Trial Reports Research Articles

Survival by depth of response and efficacy by International Metastatic Renal Cell Carcinoma Database Consortium Subgroup with lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma: analysis of the phase 3 randomized CLEAR study

Background: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival.Objective: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups.Design, setting, and participants: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC.Intervention: Patients were randomized 1:1:1 to lenvatinib 20mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment.Outcome measurements and statistical analysis: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1.Results and limitations: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75 % target-lesion reduction by 6 mo had a 24-mo OS probability of 91.7 %. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4 % vs 28.8 %) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified.Conclusions: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS.Patient summary: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a ‘‘complete response’’ or had their tumors shrunk by >75 % within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib.

The effectiveness of customised 3D-printed insoles on perceived pain, comfort, and completion time among frequent Park Runners: Study protocol for a pragmatic randomised controlled trial (The ZOLES RCT)

BackgroundRunning, a popular recreational activity, often leads to the experience of pain and discomfort among participants impacting performance and participation longevity. The ZOLES trial evaluates customised 3D-printed insoles for reducing pain in frequent parkrunners aged 35 and over. An innovative process of foot-scanning and responses to questions relating to size, pain, discomfort, and previous medical conditions are combined leading to the production of personalised 3D-printed orthotics. MethodsThe ZOLES trial is a pragmatic, outcome assessor blinded, randomised, controlled, superiority trial involving 200 recreational runners, randomised to receive either customised 3D-printed insoles (ZOLES) or to a "do-as-usual" control group. The study follows a robust protocol, ensuring adherence to established guidelines for clinical trials, and is based at St Mary's University, Twickenham, London. The primary outcome is change in running-related pain over a 10-week period, assessed using an 11-point Numeric Rating Scale. Secondary outcomes include overall pain and discomfort, running-related comfort, 5k-completion time, time-loss due to injuries, running exposure, and adherence to the intervention. A balanced-block randomisation process is stratified by sex and parkrun location, and an intention-to-treat analyses will be employed on all outcomes in the primary trial report. The trial includes a 52-week post-market surveillance to assess long-term effects of the customised insoles. DiscussionThe ZOLES trial aims to provide insights into real-world applicability and effectiveness of customised 3D-printed insoles in reducing running-related pain and enhancing overall running experience. Despite the limitation of a subjective primary outcome measure without participant blinding, the methodological rigor, including external outcome assessment and data handling, we anticipate results that are academically credible and applicable in real-world settings The results of this trial may have important implications for runners, clinicians, and the sports footwear industry, as evidence for the use of individualised insoles to improve running experience and prevention of pain may become evident. Trial registrationThe trial was pre-registered at ClinicalTrials.gov with the trial identifier NCT06034210 on September 4, 2023, and publicly posted on September 13, 2023 (https://clinicaltrials.gov/study/NCT06034210). Protocol versionVersion 1, September 27, 2023.

Biofield therapies: Guidelines for reporting clinical trials

A set of guidelines has been developed to help improve reporting of clinical trials of biofield therapies. The need for enhanced transparency when reporting trials of this family of integrative health practices, e.g., External Qigong, Healing Touch, Reiki and Therapeutic Touch, has been advocated in systematic reviews of these studies. The guidelines, called Biofield Therapies: Reporting Evidence Guidelines (BiFi REGs), supplement CONSORT 2010 by including details of the intervention protocols relevant to biofield therapy trials. BiFi REGs evolved through a draft document created by a core group, two rounds of a Delphi process with an international group of subject matter experts and two panels, meeting via Zoom, which included editors of complementary and integrative medicine journals. BiFi REGs comprises a 15-item Intervention checklist. Modifications of two other CONSORT topic areas are also proposed to enhance their relevance to trials of biofield therapies. Included for each item are an explanation, and exemplars of reporting from peer-reviewed published reports of biofield therapy trials. When used in conjunction with all other items from CONSORT 2010, we anticipate that BiFi REGs will expedite the peer review process for biofield therapy trials, facilitate attempts at trial replication and help to inform decision-making in the clinical practice of biofield therapies.

Outcomes for patients with mCRPC and liver metastasis receiving 177-Lu-PSMA-617 treatment.

175 Background: It is well-known that patients with liver metastases from metastatic castration resistant prostate cancer (mCRPC) have poorer or transient responses to many forms of systemic therapy. Data on outcomes following treatment with Lutetium-177–PSMA-617 is scarce. The VISION trial reports hazard ratios for overall survival in the subgroup of patients with liver metastases without disclosing the absolute duration of survival. Using real-world clinical data, we examine this important subgroup of patients, describing their PSA response rates and survival. Methods: A single institution database was assembled to include all patients receiving 177-Lu-PSMA-617 at Mayo Clinic Rochester, MN, and starting treatment in the interval of March 2022 to March 2023. Baseline clinicopathologic and imaging characteristics were abstracted. Patients were categorized based on the presence or absence of measurable liver metastases on their baseline PSMA PET scan. Best PSA response while on treatment was annotated and reported as percent decline from baseline. Survival was calculated from date of first cycle of 177-Lu-PSMA-617. PSA50 response and overall survival (OS) outcomes for the two groups (liver metastases versus no liver metastases) were compared using Chi square test and Kaplan-Meier method, respectively. Those with available pre-treatment circulating tumor DNA (ctDNA) genomic profiling, performed by Guardant (83 gene panel), were assessed for the presence of pathogenic and likely pathogenic alterations. Findings are summarized using descriptive statistics. Results: The overall cohort consisted of 212 patients, including 29 (14%) with liver metastases on pre-treatment PSMA PET/CT. The median number of cycles received was 4 (range, 1-6) for patients with liver metastases and 6 (range, 1-6) for those without hepatic involvement. The observed PSA50 response trended lower for those with liver metastases (34.5% [10/29] versus 51% [94/183], p= 0.091). At median (IQR) follow-up of 10 (8-12) months, there was a numerical but not statistically significant difference in median OS (11.28 months versus NR, p=0.066). In the exploratory analysis of baseline ctDNA, BRCA2 copy number loss was relatively enriched among patients with liver metastases (4 of 19, 21%) versus patients without liver disease (5.7%, 9/158). Conclusions: Our data suggest that the presence of liver metastases predict poorer outcomes in patients receiving Lutetium-177–PSMA-617 treatment, which is similar to data reported with other forms of systemic therapy for mCRPC. To maximize the anti-tumor activity of radioligand therapy in the liver, combination approaches should be explored.

The impact of pre-biopsy MRI and additional testing on prostate cancer screening outcomes: A rapid review.

This work aims to examine the latest evidence on the impact of pre-biopsy MRI, in addition to prostate-specific antigen (PSA) testing, on health outcomes and quality of life. We conducted a literature search including PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) databases, with a limited scan of (i) guidelines and (ii) references from trial reports, from January 2005 to 25th January 2023. Two independent reviewers selected randomised controlled trials (RCT) and cohort studies which met our inclusion criteria. One hundred thirty-seven articles were identified, and seven trial articles were selected. Trial interventions were as follows: (i) PSA blood test, (ii) additional tests such as pre-biopsy multiparametric magnetic resonance imaging (mpMRI) and Biparametric MRI (bpMRI), and (iii) MRI targeted biopsy and standard biopsy. Compared with standard biopsy, MRI-based interventions led to increased detection of clinically significant cancers in three studies and decreased detection of clinically insignificant cancer (Gleason grade 3 + 3) in four studies. However, PROstate Magnetic resonance Imaging Study (PROMIS) and Stockholm3 with MRI (STHLM3-MRI) studies reported different trends depending on the scenario studied in PROMIS (MRI triage and MRI directed biopsy vs. MRI triage and standard biopsy) and thresholds used in STHLM3-MRI (≥0·11 and ≥0·15). MRI also helped 8%-49% of men avoid biopsy, in six out of seven studies, but not in STHLM3-MRI at ≥0.11. Interestingly, the proportion of men who experienced sepsis and UTI was low across studies. This review found that a combination of approaches, centred on the use of pre-biopsy MRI, may improve the detection of clinically significant cancers and reduce (i) the diagnosis of clinically insignificant cancers and (ii) unnecessary biopsies, compared with PSA testing and standard biopsy alone. However, the impact of such interventions on longer term outcomes such as prostate cancer-specific mortality has not yet been assessed.

Guidelines for reporting pediatric and child health clinical trial protocols and reports: study protocol for SPIRIT-Children and CONSORT-Children

BackgroundDespite the critical importance of clinical trials to provide evidence about the effects of intervention for children and youth, a paucity of published high-quality pediatric clinical trials persists. Sub-optimal reporting of key trial elements necessary to critically appraise and synthesize findings is prevalent. To harmonize and provide guidance for reporting in pediatric controlled clinical trial protocols and reports, reporting guideline extensions to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines specific to pediatrics are being developed: SPIRIT-Children (SPIRIT-C) and CONSORT-Children (CONSORT-C).MethodsThe development of SPIRIT-C/CONSORT-C will be informed by the Enhancing the Quality and Transparency of Health Research Quality (EQUATOR) method for reporting guideline development in the following stages: (1) generation of a preliminary list of candidate items, informed by (a) items developed during initial development efforts and child relevant items from recent published SPIRIT and CONSORT extensions; (b) two systematic reviews and environmental scan of the literature; (c) workshops with young people; (2) an international Delphi study, where a wide range of panelists will vote on the inclusion or exclusion of candidate items on a nine-point Likert scale; (3) a consensus meeting to discuss items that have not reached consensus in the Delphi study and to “lock” the checklist items; (4) pilot testing of items and definitions to ensure that they are understandable, useful, and applicable; and (5) a final project meeting to discuss each item in the context of pilot test results. Key partners, including young people (ages 12–24 years) and family caregivers (e.g., parents) with lived experiences with pediatric clinical trials, and individuals with expertise and involvement in pediatric trials will be involved throughout the project. SPIRIT-C/CONSORT-C will be disseminated through publications, academic conferences, and endorsement by pediatric journals and relevant research networks and organizations.DiscussionSPIRIT/CONSORT-C may serve as resources to facilitate comprehensive reporting needed to understand pediatric clinical trial protocols and reports, which may improve transparency within pediatric clinical trials and reduce research waste.Trial RegistrationThe development of these reporting guidelines is registered with the EQUATOR Network: SPIRIT-Children (https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials-protocols/#35) and CONSORT-Children (https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-clinical-trials/#CHILD).

Peer Learning Has Double Effects in Clinical Research Education: A Qualitative Study.

Peer learning has been recognized for its effectiveness in health professional education. However, its effects on clinical research education are not clear and were explored qualitatively in this study. The peer-learning method was implemented in a clinical research education seminar for early-career physicians at a children's and mothers' hospital in 2019. We conducted semistructured interviews with participants about peer-learning experience and qualitatively analyzed verbatim transcripts using Engeström's "activity theory" framework. From framework analysis, learning processes were extracted mainly in four domains, namely, (a) instrument and its usage: research design and its match with research question, (b) outcome: research result, (c) community: seminar, and (d) division of labor: roles of participants and staff. In this report of a peer-learning trial in postgraduate clinical research education, the following two pathways of peer-learning effects were abstracted. The indirect pathway was the presentations by experienced participants providing concrete examples of research processes. The direct pathway was the questions from experienced participants to beginners about specific and concrete questions. There were also two points to consider in peer learning in clinical research education: gaps in premise knowledge and beginners' frustration about expected outcomes. We believe that these extracted pathways and points imply the significance and considerations for continuing the peer-learning trial in clinical research education. Future tasks are to promote clinical research education with a view to the learning effects, not only on individuals, but also on groups.

Benefits of equine therapies on the cognitive of children with Autism Spectrum Disorder: systematic review and meta-analysis

Autistic Spectrum Disorder (ASD) is a neurodevelopmental disorder whose main characteristics are changes in cognitive areas and social deficit. The aim of this study was to describe the benefits of equine activities and therapies in the cognitive areas of children with ASD/autism. This is a systematic review with meta-analysis of scientific articles indexed in the following online databases: BVS Salud, Periódicos CAPES, PubMed, Science.Gov and SCIELO, in addition to the website of the National Association of Riding Therapy (ANDE), Brazil, and the REDALYC platform, for inclusion of additional studies. As per Preferred Reporting Items for Systematic Reviews and Meta-analysis and assessed for quality by Consolidated Standards for Reporting of Trials - CONSORT checklist. There were 29 articles eligible for analysis, totaling 591 participants. The methods used in the interventions and evaluations differed between the articles, but it was possible to identify benefits of horse-assisted activities and therapies in the cognitive areas of children with ASD and autism, especially with regard to social and emotional cognitive, as well as, in reducing irritability, hyperactivity and aggressiveness. Therefore, this systematic review confirms the benefits of horse-assisted activities and therapies in the cognitive areas of children with ASD and autism with intellectual deficit.

Kisspeptin and its Current Clinical Status- A Systematic Review.

Kisspeptin was initially known as metastin for its role in suppressing metastasis in melanoma and breast cancer. Later, based on its ability to stimulate GPR54, its importance in maintaining an intact hypothalamic-pituitary-ovarian axis was recognised, which is the basis for the widespread application of the drug in several conditions such as secondary amenorrhea, regulation of puberty onset, ovarian function, trophoblast invasion, fertility regulation, parturition, and lactation. This systematic study aims to evaluate the current status of kisspentin in clinical trials. The keywords 'kisspeptin' or 'metastin' were used in the clinicaltrials.gov website and Clinical Trial Registry of India (CTRI) to find eligible clinical trials or records carried out without time constraints until February 26, 2023. A total of 33 records were identified through clinical trial databases. All records were screened, and four trials were rejected as they failed to meet the inclusion criteria. Finally, 29 (87.9%) reports of interventional clinical trials with kisspeptin were reviewed. Kisspeptin can be viewed as a multipurpose drug with considerably fewer side effects due to its effects simulating normal physiological processes in our body.

The effects of insufficient sleep and adequate sleep on cognitive function in healthy adults

Study objectivesAlthough sleep affects a range of waking behaviors, the majority of studies have focused on sleep loss with relatively little attention on sustained periods of adequate sleep. The goal of this study was to use an experimental design to examine the effect of both of these sleep patterns on cognitive performance in healthy adults. MethodsThis study used a randomized crossover design. Participants who regularly slept 7-9 hours/night completed two 6-week intervention conditions, adequate sleep (maintenance of habitual bed/wake times) and insufficient sleep (reduction in sleep of 1.5 hours relative to adequate sleep), separated by a 2-6weeks (median=43days) washout period. Cognitive functioning was evaluated at baseline and endpoint of each intervention using the NIH Toolbox Cognition Battery. General linear models contrasted scores following each condition to the baseline of the first condition; the baseline of the second condition was included to evaluate practice effects. ResultsSixty-five participants (age 35.9 ± 4.9years, 89% women, 52% non-White race/ethnicity) completed study procedures. There was improvement in performance on the List Sorting Working Memory task after the adequate sleep condition that exceeded practice effects. Cognitive performance after insufficient sleep did not reach the level expected with practice and did not differ from baseline. A similar pattern was found on the Flanker Inhibitory Control and Attention task. ConclusionsThese findings contribute to our understanding of the complex interplay between sleep and cognition and demonstrate that consistent, stable sleep of at least 7 hours/night improves working memory and response inhibition in healthy adults. Clinical Trial RegistrationThe manuscript reports on data from two clinical trials: Impact of Sleep Restriction on Performance in Adults (URL: https://clinicaltrials.gov/ct2/show/NCT02960776, ID Number: NCT02960776) and Impact of Sleep Restriction in Women (URL: https://clinicaltrials.gov/ct2/show/NCT02835261, ID Number: NCT02835261).

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

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. 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. 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. 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. 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.

Biofield Therapies: Guidelines for Reporting Clinical Trials.

A set of guidelines has been developed to help improve reporting of clinical trials of biofield therapies. The need for enhanced transparency when reporting trials of this family of integrative health practices, eg, External Qigong, Healing Touch, Reiki and Therapeutic Touch, has been advocated in systematic reviews of these studies. The guidelines, called Biofield Therapies: Reporting Evidence Guidelines (BiFi REGs), supplement CONsolidated Standards of Reporting Trials (CONSORT) 2010 by including details of the intervention protocols relevant to biofield therapy trials. BiFi REGs evolved through a draft document created by a core group, two rounds of a Delphi process with an international group of subject matter experts and two panels, meeting via Zoom, which included editors of complementary and integrative medicine journals. BiFi REGs comprises a 15-item Intervention checklist. Modifications of two other CONSORT topic areas are also proposed to enhance their relevance to trials of biofield therapies. Included for each item are an explanation, and exemplars of reporting from peer-reviewed published reports of biofield therapy trials. When used in conjunction with all other items from CONSORT 2010, we anticipate that BiFi REGs will expedite the peer review process for biofield therapy trials, facilitate attempts at trial replication and help to inform decision-making in the clinical practice of biofield therapies.

Biomedical Natural Language Inference on Clinical trials using the BERT-based Models

Clinical trials are crucial in experimental medicine as they assess the safety and efficiency of new treatments. Due to its unstructured and plain language nature, clinical text data often presents challenges in understanding the relationships between various elements like disease, symptoms, diagnosis, and treatment. This task is challenging as the Multi-evidence Natural Language Inference for Clinical Trial Data (NLI4CT) requires intricate reasoning involving textual and numerical elements. It involves integrating information from one or two Clinical Trial Reports (CTRs) to validate hypotheses, demanding a multi-faceted approach. To address these problems, we use BERT-base models’ ability to predict entailment or contradiction labels and compare the use of transformer-based feature extraction and pre-trained models. We utilize seven pre-trained models, including six BERT-based and one T5-based model: BERT-base uncased, BioBERT-base-cased-v1.1-mnli, DeBERTa-v3-base-mnli-fever-anli, DeBERTa-v3-base-mnli-fever-docnli-ling-2c, DeBERTa-large-mnli, BioLinkBERT-base, and Flan-T5-base. We achieve an F1-score of 61% on both DeBERTa-v3-base-mnli-fever-anli and DeBERTa-large-mnli models and 95% faithfulness on the BioLinkBERT-base model.

RAM Cannula Versus Bi-Nasal Prongs as Respiratory Device Interfaces in Neonates of Thirty-Two or More Weeks of Gestation With Respiratory Distress: The First "ProRAM" Randomized Trial Report.

Using bilateral short nasal prongs as an interface for noninvasive respiratory support is challenging, and it is associated with nasal injury. We aimed to compare RAM cannula with nasal prongs in delivering noninvasive ventilation to newborn infants. This is a single-center randomized trial (trial registry: ISRCTN10561691). The setting involves a tertiary neonatal unit with a capacity of 30 beds and more than 13 years of experience in neonatal noninvasive ventilation. We included 50 infants born at ≥ 32 weeks of gestation, who had respiratory distress at birth. We excluded those with major congenital anomalies and those who required intubation in the delivery room. Primary outcomes were intubation rate and use of noninvasive positive-pressure ventilation (NIPPV); other outcomes included air leak and nasal injury rate. The infants were assigned using randomly generated numbers into bi-nasal prong and RAM canula groups in a 1:1 ratio. Two and four babies in the RAM and prong groups, respectively, were upgraded to NIPPV (P = 0.600). One versus no baby in the RAM vs. prong groups was intubated (P = 1.000). Newborns in the prong group required oxygen support for a longer period (mean duration: 154.6 ± 255.2 h) than those in the RAM group (40.7 ± 72.6 h, P = 0.030). None of the patients in the RAM group had traumatic nasal injury compared to five babies in the prong group (P = 0.050). Four babies in our study developed air leaks, with two in each group. The use of RAM cannula in delivering noninvasive ventilation to newborns ≥ 32 weeks of age did not affect the noninvasive ventilation failure rate or incidence of air leak. The use was associated with a shorter duration of respiratory support and a reduced risk of nasal septal injury.

Insights into the statistical quality of randomized clinical trial reports submitted to the British Journal of Dermatology.

Insights into the statistical quality of randomized clinical trial reports submitted to the British Journal of Dermatology.

Pomegranate (Punica granatum L.) and Its Rich Ellagitannins as Potential Inhibitors in Ulcerative Colitis.

Ulcerative colitis, an immune-mediated inflammatory disease of the gastrointestinal tract, places a significant financial burden on patients and the healthcare system. Recently, reviews of the pomegranate and the abundant medicinal applications of its ellagitannins, as well as its pharmacological action, phytochemicals, metabolism, and pharmacokinetics, have been completed. However, summaries on their anti-ulcerative colitis effects are lacking. Numerous preclinical animal investigations and clinical human trial reports demonstrated the specific therapeutic effects of pomegranate and the effect of its ellagitannins against ulcerative colitis. According to the literature collected by Sci-finder and PubMed databases over the past 20 years, this is the first review that has compiled references regarding how the rich ellagitannins found in pomegranate have altered the ulcerative colitis. It was suggested that the various parts of pomegranates and their rich ellagitannins (especially their primary components, punicalagin, and ellagic acid) can inhibit oxidant and inflammatory processes, regulate the intestinal barrier and flora, and provide an anti-ulcerative colitis resource through dietary management.

Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii.

Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) remain a clinical challenge due to limited treatment options. Recently, cefiderocol, a novel siderophore cephalosporin, and sulbactam-durlobactam, a bactericidal β-lactam-β-lactamase inhibitor combination, have been approved by the Food and Drug Administration for the treatment of A. baumannii infections. In this review, we discuss the mechanisms of action of and resistance to cefiderocol and sulbactam-durlobactam, the antimicrobial susceptibility of A. baumannii isolates to these drugs, as well as the clinical effectiveness of cefiderocol and sulbactam/durlobactam-based regimens against CRAB. Overall, cefiderocol and sulbactam-durlobactam show an excellent antimicrobial activity against CRAB. The review of clinical studies evaluating the efficacy of cefiderocol therapy against CRAB indicates it is non-inferior to colistin/other treatments for CRAB infections, with a better safety profile. Combination treatment is not associated with improved outcomes compared to monotherapy. Higher mortality rates are often associated with prior patient comorbidities and the severity of the underlying infection. Regarding sulbactam-durlobactam, current data from the pivotal clinical trial and case reports suggest this antibiotic combination could be a valuable option in critically ill patients affected by CRAB infections, in particular where no other antibiotic appears to be effective.

Cardiac assessment and inflammatory markers in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV2 (PIMS-TS) treated with methylprednisolone versus intravenous immunoglobulins: 6-month follow-up outcomes of the randomised controlled Swissped RECOVERY trial

Previous findings from the Swissped RECOVERY trial showed that patients with Pediatric Inflammatory Multisystem Syndrome-Temporally Associated with SARS-CoV-2 (PIMS-TS) who were randomly assigned to intravenous immunoglobulins or methylprednisolone have a comparable length of hospital stay. Here, we report the 6-month follow-up outcomes of cardiac pathologies and normalisation of clinical or laboratory signs of inflammation from this study population. This pre-planned follow-up of patients with PIMS-TS included the Swissped RECOVERY Trial reports on the 6-month outcomes of the cohort after randomisation, with a focus on cardiac, haematological, and biochemical findings. The trial was an investigator-initiated randomised multicentre open-label two-arm trial in children and adolescents hospitalised with PIMS-TS at ten hospitals in Switzerland. Cardiological assessments and laboratory analyses were prospectively collected in the intention-to-treat analysis on pre-defined intervals after hospital discharge. Differences between randomised arms were investigated using Chi-square test for categorical and Wilcoxon test for continuous variables. The trial is registered with the Swiss National Clinical Trials Portal (SNCTP000004720) and ClinicalTrials.gov (NCT04826588). Between May 21, 2021 and April 15, 2022, 75 patients with a median age of 9.1 years (IQR 6.2-12.2) were included in the intention-to-treat population (37 in the methylprednisolone group and 38 in the intravenous immunoglobulin group). During follow-up, the incidence of abnormal left ventricular systolic function, coronary artery aneurysms (CAA), and other signs of inflammation were comparable in both groups. However, we detected cardiac abnormalities with low incidence and a mild degree grade of pathology. CAAs were observed in 2/38 children (5.3%) in the IVIG group and 1/37 children (2.7%) in the methylprednisolone group at 6-month follow-up (difference proportion 0.75; 95% confidence interval (CI)-0.05 to 1.0; p=0.39). Methylprednisolone alone may be an acceptable first-line treatment as left ventricular systolic dysfunction and clinical/laboratory evidence for inflammation quickly resolved in all children. However, our findings need further confirmation through larger studies as our sample size is likely to be of insufficient power to address rare clinically relevant adverse outcomes. NOMIS, Vontobel, and Gaydoul Foundation.

Gimema Seifem Real-Life Study VS Randomized CPX-351 Registrative Trial for Older Patients with Secondary ACUTE Myeloid Leukemia: An Unanchored Matching-Adjusted Indirect Comparison of Infection Rates and Survival Outcomes

Background: Unanchored MAIC (Matching-Adjusted Indirect Comparison) is an ITC (Indirect Treatment Comparison) method adjusting for cross-trial heterogeneity in patient demographic or disease that are believed to be either prognostic or treatment effect modifiers. In this analysis, two trials for adults with secondary acute myeloid leukemia (AML) were compared by an unanchored MAIC. Aims: The GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto)-SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) real-life study on the use of CPX-351 (Fianchi et al- Cancers 2023) was weighted for the aggregated patients characteristics from the standard arm(“7+3”) of the CPX-351 trial (cytarabine and daunorubicin Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia, Lancet et al - JCO 2018). This analysis aimed to test the feasibility to compare individual patients' data with aggregated published results and evaluate the rate of infections of CPX-351 in real life vs the “3+7” regimen and their impact on the survival outcomes. Methods: Patients-level data from GIMEMA-SEIFEM on the use of CPX-351 (n=202) and aggregated data from CPX-351 (“3+7” arm, n=156) trials were used to conduct an unanchored MAIC. GIMEMA-SEIFEM study included included all consecutive patients with AMLfrom 30 Italian hematologic centers who received at least 1 course of CPX-351 from July 2018 to June 2021 according to clinical practice. Patients from the GIMEMA-SEIFEM study were weighted to balance with baseline characteristics from the USA and Canada cohoort. Accordingly, weighted Overall and Event-free survival (w-OS, w-EFS) estimates, as well as rates of febrile neutropenia, pneumonia, CR, and the interval of PMN recovery, were computed. Results: Four potential effect modifiers were identified and used for adjustment: age, sex, AML subtype (tAML, sAML, MRC), and prior HMA exposure. Median w-OS and w-EFS were 14.2 (95%CI: 11.6-18.7) and 7.4 (95%CI: 3.0-10.6) months, respectively. These estimates were slightly lower than those documented in the most recent report of the GIMEMA-SEIFEM trial (median OS 17.7 months and median EFS 9.8 months) and higher than the results obtained by the standard arm of the CPX-351 trial (median OS 5.9 months, median EFS 1.3 months). Weighted rates of febrile neutropenia, pneumonia, CR, and interval of PMN recovery were comparable to the observed values and better than observed in the standard arm of the CPX-351 trial for all considered variables, except for febrile neutropenia (Table 1). Conclusions: The MAIC method allowed a robust comparison of two clinical trials for the treatment of AML patients. After adjustment, survival outcomes of the real-life cohort were slightly lower than the observed estimates and higher than the observed in the standard arm of the CPX-351 trial. Pneumonia risk was confirmed lower in GIMEMA-SEIFEM CPX-351 matched group than in “3+7” arm. This pilot analysis underlined the potentiality of this statistical method. Indeed, it could be useful to compare with high accuracy studies with strong differences in the selection of patients.

Adherence to key recommendations for design and analysis of stepped-wedge cluster randomized trials: A review of trials published 2016-2022.

The stepped-wedge cluster randomized trial (SW-CRT), in which clusters are randomized to a time at which they will transition to the intervention condition - rather than a trial arm - is a relatively new design. SW-CRTs have additional design and analytical considerations compared to conventional parallel arm trials. To inform future methodological development, including guidance for trialists and the selection of parameters for statistical simulation studies, we conducted a review of recently published SW-CRTs. Specific objectives were to describe (1) the types of designs used in practice, (2) adherence to key requirements for statistical analysis, and (3) practices around covariate adjustment. We also examined changes in adherence over time and by journal impact factor. We used electronic searches to identify primary reports of SW-CRTs published 2016-2022. Two reviewers extracted information from each trial report and its protocol, if available, and resolved disagreements through discussion. We identified 160 eligible trials, randomizing a median (Q1-Q3) of 11 (8-18) clusters to 5 (4-7) sequences. The majority (122, 76%) were cross-sectional (almost all with continuous recruitment), 23 (14%) were closed cohorts and 15 (9%) open cohorts. Many trials had complex design features such as multiple or multivariate primary outcomes (50, 31%) or time-dependent repeated measures (27, 22%). The most common type of primary outcome was binary (51%); continuous outcomes were less common (26%). The most frequently used method of analysis was a generalized linear mixed model (112, 70%); generalized estimating equations were used less frequently (12, 8%). Among 142 trials with fewer than 40 clusters, only 9 (6%) reported using methods appropriate for a small number of clusters. Statistical analyses clearly adjusted for time effects in 119 (74%), for within-cluster correlations in 132 (83%), and for distinct between-period correlations in 13 (8%). Covariates were included in the primary analysis of the primary outcome in 82 (51%) and were most often individual-level covariates; however, clear and complete pre-specification of covariates was uncommon. Adherence to some key methodological requirements (adjusting for time effects, accounting for within-period correlation) was higher among trials published in higher versus lower impact factor journals. Substantial improvements over time were not observed although a slight improvement was observed in the proportion accounting for a distinct between-period correlation. Future methods development should prioritize methods for SW-CRTs with binary or time-to-event outcomes, small numbers of clusters, continuous recruitment designs, multivariate outcomes, or time-dependent repeated measures. Trialists, journal editors, and peer reviewers should be aware that SW-CRTs have additional methodological requirements over parallel arm designs including the need to account for period effects as well as complex intracluster correlations.