Original Trial Research Articles

The Clinical Impact of Time-restricted Eating on Cancer: A Systematic Review.

In the face of the growing global burden of cancer, there is increasing interest in dietary interventions to mitigate its impacts. Pre-clinical evidence suggests that time-restricted eating (TRE), a type of intermittent fasting, induces metabolic effects and alterations in the gut microbiome that may impede carcinogenesis. Research on TRE in cancer has progressed to human studies, but the evidence has yet to be synthesized. The objective of this study was to systematically evaluate the clinical and/or metabolomic effects of TRE compared with ad libitum eating or alternative diets in people with cancer. Ovid MEDLINE, Ovid Embase, CINAHL, Ovid Cochrane Central Register of Control Trials (CENTRAL), Web of Science Core Collection (ESCI, CPCI-SSH, CPCI-S), and SCOPUS were searched up to January 4, 2023, using the core concepts of "intermittent fasting" and "cancer." Original study designs, protocols, and clinical trial registries were included. After evaluating 13 900 results, 24 entries were included, consisting of 8 full articles, 2 abstracts, 1 published protocol and 13 trial registries. All data were extracted, compared, and critically analyzed. There was heterogeneity in the patient population (eg, in tumor sites), TRE regimens (eg, degree of restriction, duration), and clinical end points. A high rate (67-98%) of TRE adherence was observed, alongside improvements in quality of life. Four articles assessed cancer markers and found a reduction in tumor marker carcinoembryonic antigen, reduced rates of recurrence, and a sustained major molecular response, following TRE. Five articles demonstrated modified cancer risk factors, including beneficial effects on body mass index, adiposity, glucoregulation, and inflammation in as short a period as 8 weeks. None of the completed studies assessed the effect of TRE on the microbiome, but analysis of the microbiome is a planned outcome in 2 clinical trials. Preliminary findings suggest that TRE is feasible and acceptable by people with cancer, may have oncological benefits, and improves quality of life. PROSPERO registration No. CRD42023386885.

Responsiveness to Selective Laser Trabeculoplasty in Open-Angle Glaucoma and Ocular Hypertension

Selective laser trabeculoplasty (SLT) is becoming the recommended first choice in the treatment of open-angle glaucoma (OAG). However, whether repeat SLT can be recommended regardless of initial response remains controversial. To assess the potential of OAG and ocular hypertension (OHT) undergoing repeat laser to respond favorably to SLT, termed responsiveness to SLT. This post hoc analysis of the Laser in Glaucoma and Ocular Hypertension Trial in China (LiGHT China) was conducted from March 2015 to April 2023 in Zhongshan Ophthalmic Center. Of 1376 newly diagnosed OAG and OHT eyes of 771 adults in the original trial, 180 eyes of 105 participants were included in the present study, which underwent initial and repeat SLT as primary treatments. Standard SLT was the primary treatment. Repeat SLT was the first choice of treatment escalation regardless of initial response. IOP reduction after SLT and the duration of effect were analyzed. The maximum reduction in IOP within 2 years after initial SLT and repeat SLT was used to identify potential nonresponsiveness. IOP reduction 2 months after SLT. A total of 180 eyes from 105 Chinese participants (mean [SD] age, 45.6 [14.5] years; 58 [55.2%] male and 47 [44.8%] female) underwent repeat SLT. Initial SLT and repeat SLT were both associated with a reduction in IOP (mean, 4.5 mm Hg; 95% CI, 3.9 to 5.1; P < .001 and mean, 3.3 mm Hg; 95% CI, 2.7 to 3.8; P < .001, respectively). The mean (SD) IOP after repeat SLT was 15.8 (3.4) mm Hg, similar to 16.0 (4.0) mm Hg after initial SLT (difference, -0.4mm Hg; 95% CI, -1.0 to 0.3; P = .24). Duration of effect after repeat SLT was longer than after initial SLT (1043 days vs 419 days; hazard ratio, 0.38; 95% CI, 0.29 to 0.50; P < .001). IOP reduction after initial SLT was uncorrelated with that after repeat SLT, and 153 eyes (85.0%) responded favorably to SLT at least once. A subset of 27 eyes (15.0%) was identified as potentially nonresponsive and found distinctive with older age (mean [SD], 54.1 [12.5] years vs 44.2 [14.2] years; difference, 10.5 years; 95% CI, 2.9 to 18.1; P = .009), higher proportion of female participants (difference, 27.5%; 95% CI, 3.6 to 51.5; P = .03), and lower baseline IOP (difference, -3.2 mm Hg; 95% CI, -5.2 to -1.3; P = .001). These post hoc analyses showed that most cases of OAG and OHT were highly responsive to SLT and support the consideration of repeat SLT regardless of initial response, while individuals who are nonresponsive to this treatment may have specific features.

Nutritional support in hospitalised patients with diabetes and risk for malnutrition: a secondary analysis of an investigator-initiated, Swiss, randomised controlled multicentre trial

ObjectivesThe main objective of this study was to investigate the effects of nutritional support on mortality in hospitalised patients with diabetes and nutritional risk participating in the Effect of early...

Adenomyosis-A Call for Awareness, Early Detection, and Effective Treatment Strategies: A Narrative Review.

To provide a brief summary of the high incidence, symptomatology, different types, and diagnosis of adenomyosis and to explore various aspects of the disease, with the primary aim of raising awareness among gynecologists for appropriate and early detection. Adenomyosis, a benign gynecological condition characterized by the infiltration of endometrial tissue into the myometrium, poses significant challenges to women's reproductive health. A narrative review was conducted by searching PubMed, Scopus, and Cochrane databases and offering a non-systematic summary and critical analysis of current knowledge on the impact of adenomyosis on women's health. Articles published in the English language up to May 2023, including original scientific papers, clinical trials, meta-analyses, and reviews focusing on various aspects of adenomyosis, were included in the synthesis of this review. Approximately 20% of women are affected by adenomyosis, which manifests with various subtypes, distinct epidemiological profiles, symptomatology, and treatment responses. Despite its clinical significance, adenomyosis remains understudied, resulting in a significant disparity in research and the literature compared to other gynecological conditions. The severity of adenomyosis is compounded when coexisting with endometriosis, particularly deep-infiltrating endometriosis (DIE), leading to exacerbated fertility issues and severe symptomatology. The wide range of symptoms, including adverse pregnancy outcomes such as pre-eclampsia, highlights its wider impact and emphasizes the need for increased awareness of the condition. Adenomyosis is frequently associated with treatment failure in endometriosis, contributing to dienogest resistance, elevated discontinuation rates, and persistent pain post-endometriosis surgery. Additionally, the lack of specific treatments tailored to adenomyosis poses a considerable challenge in clinical management.

Role of imaging techniques in the assessment of vulnerable plaques and the effectiveness of lipid-lowering therapy

The aim was to evaluate the potential of various imaging methods in the diagnosis of vulnerable coronary plaques and their stabilization using various lipid-lowering therapy regimens.The sources were searched in the PubMed database using the following keywords: "vulnerable (unstable) plaque" AND "PCSK9 inhibitors" AND "intravascular ultrasound" OR "optical coherence tomography" OR "computed tomography angiography". As a result, 8 original clinical trials were selected that corresponded to the review purpose. We assessed the results of following studies on plaque imaging and their regression with various lipid-lowering therapy regimens: GLAGVO, ODYSSEY J, PACMAN-AMI, HUYGENS, ALTAIR, ARCHITECT, etc. The results of most studies have established the advantages of a combined regimen of lipid-lowering therapy (statin+PCSK9 inhibitor) in reducing the rate of cardiovascular events in com­parison with statin monotherapy. The reduction in plaque volume ranged from 0,95% to 2,13% in patients receiving a combination of lipid-lowering drugs, while in monotherapy, it increased from 0,05% to 0,92% (GLAGOV, PACMAN-AMI). The changes of minimum fibrous cap thickness varied from 18,0-62,67 µm with combined therapy and 13,2-33,19 µm with monotherapy (PACMAN-AMI, Gao F). Lipid arc regression was 57,5о in combination therapy (statin+PCSK9 inhibitor) and 31,4о in statin monotherapy (HUYGENS). Imaging diagnostic methods makes it possible to identify vulnerable plaques, which helps in consideration of combination lipid-lowering therapy. In addition, plaque visualization makes it possible to evaluate the treatment effectiveness.

Postoperative radiotherapy in women with early operable breast cancer (Scottish Breast Conservation Trial): 30-year update of a randomised, controlled, phase 3 trial

Breast-conserving surgery, adjuvant systemic therapy, and radiotherapy are the standard of care for most women with early breast cancer. There are few reports of clinical outcomes beyond the first decade of follow-up of randomised trials comparing breast-conserving surgery with or without radiotherapy. We present a 30-year update of the Scottish Breast Conservation Trial. In this randomised, controlled, phase 3 trial across 14 hospitals in Scotland, women aged younger than 70 years with early breast cancer (tumours ≤4 cm [T1 or T2 and N0 or N1]) were included. They underwent breast-conserving surgery (1 cm margin) with axillary node sampling or clearance. Oestrogen receptor (ER)-rich patients (≥20 fmol/mg protein) received 20 mg oral tamoxifen daily for 5 years. ER-poor patients (<20 fmol/mg protein) received chemotherapy (cyclophosphamide 600 mg/m2, methotrexate 50 mg/m2, and fluorouracil 600 mg/m2 every 21 days intravenously in eight courses). Stratification was by menstrual status (within or more than 12 months from last menstrual period) and ER status (oestrogen concentration ≥20 fmol/mg protein, <20 fmol/mg protein, or unknown) and patients were randomly assigned (1:1) to high-dose (50 Gy in 20-25 fractions) local or locoregional radiotherapy versus no radiotherapy. No blinding was possible due to the nature of the treatment. We report the primary endpoint of the original trial, ipsilateral breast tumour recurrence, and the co-primary endpoint, overall survival. Clinical outcomes were compared by the log-rank test. Hazard ratios (HRs) are reported, with no radiotherapy as the reference group. Failures of the proportional hazards assumption are reported if significant. All analyses are by intention to treat. Between April 1, 1985, and Oct 2, 1991, 589 patients were enrolled and randomly assigned to the two treatment groups (293 to radiotherapy and 296 to no radiotherapy). After exclusion of four ineligible patients (two in each group), there were 291 patients in the radiotherapy group and 294 patients in the no radiotherapy group. Median follow-up was 17·5 years (IQR 8·4-27·9). Ipsilateral breast tumour recurrence was significantly lower in the radiotherapy group than in the no radiotherapy group (46 [16%] of 291 vs 107 [36%] of 294; HR 0·39 [95% CI 0·28-0·55], p<0·0001). Although there were differences in the hazard rate for ipsilateral breast tumour recurrence in the first decade after treatment (HR 0·24 [95% CI 0·15-0·38], p<0·0001), subsequent risks of ipsilateral breast tumour recurrence were similar in both groups (0·98 [0·54-1·79], p=0·95). There was no difference in overall survival between the two groups (median 18·7 years [95% CI 16·5-21·5] in the no radiotherapy group vs 19·2 years [16·9-21·3] in the radiotherapy group; HR 1·08 [95% CI 0·89-1 ·30], log-rank p=0·43). Our findings suggest that patients whose biology predicts a late relapse a decade or more after breast-conserving surgery for early breast cancer might gain little from adjuvant radiotherapy. Breast Cancer Institute (part of Edinburgh and Lothian Health Foundation) and PFS Genomics (now part of Exact Sciences).

Long-term cost-effectiveness of insertion of a biological mesh during stoma-site closure: 5-8-year follow-up of the ROCSS randomized controlled trial.

The original ROCSS trial demonstrated a significant reduction in clinically detectable incisional hernias at 2 years in patients receiving prophylactic biological mesh during stoma closure. ROCSS-Ex was designed to investigate the 5-8-year cost-effectiveness of mesh in the surviving cohort using an abdominal wall-specific quality of life score. Eligible participants from original UK centres were identified. The primary outcome (abdominal wall-specific quality of life) was measured using the HerQLes score and EQ-5D-5L. Assessors remained blind to patients' original allocation, even if the patient was aware of their treatment. Of the original 790 patients, 598 were available for long-term follow-up. HerQLes scores were available for 396 patients (no mesh: 191, mesh: 205). There was no difference in primary outcome between the two groups (mean difference of 1.48, 95% c.i. (-2.35, 5.32), P = 0.45) and no cost benefit of routine insertion of prophylactic biological mesh across the entire cohort in the long term. However, patients who received mesh experienced significantly fewer stoma site complications within the first 3 years after reversal and needed fewer surgical reinterventions (32 versus 54 for the no mesh group; incidence rate ratio of 0.55, 95% c.i. (0.31, 0.97), P = 0.04). ROCSS-Ex has shown equivocal outcomes for prophylactic mesh insertion versus standard repair on abdominal wall-specific quality of life 5-8 years after surgery. As most reinterventions occurred within the first 3 years post-surgery, there may be a role for prophylactic mesh in a subset of patients who would be most adversely affected by repeated surgery early on. ISRCTN25584182 (http://www.clinicaltrials.gov).

Otitis media sequelae and hearing in adolescence after administration of an 11-valent conjugate pneumococcal vaccine in infancy: a prospective cohort study with long-term follow-up of the ARIVAC trial

Pneumococcal conjugate vaccines (PCVs) have been shown in randomised controlled trials and epidemiological studies to prevent acute otitis media caused by vaccine serotype pneumococci, although their role in preventing complications of acute otitis media is less clear. We hypothesised that the 11-valent PCV would reduce the long-term sequelae of acute otitis media, including moderate-to-severe ear disease and hearing loss. This prospective cohort study, referred to as 11PCV study, included follow-up after 16-20 years of children previously enrolled in 2000-04, at age 6 weeks to 6 months, in the randomised, placebo-controlled, ARIVAC trial of 11-valent PCV for the prevention of radiographical pneumonia. The ARIVAC trial and this 11PCV study were conducted at six study centres in Bohol, Philippines. Ear disease was classified using video-otoscopy review and observations derived from the ear exam. The final classification of the worst ear disease was mild (ie, acute otitis media, otitis media with effusion, healed perforation, or tympanosclerosis), moderate (ie, dry perforation or adhesive otitis media), or severe (chronic suppurative otitis media). Hearing loss was assessed following a standard schema and classified according to the worst ear as mild (>15 to 30 dB puretone average) or moderate-to-profound (>30 dB pure tone average). We calculated the relative and absolute risk reduction in the primary outcome of moderate-to-severe ear disease and the secondary outcomes of mild or moderate-to-profound hearing loss in adolescents who previously received the 11-valent PCV compared with those who received placebo during infancy in ARIVAC. Of the 15 593 children assessed for eligibility in ARIVAC, 12 194 were randomly assigned and 8926 were alive and could be located for enrolment in this 11PCV study between Sept 19, 2016, and Dec 13, 2019. 8321 (4188 in the vaccine group and 4133 in the placebo group) completed follow-up of the 11PCV study by March 30, 2020, and had sufficient data to classify ear disease and be included in the primary outcome analysis. The primary outcome of the absolute risk reduction in moderate-to-severe ear disease in the vaccine group (310 [7·4%] of 4188) versus those in the placebo group (356 [8·6%] of 4133) was 1·2% (95% CI 0·0-2·4; p=0·046) and the relative risk reduction was 14·1% (0·0 to 26·0). There were no differences in secondary outcomes of mild hearing loss or moderate-to-profound hearing loss between the vaccine and placebo groups. The absolute risk reduction for moderate-to-severe ear disease in adolescence of 1·2% (12 per 1000 children) was almost three times higher than the 0·45% reduction (4·5 per 1000 children) in radiographical pneumonia in the first 2 years of life shown in ARIVAC. Administration of 11-valent PCV in infancy was associated with absolute and relative risk reductions in the sequelae of acute otitis media 16-20 years after the original ARIVAC trial. Bill & Melinda Gates Foundation.

Analysis of post-marketing requirements for oncology drug conditional approvals in the United States and China

BackgroundConditional approvals, also known as accelerated approvals, have been introduced by many pharmaceutical regulators around the world, allowing innovative drugs to enter the market earlier on the basis of limited evidence. This research aims to systematically analyze and compare the post-marketing requirements for conditional approvals of oncology drugs in China and the United States. By collecting and categorizing different types of post-marketing requirements, this study seeks to elucidate how these requirements are proposed and discern the underlying logic and patterns. MethodsThis study delved into oncology drug approvals, encompassing FDA accelerated approvals (up to December 31, 2022) and NMPA conditional approvals (from 2017 to December 31, 2022). Leveraging review documents from FDA and NMPA, comprehensive data on product characteristics, all post-marketing commitments and requirements, and especially those related to confirmatory requirements were extracted. The analysis incorporated descriptive statistics, visualizations such as Upset plots, and thorough examination of confirmatory requirement timeframes. FindingsThis study examined 168 FDA accelerated approvals and 41 NMPA conditional approvals for oncology indications. Post-marketing requirements displayed diversity: FDA emphasized confirmatory studies, clinical pharmacology studies, and more, while NMPA predominantly focused on confirmatory studies. Confirmatory requirement timeframes indicated higher FDA-required completion times for new confirmatory trials compared to continued completion of original pivotal trials. In contrast, NMPA's requirement patterns were comparatively singular, with relatively fixed timeframes. FDA's evolving trend showed decreasing timeframes over time, suggesting an increasing demand for timely confirmatory data. InterpretationConditional approvals offer a unique approach to bring potentially life-saving drugs to the market faster, despite limited supporting evidence. Our analysis of oncology drug conditional approvals in the U.S. and China reveals diverse post-marketing requirement patterns. This study provides valuable insights for regulatory decision-making in a dynamic pharmaceutical landscape. Balancing the risks and rewards of conditional approvals is crucial in ensuring both patient safety and timely access to innovative treatments.

Factors predicting long-term outcomes following physiotherapy in patients with subacromial pain syndrome: a secondary analysis

BackgroundAlthough patients with shoulder complaints are frequently referred to physiotherapy, putative predictive factors for outcomes are still unclear. In this regard, only a limited amount of scientific data for patients with subacromial pain syndrome exist, with inconsistent results. An improved knowledge about the ability of baseline variables to predict outcomes could help patients make informed treatment decisions, prevent them from receiving ineffective treatments, and minimize the risk of developing chronic pain.AimThe aims of this secondary longitudinal analysis are threefold: First, to investigate baseline differences between patients with and without successful long-term outcomes following physiotherapy. Second, to compare the predictive ability of two sets of putative predictive variables on outcomes, one based on the literature and one based on the data of the original trial. Third, to explore the contribution of short-term follow-up data to predictive models.MethodsDifferences between responders and nonresponders were calculated. The predictive ability of variables defined through literature and of variables based on the Akaike Information Criterion (AIC) from the original trial dataset on the Shoulder Pain and Disability Index and the Patients’ Global Impression of Change at the one-year follow-up were analyzed. To test the robustness of the results, different statistical models were used. To investigate the contribution of follow-up data to prediction, short-term data were included in the analyses.ResultsA sample of 87 patients with subacromial pain syndrome was analyzed. 77% (n = 67) of these participants were classified as responders. Higher expectations and short-term change scores were positive, and higher fear avoidance beliefs, greater baseline disability and pain levels were negative predictors of long-term outcomes in patients with subacromial pain syndrome.ConclusionsAlthough our results are in line with previous research and support the use of clinical factors for prediction, our findings suggest that psychological factors, especially patient expectations and fear avoidance beliefs, also contribute to long-term outcomes and should therefore be considered in the clinical context and further research. However, the hypotheses and recommendations generated from our results need to be confirmed in further studies due to their explorative nature.Trial registrationThe original trial was registered at Current Controlled Trials under the trial registration number ISRCTN86900354 on March 17, 2010.

Long-Term Outcomes of Self-Fit vs Audiologist-Fit Hearing Aids

With rising interest in over-the-counter (OTC) hearing aids as an alternative to traditional audiologist-fit devices, understanding their long-term efficacy is crucial. However, given the novelty of the US Food and Drug Administration category of OTC hearing aids, minimal evidence currently supports their long-term efficacy. To compare the long-term self-reported outcomes at 8 months of self-fit OTC hearing aids to the same hearing aids fit by audiologists. Building on a previous randomized clinical trial, this follow-up comparative effectiveness research study reassessed a number of the original participants that were not lost to follow-up. Participants were initially divided into those with self-fit OTC hearing aids and those with audiologist-fit devices. Approximately 8 months after fitting, participants completed self-reported questionnaires. Missing data were addressed through multiple imputation. The original noninferiority trial was conducted at the University of Pretoria in South Africa from April 2022 to August 2022. The current analysis took place between July 7, 2023, to November 20, 2023. In the original trial, participants in the self-fit device group received a pair of OTC hearing aids and independently fit them with remote support as needed. The audiologist-fit device group received the same hearing aids fit by a certified audiologist using best practices. The main outcomes were self-reported hearing aid benefit, measured using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the International Outcome Inventory for Hearing Aids (IOI-HA). Of 64 participants in the trial, 44 participants were included in the extension study (21 [47.7%] in the audiologist-fit group; 23 [52.3%] in the self-fit group). The mean (SD) age of these participants was 63.0 (13.2) years, and 21 (47.7%) were male. At the long-term follow-up, self-fit and audiologist-fit groups showed no significant differences in the APHAB global score (mean difference, 0.02 [95% CI, -7.1 to 7.1]; Cohen d, 0.01 [95% CI, -0.5 to 0.5]) or the IOI-HA total score (mean difference, 1.5 [95% CI, -1.4 to 4.4]; Cohen d, 0.3 [95% CI, -0.2 to 0.8]). From 6 weeks to 8 months, no clinically meaningful group-time interaction was found between groups for the APHAB global score (Cohen d, 0.1 [95% CI, -0.2 to 0.3]), but a significant interaction for the IOI-HA total score was found (Cohen d, -0.6 [95% CI, -0.8 to -0.3]), with the self-fit group generally performing better. This comparative effectiveness research study demonstrated that self-fit OTC hearing aids can offer comparable long-term benefits to audiologist-fit hearing aids for individuals with mild to moderate hearing loss.

Community health promotion and medical provision and impact on neonates (CHAMPION2) and support to rural India’s public education system and impact on numeracy and literacy scores (STRIPES2): an update to the study protocol (v 11) for a cluster randomised trial in Madhya Pradesh, India

BackgroundThis update outlines amendments to the CHAMPION2/STRIPES2 cluster randomised trial protocol primarily made due to the COVID-19 pandemic and nationwide lockdown in India in 2020. These amendments were in line with national guidelines for health research during the COVID-19 pandemic.MethodsWe did not change the original trial design, eligibility, and outcomes. Amendments were introduced to minimise the risk of COVID-19 transmission and ensure safety and wellbeing of trial staff, participants, and other villagers. CHAMPION2 intervention: participatory learning and action (PLA) and fixed day service (FDS) meeting were revised to incorporate social distancing and hygiene precautions. During the COVID-19 pandemic, PLA participation was limited to pregnant women and birthing partners. STRIPES2 intervention: before/after-school classes were halted for a period and then modified temporarily (reducing class sizes, and/or changing meeting places) with hygiene and safe distancing practices introduced. Data collection: The research team gathered as much information as possible from participants by telephone. If the participant had no telephone or could not be contacted by telephone, data were collected in person. COVID-19 precautions: trial teams were trained on COVID-19 precautions and used personal protective equipment whilst in the villages for trial-related activities.After restarting the trial between June and September 2020 in a phased manner, some trial activities were suspended again in all the trial villages from April to June 2021 due to the second wave of COVID-19 cases and lockdown imposed in Satna, Madhya Pradesh. Trial timelines were also revised, with outcomes measured later than originally planned.Trial registrationClinical Trial Registry of India CTRI/2019/05/019296. Registered 23 May 2019.https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MzExOTg=&Enc=&userName=champion2.

The effects of intermittent fasting on body composition and cardiometabolic health in adults with prediabetes or type 2 diabetes: A systematic review and meta-analysis.

To perform a meta-analysis to investigate the effects of intermittent fasting (IF), as compared with either a control diet (CON) and/or calorie restriction (CR), on body composition and cardiometabolic health in individuals with prediabetes and type 2 diabetes (T2D). PubMed, Web of Science, and Scopus were searched from their inception to March 2024 to identify original randomized trials with parallel or crossover designs that studied the effects of IF on body composition and cardiometabolic health. Weighted mean differences (WMDs) or standardized mean differences with 95% confidence intervals (CIs) were calculated using random-effects models. Overall, 14 studies involving 1101 adults with prediabetes or T2D were included in the meta-analysis. IF decreased body weight (WMD -4.56 kg [95% CI -6.23 to -2.83]; p = 0.001), body mass index (BMI; WMD -1.99 kg.m2 [95% CI -2.74 to -1.23]; p = 0.001), glycated haemoglobin (HbA1c; WMD -0.81% [95% CI -1.24 to -0.38]; p = 0.001), fasting glucose (WMD -0.36 mmol/L [95% CI -0.63 to -0.09]; p = 0.008), total cholesterol (WMD -0.31 mmol/L [95% CI -0.60 to -0.02]; p = 0.03) and triglycerides (WMD -0.14 mmol/L [95% CI -0.27 to -0.01]; p = 0.02), but did not significantly decrease fat mass, insulin, low-densitiy lipoprotein, high-density lipoprotein, or blood pressure as compared with CON. Furthermore, IF decreased body weight (WMD -1.14 kg [95% CI -1.69 to -0.60]; p = 0.001) and BMI (WMD -0.43 kg.m2 [95% CI -0.58 to -0.27]; p = 0.001), but did not significantly affect fat mass, lean body mass, visceral fat, insulin, HbA1c, lipid profiles or blood pressure. Intermittent fasting is effective for weight loss and specific cardiometabolic health markers in individuals with prediabetes or T2D. Additionally, IF is associated with a reduction in body weight and BMI compared to CR, without effects on glycaemic markers, lipid profiles or blood pressure.

Fetal femur length and risk of diabetes in adolescence: a prospective cohort study

BackgroundDiabetes is more apparent in adulthood but may be dormant in childhood and originates during early fetal development. In fetal biometry, femur length (FL) is crucial for assessing fetal growth and development. This study aimed to assess potential associations between fetal femur growth and prediabetic biomarkers in Bangladeshi children.MethodsA cohort study embedded in a population-based maternal food and micronutrient supplementation (MINIMat) trial was conducted in Matlab, Bangladesh. The children in the cohort were followed up until 15 years of age. In the original trial, pregnancy was confirmed by ultrasound before 13 gestational weeks (GWs). Afterward, ultrasound assessments were performed at 14, 19, and 30 GWs. FL was measured from one end to the other, capturing a complete femoral image. The FL was standardized by GW, and a z-score was calculated. FBG and HbA1c levels were determined in plasma and whole blood, and the triglyceride–glucose index, a biomarker of insulin resistance, was calculated as Ln [fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2]. Multivariable linear regression analysis using a generalized linear model was performed to estimate the effects of FL at 14, 19 and 30 GWs on prediabetic biomarkers at 9 and 15 years of age. Maternal micronutrient and food supplementation group, parity, child sex, and BMI at 9 years or 15 years were included as covariates.ResultsA total of 1.2% (6/515) of the participants had impaired fasting glucose during preadolescence, which increased to 3.5% (15/433) during adolescence. At 9 years, 6.3% (32/508) of the participants had elevated HbA1c%, which increased to 28% (120/431) at 15 years. Additionally, the TyG index increased from 9.5% (49/515) (during preadolescence) to 13% (56/433) (during adolescence). A one standard deviation decrease in FL at 14 and 19 GWs was associated with increased FBG (β = − 0.44 [− 0.88, − 0.004], P = 0.048; β = − 0.59 [− 1.12, − 0.05], P = 0.031) and HbA1c (β = − 0.01; [− 0.03, -0.005], P = 0.007; β = − 0.01 [− 0.03, − 0.003], P = 0.018) levels at 15 years. FL was not associated with diabetic biomarkers at 9 years.ConclusionMid-trimester impaired femur growth may be associated with elevated prediabetic biomarkers in Bangladeshi adolescents.

Quality of life and patient-reported toxicities in patients with advanced Merkel cell carcinoma treated with combined nivolumab and ipilimumab with or without stereotactic body radiation therapy.

Merkel cell carcinoma is a rare skin cancer associated with poor survival. Based on a previous Phase II trial of adults with advanced Merkel cell carcinoma by Kim and colleagues (2022), there is now a strong rationale for combination therapy (i.e., nivolumab and ipilimumab) to become a treatment option for patients with advanced Merkel cell carcinoma. The goal of this paper was to report on the secondary outcome of quality of life (QOL) among patients on this trial. Patients receiving combined nivolumab and ipilimumab, with or without stereotactic body radiation therapy (SBRT), completed the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 prior to starting treatment and every 2 weeks thereafter. Changes in QOL during treatment and post-treatment were evaluated using piecewise random-effects mixed models. Exploratory analyses compared changes in QOL between study arms. The original trial was registered with ClinicalTrials.gov (NCT03071406). Study participants (n = 50) reported no changes in overall QOL (ps > 0.05), but emotional functioning improved during treatment (p = 0.01). Cognitive and social functioning worsened post-treatment (ps < 0.01). In general, patients treated with combination therapy only (n = 25) reported no change in QOL over time, whereas patients also treated with SBRT (n = 25) consistently demonstrated worsening QOL post-treatment. QOL is generally preserved in patients treated with combination therapy, but the addition of SBRT may worsen QOL. Combined with clinical efficacy data published previously, results support the use of combination therapy with nivolumab and ipilimumab as a treatment option for patients with advanced Merkel cell carcinoma.

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF

BackgroundThe extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition...

Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial.

Oliceridine is a novel G protein-biased ligand μ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain. Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs). 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85-2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed. Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg. The trial is registered at chictr.org.cn (ChiCTR2100047180).

COVID-19 Modified mRNA “Vaccines”: Lessons Learned from Clinical Trials, Mass Vaccination, and the Bio-Pharmaceutical Complex, Part 1

Our understanding of COVID-19 synthetic, modified mRNA (modmRNA) products and their public health impact has evolved substantially since December 2020. Published reports from the original randomized placebo-controlled trials concluded that the modmRNA injections could greatly reduce COVID-19 symptoms. However, the premature termination of both trials obviated any reliable assessment of potential adverse events due to an insufficient timeframe for proper safety evaluation. Following authorization of the modmRNA products for global distribution, problems with the methods and execution of the trials have emerged. The usual safety testing protocols and toxicology requirements were bypassed. Many key trial findings were either misreported or omitted entirely from published trial reports. By implication, the secondary estimates of excess morbidity and mortality in both trials must be deemed underestimates. Rigorous re-analyses of trial data and post-marketing surveillance studies indicate a substantial degree of modmRNA-related harms than was initially reported. Confidential Pfizer documents had revealed 1.6 million adverse events by August 2022. A third were serious injuries to cardiovascular, neurological, thrombotic, immunological, and reproductive systems, along with an alarming increase in cancers. Moreover, well-designed studies have shown that repeated modmRNA injections cause immune dysfunction, thereby potentially contributing to heightened susceptibility to SARS-CoV-2 infections and increased risks of COVID-19. This paper also discusses the insidious influence of the Bio-Pharmaceutical Complex, a closely coordinated collaboration between public health organizations, pharmaceutical companies, and regulatory agencies. We recommend a global moratorium on the modmRNA products until proper safety and toxicological studies are conducted.

Bayesian Interim Analysis and Efficiency of Phase III Randomized Trials.

Improving the efficiency of interim assessments in phase III trials should reduce trial costs, hasten the approval of efficacious therapies, and mitigate patient exposure to disadvantageous randomizations. We hypothesized that in silico Bayesian early stopping rules improve the efficiency of phase III trials compared with the original frequentist analysis without compromising overall interpretation. Cross-sectional analysis. 230 randomized phase III oncology trials enrolling 184,752 participants. Individual patient-level data were manually reconstructed from primary endpoint Kaplan-Meier curves. Trial accruals were simulated 100 times per trial and leveraged published patient outcomes such that only the accrual dynamics, and not the patient outcomes, were randomly varied. Early stopping was triggered per simulation if interim analysis demonstrated ≥ 85% probability of minimum clinically important difference/3 for efficacy or futility. Trial-level early closure was defined by stopping frequencies ≥ 0.75. A total of 12,451 simulations (54%) met early stopping criteria. Trial-level early stopping frequency was highly predictive of the published outcome (OR, 7.24; posterior probability of association, >99.99%; AUC, 0.91; P < 0.0001). Trial-level early closure was recommended for 82 trials (36%), including 62 trials (76%) which had performed frequentist interim analysis. Bayesian early stopping rules were 96% sensitive (95% CI, 91% to 98%) for detecting trials with a primary endpoint difference, and there was a high level of agreement in overall trial interpretation (Bayesian Cohen's κ, 0.95; 95% CrI, 0.92 to 0.99). However, Bayesian interim analysis was associated with >99.99% posterior probability of reducing patient enrollment requirements ( P < 0.0001), with an estimated cumulative enrollment reduction of 20,543 patients (11%; 89 patients averaged equally over all studied trials) and an estimated cumulative cost savings of 851 million USD (3.7 million USD averaged equally over all studied trials). Bayesian interim analyses may improve randomized trial efficiency by reducing enrollment requirements without compromising trial interpretation. Increased utilization of Bayesian interim analysis has the potential to reduce costs of late-phase trials, reduce patient exposures to ineffective therapies, and accelerate approvals of effective therapies. Question: What are the effects of Bayesian early stopping rules on the efficiency of phase III randomized oncology trials?Findings: Individual-patient level outcomes were reconstructed for 184,752 patients from 230 trials. Compared with the original interim analysis strategy, in silico Bayesian interim analysis reduced patient enrollment requirements and preserved the original trial interpretation. Meaning: Bayesian interim analysis may improve the efficiency of conducting randomized trials, leading to reduced costs, reduced exposure of patients to disadvantageous treatments, and accelerated approval of efficacious therapies.

Renal function in PUSH-AHF: a summary of newly released data from the 2024 Annual Congress of the Heart Failure Association of the ESC.

The Pragmatic Urinary Sodium-based algoritHm in Acute Heart Failure (PUSH-AHF) study, published in August of 2023, was the first randomized clinical trial to compare natriuresis-guided decongestion (based on spot urinary sodium measurement) to standard of care in patients with acute heart failure with congestion receiving loop diuretic therapy. Based on results from their trial, the authors concluded that natriuresis-guided loop diuretic treatment was safe and improved natriuresis and diuresis without impacting long-term clinical outcomes. The original PUSH-AHF trial included limited information about renal outcomes and left clinicians with important questions about how natriuresis-guided decongestion might affect their patients' renal function. On May 12, 2024, however, at the 2024 Annual Congress of the HFA-ESC, Dr. Kevin Damman provided an in-depth exploration of renal outcomes from the trial when he presented a pre-specified, secondary analysis, renal function in the PUSH-AHF trial. This review puts the sub-study findings into context by considering the history of the original trial from which they came from and explaining the need for a close study of its renal outcomes particularly. It highlights the potential impact of renal function in PUSH-AHF on clinical practice and future directions that should be considered by the cardiology research community.