [30/204]). The estimated ongoing pregnancy rate per started cycle was numerically higher in the GnRH agonist group (36.9% versus 29.1%; difference: 7.74% [95% CI: -1.49; 16.97, P = 0.1002]). The most commonly reported adverse events (≥1% in either group; headache, OHSS, nausea, pelvic pain, or discomfort and abdominal pain) were similar in both groups. The incidence of early moderate/severe OHSS was low (1.5% for the agonist group versus 2.5% for antagonist groups). Estimated live birth rates per started cycle were 35.8% and 28.7% in the GnRH agonist and antagonist groups, respectively (treatment difference 7.15%; 95% CI: -2.02; 16.31; P = 0.1265). The two treatment groups were comparable with respect to neonatal health data for singletons and twins and for incidence of congenital malformations (2.7% and 3.3% for the GnRH agonist versus antagonist groups, respectively). LIMITATIONS, REASONS FOR CAUTION: All participants had AMH ≤35 pmol/l and were ≤40 years old. Clinicians should remain cautious when using a GnRH agonist protocol in patients with AMH >35 pmol/l (i.e. those with an increased OHSS risk). The incidence of OHSS in the GnRH antagonist group may have been lower if a GnRH agonist trigger had been allowed. Outcomes of transfers with cryopreserved blastocysts were not followed up, therefore the cumulative live birth rates and neonatal outcomes after cryotransfer are unknown. WIDER IMPLICATIONS OF THE FINDINGS: In women with AMH ≤35 pmol/l, an individualized fixed daily dose of follitropin delta resulted in a significantly higher number of oocytes retrieved when used in a GnRH agonist protocol compared with a GnRH antagonist protocol, with no additional safety signals observed and no additional risk of OHSS. Live birth rates following ovarian stimulation with individualized follitropin delta were not statistically different between the GnRH protocols; however, the trial was not powered to assess this endpoint. There were no safety concerns with respect to neonatal health after ovarian stimulation with follitropin delta in either protocol. STUDY FUNDING/COMPETING INTEREST(S): The trial was funded by Ferring Pharmaceuticals. EE, EP, and MS have no competing interests. AP has received research support from Ferring, and Gedeon Richter, and honoraria or consultation fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, Merck A/S. BC has received consulting fees from Ferring and Merck, and his department received fees from Ferring to cover the costs of patient enrolment. MBS has received support to attend meetings and/or travel from Ferring, and was a board member for FertiPROTEKT e.V. until 2023. JS has received honoraria or consultation fees from Ferring and Merck, and support for attending meetings and/or travel from Ferring, Merck, and GoodLife. TS has received support/travel expenses from Ferring for attending a congress meeting, and participated in an advisory board for Merck. YS has received grants/research support from Ferring and support to attend a professional society congress meeting from Merck. RL and PP are employees of Ferring Pharmaceuticals. PP is a BOD member of PharmaBiome and owns stocks of Takeda Pharmaceuticals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT03809429; EudraCT Number 2017-002783-40. TRIAL REGISTRATION DATE: 7 April 2019. DATE OF FIRST PATIENT'S ENROLMENT: 2 May 2019.

Eggsurance? A randomized controlled trial of a decision aid for elective egg freezing.

STUDY QUESTION: Does a purpose-designed Decision Aid for women considering elective egg freezing (EEF) impact decisional conflict and other decision-related outcomes? SUMMARY ANSWER: The Decision Aid reduces decisional conflict, prepares women for decision-making, and does not cause distress. WHAT IS ALREADY KNOWN: Elective egg-freezing decisions are complex, with 78% of women reporting high decisional conflict. Decision Aids are used to support complex health decisions. We developed an online Decision Aid for women considering EEF and demonstrated that it was acceptable and useful in Phase 1 testing. STUDY DESIGN, SIZE, DURATION: A single-blind, two-arm parallel group randomized controlled trial was carried out. Target sample size was 286 participants. Randomization was 1:1 to the control (existing website information) or intervention (Decision Aid plus existing website information) group and stratified by Australian state/territory and prior IVF specialist consultation. Participants were recruited between September 2020 and March 2021 with outcomes recorded over 12 months. Data were collected using online surveys and data collection was completed in March 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females aged ≥18 years, living in Australia, considering EEF, proficient in English, and with internet access were recruited using multiple methods including social media posts, Google advertising, newsletter/noticeboard posts, and fertility clinic promotion. After completing the baseline survey, participants were emailed their allocated website link(s). Follow-up surveys were sent at 6 and 12 months. Primary outcome was decisional conflict (Decisional Conflict Scale). Other outcomes included distress (Depression Anxiety and Stress Scale), knowledge about egg freezing and female age-related infertility (study-specific measure), whether a decision was made, preparedness to decide about egg freezing (Preparation for Decision-Making Scale), informed choice (Multi-Dimensional Measure of Informed Choice), and decision regret (Decision Regret Scale). MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 306 participants (mean age 30 years; SD: 5.2) were randomized (intervention n = 150, control n = 156). Decisional Conflict Scale scores were significantly lower at 12 months (mean score difference: -6.99 [95% CI: -12.96, -1.02], P = 0.022) for the intervention versus control group after adjusting for baseline decisional conflict. At 6 months, the intervention group felt significantly more prepared to decide about EEF than the control (mean score difference: 9.22 [95% CI: 2.35, 16.08], P = 0.009). At 12 months, no group differences were observed in distress (mean score difference: 0.61 [95% CI: -3.72, 4.93], P = 0.783), knowledge (mean score difference: 0.23 [95% CI: -0.21, 0.66], P = 0.309), or whether a decision was made (relative risk: 1.21 [95% CI: 0.90, 1.64], P = 0.212). No group differences were found in informed choice (relative risk: 1.00 [95% CI: 0.81, 1.25], P = 0.983) or decision regret (median score difference: -5.00 [95% CI: -15.30, 5.30], P = 0.337) amongst participants who had decided about EEF by 12 months (intervention n = 48, control n = 45). LIMITATIONS, REASONS FOR CAUTION: Unknown participant uptake and potential sampling bias due to the recruitment methods used and restrictions caused by the coronavirus disease 2019 pandemic. Some outcomes had small sample sizes limiting the inferences made. The use of study-specific or adapted validated measures may impact the reliability of some results. WIDER IMPLICATIONS OF THE FINDINGS: This is the first randomized controlled trial to evaluate a Decision Aid for EEF. The Decision Aid reduced decisional conflict and improved women's preparation for decision making. The tool will be made publicly available and can be tailored for international use. STUDY FUNDING/COMPETING INTEREST(S): The Decision Aid was developed with funding from the Royal Women's Hospital Foundation and McBain Family Trust. The study was funded by a National Health and Medical Research Council (NHMRC) Project Grant APP1163202, awarded to M. Hickey, M. Peate, R.J. Norman, and R. Hart (2019-2021). S.S., M.P., D.K., and S.B. were supported by the NHMRC Project Grant APP1163202 to perform this work. R.H. is Medical Director of Fertility Specialists of Western Australia and National Medical Director of City Fertility. He has received grants from MSD, Merck-Serono, and Ferring Pharmaceuticals unrelated to this study and is a shareholder of CHA-SMG. R.L. is Director of Women's Health Melbourne (Medical Practice), ANZSREI Executive Secretary (Honorary), RANZCOG CREI Subspecialty Committee Member (Honorary), and a Fertility Specialist at Life Fertility Clinic Melbourne and Royal Women's Hospital Public Fertility Service. R.A.A. has received grants from Ferring Pharmaceuticals unrelated to this study. M.H., K.H., and R.J.N. have no conflicts to declare. TRIAL REGISTRATION NUMBER: ACTRN12620001032943. TRIAL REGISTRATION DATE: 11 August 2020. DATE OF FIRST PATIENT'S ENROLMENT: 29 September 2020.

The effect of subcutaneous dulaglutide on weight loss in patients with Type 2 diabetes mellitus: Systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Dulaglutide, a subcutaneously administered glucagon-like peptide 1 receptor agonist, has been hypothesized to lead to weight loss in patients with Type 2 diabetes mellitus (T2DM). However, the consequences of its prescription on body weight (BW) and other anthropometric indices, for example, body mass index (BMI) or waist circumference (WC), have not been completely clarified. Therefore, we aimed to assess the effects of subcutaneous dulaglutide administration on BW, BMI and WC values in T2DM subjects by means of a systematic review and meta-analysis of RCTs. METHODS: We computed a literature search in five databases (PubMed/Medline, Web of Science, EMBASE, Scopus and Google Scholar) from their inception to February 2023 to identify RCTs that examined the influence of subcutaneous dulaglutide on obesity indices. We calculated effect sizes using the random-effects model (using DerSimonian-Laird method). Results were derived across weighted mean differences (WMD) and 95% confidence intervals (CI). Subgroup analyses were applied to explore possible sources of heterogeneity among the RCTs. The current systematic review and meta-analysis was conducted in compliance with The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: In total, 18 studies with 33 RCT arms (BW = 33 RCT arms, 14,612 participants, 7869 cases and 6743 controls; BMI = 10 RCT arms, 14,612 subjects, 7869 cases and 6743 controls; WC = 10 RCT arms, 1632 participants, 945 cases and 687 cases) were included in the meta-analysis. BW (WMD: -0.86 kg, 95% CI: -1.22, -0.49, p < 0.001), BMI (WMD: -0.68 kg/m2 , 95% CI: -0.88, -0.49, p < 0.001) and WC (WMD: -1.23 cm, 95% CI: -1.82, -0.63, p < 0.001) values decreased notably following subcutaneous dulaglutide administration versus placebo. BW notably decreased in RCTs lasting >18 weeks (WMD: -1.42 kg, 95% CI: -1.90, -0.94, p < 0.001), whereas notable reductions in WC were seen in RCTs lasting ≤18 weeks (WMD: -1.78 cm, 95% CI: -2.59, -0.98, p < 0.001). Dulaglutide dosages >1 mg/day significantly decreased BW (WMD: -1.94 kg, 95% CI: -2.54, -1.34, p < 0.001), BMI (WMD: -0.80 kg/m2 , 95% CI: -1.07, -0.54, p < 0.001) and WC (WMD: -1.47 cm, 95% CI: -1.80, -1.13, p < 0.001). BW decreased particularly following dulaglutide prescription in individuals with obesity (WMD: -1.05 kg, 95% CI: -1.28, -0.82, p < 0.001) versus overweight. The dose-response meta-analysis revealed that BW decreased significantly when dulaglutide was prescribed in doses ≤3 mg/day versus >3 mg/day. CONCLUSIONS: Subcutaneous dulaglutide administration in T2DM reduces BW, BMI and WC. The decrease in BW and WC was influenced by the dose and the duration of dulaglutide administration. The reduction in BMI was only influenced by the dosage of dulaglutide. Moreover, T2DM patients who suffered from obesity experienced a notable decrease in BW versus T2DM subjects without obesity.

Eligibility of patients with chronic obstructive pulmonary disease for inclusion in randomised control trials investigating triple therapy: a study using routinely collected data.

BACKGROUND: Randomised control trials (RCTs) with strict eligibility criteria can lead to trial populations not commonly seen in clinical practice. We described the proportion of people with chronic obstructive pulmonary disease (COPD) in England eligible for RCTs investigating treatment with triple therapy. METHODS: MEDLINE and Clinicaltrials.gov were searched for RCTs investigating triple therapy and eligibility criteria for each trial were extracted. Using routinely collected primary care data from Clinical Practice Research Datalink Aurum linked with Hospital Episode Statistics, we defined a population of COPD patients registered at a general practice in England, who were ≥ 40 years old, and had a history of smoking. Inclusion date was January 1, 2020. Patients who died earlier or left the general practice were excluded. Eligibility criteria for each RCT was applied to the population of COPD patients and the proportion of patients meeting each trial eligibility criteria were described. RESULTS: 26 RCTs investigating triple therapy were identified from the literature. The most common eligibility criteria were post-bronchodilator FEV1% predicted 30-80%, ≥ 2 moderate/≥ 1 severe exacerbations 12-months prior, no moderate exacerbations one-month prior and no severe exacerbations three-months prior, and the use of maintenance therapy or ICS use prior to inclusion. After applying each RCT eligibility criteria to our population of 79,810 COPD patients, a median of 11.2% [interquartile range (IQR) 1.8-17.4] of patients met eligibility criteria. The most discriminatory criteria included the presence exacerbations of COPD and previous COPD related medication use with a median of 67.6% (IQR 8.5-73.4) and 63% (IQR 69.3-38.4) of COPD patients not meeting these criteria, respectively. CONCLUSION: Data from these RCTs may not be generalisable to the wider population of people with COPD seen in everyday clinical practice and real-world evidence studies are needed to supplement trials to understand effectiveness in all people with COPD.

Impact of timing and format of patient decision aids for breast cancer patients on their involvement in and preparedness for decision making - the IMPACTT randomised controlled trial protocol.

BACKGROUND: After curative surgery for early-stage breast cancer, patients face a decision on whether to undergo surgery alone or to receive one or more adjuvant treatments, which may lower the risk of recurrence. Variations in survival outcomes are often marginal but there are differences in the side effects and other features of the options that patients may value differently. Hence, the patient's values and preferences are critical in determining what option to choose. It is well-researched that the use of shared decision making and patient decision aids can support this choice in a discussion between patient and clinician. However, it is still to be investigated what impact the timing and format of the patient decision aid have on shared decision making outcomes. In this trial, we aim to investigate the impact of a digital pre-consult compared to a paper-based in-consult patient decision aid on patients' involvement in shared decision making, decisional conflict and preparedness to make a decision. METHODS: The study is a randomised controlled trial with 204 patients at two Danish oncology outpatient clinics. Eligible patients are newly diagnosed with early-stage breast cancer and offered adjuvant treatments after curative surgery to lower the risk of recurrence. Participants will be randomised to receive either an in-consult paper-based patient decision aid or a pre-consult digital patient decision aid. Data collection includes patient and clinician-reported outcomes as well as observer-reported shared decision making based on audio recordings of the consultation. The primary outcome is the extent to which patients are engaged in a shared decision making process reported by the patient. Secondary aims include the length of consultation, preparation for decision making, preferred role in shared decision making and decisional conflict. DISCUSSION: This study is the first known randomised, controlled trial comparing a digital, pre-consult patient decision aid to an identical paper-based, in-consult patient decision aid. It will contribute evidence on the impact of patient decision aids in terms of investigating if pre-consult digital patient decisions aids compared to in-consult paper-based decision aids support the cancer patients in being better prepared for decision making. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05573022).

Peer support for adults with type 2 diabetes starting continuous glucose monitoring-An exploratory randomised controlled trial.

AIMS: To explore the feasibility and potential benefits of a peer support programme for adults with insulin-treated type 2 diabetes (T2D) starting continuous glucose monitoring (CGM). METHODS: This part of the Steno2tech study is an exploratory, single-centre, open-labelled, prospective, randomised controlled trial (RCT). A total of 60 participants were randomised 2:1 to 12 months of CGM with or without peer support. All participants received a 3-h diabetes self-management education course including a CGM part on how to use the CGM and interpret the CGM-derived data. Peer support consisted of three 3-h peer support meetings over the first 6 months of the study period with groups of three to six people. The exploratory outcomes included the acceptability and feasibility of the peer support intervention, and the between-group difference in change in several glycaemic, metabolic and participant-reported outcomes measured at baseline, 6 and 12 months. RESULTS: The peer support intervention was found acceptable and feasible. Participants shared their experiences of using and interpreting CGM data and its association with health behaviour. While both groups had improvements in glycaemic, metabolic and participant-reported outcomes, there were no significant between-group differences. CONCLUSIONS: Although feasible, we found no measured additional benefits when adding a peer support programme after starting CGM in this exploratory RCT including adults with insulin-treated T2D. Understanding the perceived effect of and preferences for a peer support intervention from the participants' points of view, including why individuals declined to participate, would be of value for future research.

Effect of reduced follow-up care on patient satisfaction with care among patients with endometrial cancer: The ENSURE randomized controlled trial.

BACKGROUND: Evidence on the optimal follow-up schedule after endometrial cancer is lacking. The study aim was to compare satisfaction with care between women who received reduced follow-up care and women who received usual guideline-directed follow-up care for three years after surgery. METHODS: The ENSURE (ENdometrial cancer SURvivors' follow-up carE) trial was a non-inferiority randomized controlled multicenter trial in 42 hospitals in the Netherlands. The intervention arm received reduced follow-up care (4 visits/3 years), while the control group received usual follow-up care (8-11 visits/3 years). Primary outcome was overall satisfaction with care, PSQIII score, over three years follow-up, with a non-inferiority margin of 6. Mixed linear regression, intention-to-treat and per-protocol analyses (presented below) were used. RESULTS: Among 316 women included, overall satisfaction with care was not lower in the reduced follow-up (mean 82; SD = 15) compared with the usual follow-up group (mean 80; SD = 15) group (B = 1.80(-2.09;5.68)). At 6, 12 and 36 months, more women (93/94/90%) in the reduced follow-up group were satisfied with their follow-up schedule than in the usual follow-up group (79/79/82%; p < 0.001; p < 0.001; p = 0.050). CONCLUSIONS AND RELEVANCE: Women with low-risk, early-stage endometrial cancer who received reduced follow-up care were no less satisfied with their care than women receiving usual follow-up care. Compared with usual follow-up, women in the reduced follow-up group had fewer clinical visits and, at the same time, more often reported being satisfied with their follow-up schedule. Findings suggest that reduced follow-up care may be the new standard, but should be tailored to meet additional needs where indicated.

Oral language enrichment in preschool improves children's language skills: a cluster randomised controlled trial.

BACKGROUND: Oral language skills provide the foundation for formal education, yet many children enter school with language weaknesses. This study evaluated the efficacy of a new language enrichment programme, the Nuffield Early Language Intervention-Preschool (NELI Preschool), delivered to children in the year before they enter formal education. METHODS: We conducted a preregistered cluster randomised controlled trial in 65 nursery schools in England (https://doi.org/10.1186/ISRCTN29838552). NELI Preschool consists of a 20-week whole-class language enrichment programme delivered by a teacher each day for 20 min. In addition, children with the weakest language skills in each class are allocated to receive additional targeted support delivered by classroom assistants (whole-class + targeted). The language skills of all children (n = 1,586) in participating classrooms were assessed using the LanguageScreen automated app (https://oxedandassessment.com/languagescreen/). Settings were then randomly allocated to an intervention or control group. The children with the weakest language in each class (whole-class + targeted children n = 438), along with four randomly selected children in each class allocated to the whole-class only programme (n = 288) were individually tested on a range of language measures. RESULTS: Children receiving NELI Preschool made larger gains than children in the control group on an oral language latent variable (whole-class children d = .26; whole-class + targeted children d = .16). CONCLUSIONS: This study provides good evidence that whole-class intervention delivered in preschool can produce educationally significant improvements in children's language skills. The intervention is scaleable and relatively low cost. These findings have important implications for educational and social policy.

Moving forward. Use of the START NOW skills training program for female youth with ODD and CD - a commentary on Stadler et al. (2024).

Female youth with oppositional defiant disorder (ODD) and conduct disorder (CD) are an under studied and underserved population at high risk for poor adjustment in later life. Stadler et al. (2024) attempt to redress this situation for adolescent females with CD or ODD with an adapted version of the skills training program START NOW. They describe the results of an ambitious randomized control trial, comparing START NOW with standard care in youth welfare settings in Germany, Switzerland, and The Netherlands. The findings appear promising, but the paper is especially valuable for the spotlight it shines on the needs of this underserved population and those caring for them, together with the importance of undertaking such trials despite their challenges. This commentary seeks to encourage readers to engage with the START NOW trial.

Effects of salt and protein intake on polyuria in V2RA-treated ADPKD patients.

BACKGROUND: The only treatment proven to be renoprotective in autosomal dominant polycystic kidney disease (ADPKD) is a vasopressin V2-receptor antagonist (V2RA). However, aquaresis-associated side effects limit tolerability. We investigated whether salt and/or protein intake influences urine volume and related endpoints in V2RA-treated ADPKD patients. METHODS: In this randomized, controlled, double-blind, crossover trial, ADPKD patients treated with maximally tolerated dose of a V2RA were included. While on a low salt and low protein diet, patients were given additional salt and protein to mimic regular intake, which was subsequently replaced by placebo in random order during four 2-week periods. Primary endpoint was change in 24-h urine volume. Secondary endpoints were change in quality of life, measured glomerular filtration rate (mGFR), blood pressure and copeptin level. RESULTS: Twelve patients (49 ± 8 years, 25.0% male) were included. Baseline salt and protein intake were 10.8 ± 1.3 g/24-h and 1.2 ± 0.2 g/kg/24-h, respectively. During the low salt and low protein treatment periods, intake decreased to 5.8 ± 1.6 g/24-h and 0.8 ± 0.1 g/kg/24-h, respectively. Baseline 24-h urine volume (5.9 ± 1.2 L) decreased to 5.2 ± 1.1 L (-11%, P = .004) on low salt and low protein, and to 5.4 ± 0.9 L (-8%, P = .04) on low salt. Reduction in 24-h urine volume was two times greater in patients with lower urine osmolality (-16% vs -7%). Polyuria quality of life scores improved in concordance with changes in urine volume. mGFR decreased during the low salt and low protein, while mean arterial pressure did not change during study periods. Plasma copeptin decreased significantly during low salt and low protein periods. CONCLUSION: Lowering dietary salt and protein intake has a minor effect on urine volume in V2RA-treated ADPKD patients. Reduced intake of osmoles decreased copeptin concentrations and might thus increase the renoprotective effect of a V2RA in ADPKD patients.

Efficacy of Op Koers Online, an online group intervention for parents of children with cancer: Results of a randomized controlled trial.

OBJECTIVE: Parents of children with cancer are at risk for developing psychosocial problems. The present study aims to evaluate the effect of an online group intervention (Op Koers Online, in English: On Track Online) on psychosocial wellbeing and coping skills. METHODS: Parents of a child with cancer (diagnosis <5 years ago) participated in a randomized controlled trial. In six consecutive (and one booster-) protocolled sessions in an online chatroom, trained psychologists and social workers taught coping skills using cognitive behavioral and acceptance and commitment techniques. Questionnaires assessed anxiety, depression, distress, situation-specific emotional reactions and coping skills (Op Koers Questionnaire/Cognitive Coping Strategies Scale Parent Form) and evaluated the intervention. Linear mixed-model analyses were performed to detect differences between the conditions in changes over time; T0-T1 and T0-T2 (6-week and 6-month follow-up), and to detect changes in scores T2-T3 (12-month follow-up) for the intervention group only. RESULTS: 89 parents were included in analyses (mean age 41.9 years, 86% female, 62%/38% post/during treatment of their child). Beneficial intervention effects (p < 0.05) were found at T1 for anxiety, depression, distress, loneliness and relaxation, and at T2 for anxiety, uncertainty and relaxation. In the intervention condition, scores did not change from T2 to T3, except loneliness that decreased and relaxation that improved. All effect sizes were small to medium (ß = -0.21 to 0.46). Parents were generally positive about the intervention. CONCLUSIONS: Op Koers Online for parents of children with cancer has a positive effect on psychosocial wellbeing and the coping skill relaxation. Implementation is recommended to prevent psychosocial problems. CLINICAL TRIAL REGISTRATION: Dutch Trial Register https://onderzoekmetmensen.nl/en NL73763.041.20.