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Objectives: To explore patient and staff experience of best-practice rehabilitation advice (one session of face-to-face self-management advice with up to two additional optional sessions) compared with progressive functional exercise (up to six sessions of face-to-face physiotherapy) after ankle fracture., Design: The study drew on phenomenology using interviews and a focus group., Setting: Participants were from three NHS Trusts in England, UK., Participants: A purposive sample of 20 patients with ankle (malleolar) fractures from the Ankle Fracture Treatment: Enhancing Rehabilitation-pilot trial (now completed) were interviewed (median 50 min) from May 2019 to January 2020. They were 6 months post injury, over 50 years of age, (median 66, 12 females) and had received surgical or non-surgical treatment (seven internal fixation surgery, seven close contact casting, six walking boot). A focus group of five physiotherapists who had provided the study interventions (2.5 hours) was undertaken., Results: The findings show the acceptability of both interventions through the themes, 'being helped' (for patients) and 'developing expertise' (for staff) with subthemes of choosing and progressing. Progressive exercise added value with a perceived increase in strength, motion, ability to undertake activities and continued use of the workbook. Both staff and patients valued physiotherapy expertise demonstrated through interpersonal skills, advice, individualised exercise plans and active monitoring of progression. Best practice advice was particularly helpful in the early stages of recovery and with the use of mobility aids., Conclusion: Both interventions were acceptable but progressive exercise was highly valued by patients. Developing expertise through experiential learning enabled staff to facilitate progression. Adjustments to the workbook and the addition of exercises for continued recovery in the best practice advice would enhance a future study. Research during treatment provision may provide further insights into the challenges of facilitating progression of exercise., Trial Registration: ISRCTN16612336; AFTER-pilot trial)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract Background Recruiting a sufficient number of patients is often a challenge for conducting clinical trials. Published data reveal that only 10% of eligible patients according to inclusion and exclusion criteria are enrolled in clinical trials. Consequentially, identifying barriers and facilitators may improve enrollment. These factors may differ in the pediatric population, for example, due to the involvement of parents in the decision-making process. We aimed to conduct an overview of systematic reviews to summarize the barriers and facilitators influencing the enrollment of pediatric participants in clinical trials. Methods A systematic literature search in PubMed and Epistemonikos of published systematic reviews focusing on barriers and facilitators influencing the enrollment of pediatric patients in clinical trials was conducted. Study selection, data extraction, and quality assessment were performed by two authors independently. The methodological quality was judged using a critical appraisal tool. Finally, data were narratively synthesized. Results Of 283 identified systematic reviews, four met the inclusion criteria and were included in the overview. Parents belonging to an ethnic minority or having low socioeconomic status were identified as barriers to enrollment whereas higher parental education and higher age served as facilitators. Additionally, existing expectations, previous treatment experiences and preferences, study duration, type of control group, and the child’s attitude toward study participation could favor or hinder participation. Furthermore, physicians’ opinions of study-related treatments may also influence the enrollment process. Conclusion This overview provides a summary of barriers and facilitators to the enrollment of pediatric patients in clinical trials. Taking into account this information may enhance the enrollment of this hard-to-reach population.

Abstract Alzheimer’s Disease (AD), a neurodegenerative disorder escalating worldwide, remains incurable with existing interventions merely mitigating symptoms. Hydralazine, an antihypertensive agent, has displayed neuroprotective potential in AD animal models via amplification of mitochondrial functionality and stimulation of stress management and repair pathways. Nevertheless, its effectiveness and tolerability in human AD cohorts are yet to be confirmed. This study protocol describes the design of an ongoing, single-center, randomized, triple-blind, placebo-controlled trial to assess hydralazine’s effects on cognitive function in mild to moderate -stage AD patients. We will enroll 424 patients aged 50 and older, meeting NINCDS-ADRDA criteria for probable AD with Mini-Mental State Examination scores from 12–26. They’ll be randomly assigned to receive either hydralazine HCL (25 mg, thrice daily) or a placebo for 12 months. The primary outcome is the Alzheimer’s Disease Assessment Scale change from baseline to 12 months. Secondary outcomes include various measures using Lawton instrumental activities of daily living scale, neuropsychiatry inventory, and caregiver activity survey. This trial will explore the potential benefits and risks of hydralazine in mild to moderate AD treatment. It’s the first trial examining hydralazine’s impact on mild to moderate -stage AD in human and is registered at the Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552AQ, registered 13/04/2021). Ethics approval was granted by the Research Ethics Committee of the National Institute for Medical Research Development (IR.NIMAD.REC.1398.424), following the SPIRIT Statement guidelines. Findings will be disseminated via peer-reviewed publications and conferences. This inaugural human clinical trial evaluates hydralazine’s impact on patients in the mild to moderate AD. Executed with a randomized, triple-blind, placebo-controlled methodology, this study incorporates a significant sample size and an extended monitoring duration. Multiple parameters, including cognitive capabilities, will be assessed. Potential limitations include the inherent homogeneity of the AD cohort, the lack of biomarker assays, and the unpredictable progression of the disease. Notably, the study might not elucidate the protracted effects of hydralazine beyond a 12-month period. Another limitation of our clinical trial is that patients were diagnosed with Alzheimer’s disease based solely on clinical evaluation and MRI findings, without the inclusion of specific biomarkers, which may impact the accuracy and specificity of the diagnosis. Trial registration: Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552, registered 13/04/2021).

Abstract Background Chronic insomnia increases the risk of various health problems and mental illness. Existing research suggests promise for both transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) in treating chronic insomnia individually. However, the combined effects of tDCS and rTMS on this condition remain unclear. This study aimed to verify the efficacy and safety of tDCS combined with rTMS for the treatment of adult patients with chronic insomnia. Methods This was a randomised double-blind parallel-group controlled study. Overall, 157 participants with chronic insomnia were randomly assigned to one of three neurotherapy regimens: tDCS + rTMS, sham tDCS + rTMS, or tDCS + sham rTMS. All groups received 20 treatment sessions over 4 consecutive weeks. The primary outcome was the change in patients’ sleep as assessed by the Pittsburgh Sleep Quality Index (PSQI) at 2 weeks, 4 weeks, and 3 months of follow-up. The secondary outcome was the assessment of different dimensions of depression and anxiety in patients through the Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA), as well as the occurrence of adverse events. Results Throughout the intervention and after the 3-month follow-up, the tDCS + rTMS group had significantly reduced total PSQI scores compared with the other two groups [tDCS + rTMS, 9.21 vs. sham tDCS + rTMS, 10.03; difference − 1.10; 95% confidence interval (CI), − 1.82 to − 0.38; p = 0.003; tDCS + rTMS, 9.21 vs. tDCS + sham rTMS, 10.76; difference − 2.14; 95% CI, − 2.90 to − 1.38; p

Abstract Ketogenic diet (KD) is an excess fat, enough protein, and minimal carbohydrate diet. The high fat content in KD lowers the oesophageal sphincter tone, slows gastric emptying, and decreases intestinal transit time. The primary aim of the current clinical trial was to study the effect of L-carnitine supplementation on gastric emptying in children with drug resistant epilepsy (DRE) on KD. Assessment of the protective effect of L-carnitine on bowel function and habits in those patients was a secondary aim. The current study recruited 30 patients aged 12 months to 18 years newly diagnosed with DRE assigned to start KD who were following up at the Pediatric Clinical Nutrition and Neurology Outpatient Clinics or were admitted due to DRE at the Pediatric Neurology Inpatient Department, Children’s Hospital, Ain Shams University (Egypt). Participants were assigned randomly into 2 arms; arm I: received KD with L-carnitine supplementation, arm II: received KD only. Patients were assessed at baseline and after 3 months of starting KD, the assessments of children included: 24-hour dietary recall, Chalfont Seizures Severity Scale, gastrointestinal symptoms score and Bristol stool chart, frequency of defecation per week, anthropometric measurements assessment, fasting serum lipid profile and measurement of the antral length by ultrasound. There was significant increase in antral length in the patients who received KD with L-carnitine supplementation compared to the non-supplemented group. The antral length showed a significant negative correlation with GI symptoms score in all cases and the L-carnitine supplemented group. It also showed a significant positive correlation with Bristol stool score in all patients and a significant positive correlation with stool frequency in the L-carnitine supplemented group only. L-carnitine supplementation to children with DRE on KD has a significant role in improving gastric motility and it increases the frequency of defecation. Further studies are recommended to explore additional benefits, meanwhile it is prudent to advise L-carnitine supplementation for such patients.

Abstract Background Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence. Methods Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing. Results Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4–20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7–100%) in the cohort of vaccinated patients. Conclusion Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses. Clinical trial registration number NCT02348320.

Abstract Background African children with severe malaria are at increased risk of non-typhoidal salmonellae co-infection. Broad-spectrum antibiotics are recommended by guidelines but the optimal class and dose have not been established. We investigated the optimal dose of oral dispersible azithromycin and whether simple clinical criteria and point-of-care biomarkers could target antibiotics to those at greatest risk of bacterial co-infection. Methods We conducted a phase I/II trial in Ugandan children with severe malaria comparing a 5-day course of azithromycin: 10, 15 and 20 mg/kg of azithromycin (prescribed by weight bands) spanning the dose-range effective for other salmonellae infection. We generated relevant pharmacokinetic (PK) data by sparse sampling during dosing intervals and investigated associations between azithromycin exposure and potential mechanisms (PK-pharmacodynamics) using change in C-reactive protein (CRP), a putative marker of sepsis, at 72 h (continuous) and microbiological cure (7-day) (binary), alone and as a composite with 7-day and 90-day survival. To assess whether clinical or biomarkers could identify those at risk of sepsis, a non-severe malaria control was concurrently enrolled. Results Between January 2020 and January 2022, 105 cases were randomised azithromycin doses: 35 to 10 mg/kg, 35 to 15 mg/kg and 35 to 20 mg/kg. Fifty non-severe malaria controls were concurrently enrolled. CRP reduced in all arms by 72 h with a mean reduction of 65.8 mg/L (95% CI 57.1, 74.5) in the 10 mg/kg arm, 64.8 mg/L (95% CI 56.5, 73.1; p = 0.87) in the 20 mg/kg arm and a smaller reduction 51.2 mg/L (95% CI 42.9, 59.5; p = 0.02) in the 15 mg/kg arm. Microbiological cure alone outcome was not analysed as only one pathogen was found among cases. Three events contributed to the composite outcome of 7-day survival and microbiological cure, with no events in the 15 mg/kg arm. The odds ratio comparing 20 vs 10 mg/kg was 0.50 (95% CI 0.04, 5.79); p = 0.58. Due to the low number of pathogens identified, it was not possible to identify better methods for targeting antibiotics including both the cases and controls. Conclusions We found no evidence for an association between systemic azithromycin exposure and reduction in CRP. Further work is needed to better identify children at highest risk from bacterial co-infection. Trial registration ISRCTN49726849 (registered on 27th October 2017).

Abstract Background Myositis is a rare disease associated with impaired health-related quality of life. A study evaluating the effectiveness of an intervention to improve the quality of life and well-being of myositis patients is presented. Methods All myositis patients in a health district were contacted. Thirty-four eligible patients were randomly assigned to the experimental (n = 17) or control (n = 17) group. A psychoeducational intervention of 5 100-min sessions focusing on the disease as related to daily life was conducted only in experimental patients. Several reliable tools to measure quality of life and well-being were administered twice, before and after the intervention, to both groups. Results In the experimental group, post-test scores were higher than pre-test in quality of life, well-being, and self-efficacy to manage the disease. Improvements were more evident in the experimental group than controls in 70% of the variables studied. Specifically, sedentariness decreased and satisfaction with social relationships increased in the post-test evaluation to a greater degree in the experimental group than in controls. Conclusions This randomized controlled trial on a representative sample of myositis patients in an extensive population provides evidence indicating the effectiveness of a psychoeducational intervention for improving HRQoL, well-being, and self-efficacy to manage the disease. Trial registration: NCT06300983.

Background. Currently, birth experience is considered an indicator for evaluating the quality of care provided during labor and birth. This study examined the effect of the Iranian positive birth experience guideline on the birth experience of primiparous women. Methods. This randomized controlled clinical trial was conducted at Taleghani Hospital, Tabriz, Iran (2019). Thirty pregnant women admitted to labor after checking the eligibility criteria were randomly assigned to intervention (developed guidelines) and control (routine hospital care) groups. Women’s birth experience was evaluated 24 hours postpartum using the Childbirth Experience Questionnaire (CEQ 2.0). An independent sample t-test was employed to compare the average scores between the groups. Results. The mean (standard deviation) of the total score of birth experience in the intervention and control groups was 3.0 (0.4) and 2.1 (0.5), respectively. The average score of the childbirth experience in the intervention group was significantly greater than that of the control group [Mean difference: 0.9; 95% confidence interval: 0.5–1.2; P < 0.001]. Conclusion. The Iranian guideline for improving birth experiences was able to improve primiparous women’s birth experiences more effectively than routine care. Practical Implications. The findings of this study can be considered in the policies and management of healthcare centers.

Introduction: With the advent of time, the removal of caries has shifted from hand instruments to rotary instruments. A disadvantage of conventional burs is that they non selectively lead to over-preparation. A new polymer bur can be substituted to eliminate these undesirable effects. Aim: To compare and evaluate the efficacy of smart burs and conventional burs in removing infected dentine while preserving affected dentin in carious lesions in primary teeth. Materials and Methods: This was a double-blinded randomised controlled trial conducted in the Department of Paediatric and Preventive Dentistry at Swargiya Dadasaheb Kalmegh Smruti Dental College and Hospital, Nagpur, Maharashtra, India over a period of three months, from August 2023 to October 2023. A total of 40 children aged 6-12 years were selected and evaluated for caries removal efficacy using visual and tactile criteria, which were further confirmed by dye application and numerically scored. Group 1 included 20 children who underwent caries excavation with smart burs, while Group 2 included 20 children who underwent the procedure with diamond points. Statistical analysis was conducted using descriptive and inferential statistics, specifically the Chi-square test. Results: A total of 40 children aged 6-12 years were divided into two groups: Group 1 comprised 11 boys and 9 girls, whereas Group 2 included 10 boys and 10 girls. Of these, 12 cases (60%) showed complete caries removal after the first application of dye, regardless of which burs was used. However, 4 cases (20%) showed some residual caries when using smart burs, while 6 cases (30%) exhibited residual caries with diamond points at the base of the cavity preparation. Additionally, there were 4 cases (20%) with caries present at the base and/or in one wall of the cavity preparation when using smart burs, compared to 2 cases (10%) with conventional burs. Nonetheless, there was no statistically significant difference between the smart burs and the conventional diamond points regarding caries removal. Conclusion: It can be concluded that smart burs are equally effective in removing soft caries compared to conventional methods. Although the results were statistically insignificant, polymer burs were found to be more convenient and can be considered a viable alternative to conventional caries removal techniques.

Abstract Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.

Abstract To assess the safety and efficacy of fecal microbiota transplantation (FMT) as an adjunctive therapeutic intervention for IgA nephropathy (IgAN). Fifteen patients with IgA nephropathy were recruited based on inclusion and exclusion criteria and underwent FMT using enteric microbial capsules. Clinical indicators, intestinal microbiota and metabolomic profiles, as well as changes in serum immune cells and cytokines, were monitored before and after FMT. No severe adverse reactions were observed in the subjects. After FMT, there was a reduction in the 24-h urinary protein quantification in subjects. The relative abundances of Phocaeicola_vulgatus, Bacteroides_uniformis, Prevotella_copri, Phocaeicola_dorei, Bacteroides_ovatus, Bacteroides_xylanisolvens, Parabacteroides _distasonis, Bifidobacterium_pseudocatenulatum, Bacteroides_sp._HF-162, and Bifidobacterium_longum changed after FMT. In terms of intestinal metabolites, the levels of acylcarnitine18:0 (ACar.18:0), cotinine, N-arachidonoyl-L-serine, phosphatidylcholine (PC. (18:3e/22:6)), serotonin, and fumagillin showed significant changes. Flow cytometry analysis showed the absolute count of plasma B cells decreased in subjects, and this change correlated with alterations in the intestinal microbiota and metabolites. This study preliminarily evaluates the safety and efficacy of FMT in patients with IgAN. No significant adverse reactions were observed, and the administration of FMT alongside ACEI/ARB therapy was effective in reducing urinary protein levels in patients with IgAN, a process that may be associated with B-cell immunity.

Purpose: To evaluate patient satisfaction and symptom control in hypogonadal men transitioning from other testosterone therapies to oral testosterone undecanoate (TU). Materials and Methods: In this open-label clinical trial, men aged 18 to 75 years with hypogonadism were switched to oral TU after a sufficient washout of previous testosterone therapies. Treatment satisfaction and symptom control were primarily measured using the 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9) and quantitative androgen deficiency in aging males (qADAM) questionnaires, respectively. Secondary outcomes included changes in serum testosterone (T), estradiol (E2), hematocrit (HCT), and prostate-specific antigen (PSA) levels. Results: Forty-one men participated, with significant improvements in all TSQM-9 scores observed over 6 months. Symptom control as measured by qADAM remained consistent. There was a significant increase in serum T and E2 levels, but HCT and PSA levels remained stable. Conclusions: Switching to oral TU from other testosterone therapies is associated with increased patient satisfaction and stable hypogonadal symptom control.

The incidence of diabetes is continuously increasing worldwide, resulting in a considerable socioeconomic burden. Glycemic control using traditional diabetes medications prevents microvascular complications; however, there is no objective evidence that it prevents macrovascular complications. In the 21st century, concerns have arisen that strict glycemic control and the diabetes drug rosiglitazone might increase mortality. This led the United States Food and Drug Administration to establish guidelines that require that cardiovascular outcome trials (CVOTs) with 3-point major adverse cardiovascular events (3-P MACE) as the primary endpoints be performed for new diabetes drugs. Since then, 20 CVOTs have been reported. Dipeptidyl peptidase 4 inhibitors do not increase the incidence of cardiovascular disease; however, saxagliptin increases the risk of heart failure. Sodium-glucose cotransporter inhibitors (SGLT2is) and glucagonlike peptide 1 receptor agonists (GLP-1RAs) not only have proven cardiovascular safety but also have shown results beyond expectations by reducing the incidence of cardiovascular diseases. Additionally, SGLT2is have been reported to markedly prevent heart failure and kidney disease. The reduction in 3-P MACE by GLP-1RAs was observed only with long-acting agents; long-acting GLP-1RAs also markedly reduced renal endpoints. However, no preventive effect against heart failure was observed with GLP-1RAs. The preventive effects of both drug types against cardiovascular and kidney diseases appear to be independent of glycemic control. In conclusion, based on CVOT results, it is necessary to actively prescribe SGLT2is and GLP-1RAs to prevent cardiovascular disease in patients with diabetes, regardless of glycemic control.

Objective·To analyze the development trend and current situation of high-level clinical research at Shanghai Jiao Tong University School of Medicine (SJTUSM) from 2015 to 2023, and to summarize the strategies for improving clinical research capability of SJTUSM, aiming to provide reference and inspiration for medical universities to promote high-level clinical research.Methods·Papers published by first authors from SJTUSM or its affiliated hospitals during this period were retrieved in the Web of Science core collection database. General descriptive methods were used to quantify the number of clinical research papers, registered clinical trials, clinical research talent teams, and the current status of clinical research cooperation. Bibliometric methods were used to visualize the international collaboration and topic distribution of retrieved clinical research papers. The differences in the number of clinical research publications, Q1 publications, publications in top clinical medical journals, and full-time researchers between the periods of 2015‒2018 and 2019‒2023 were compared and analyzed.Results·From 2015 to 2023, a total of 9 468 clinical research papers were published by SJTUSM or its affiliated hospitals as the first author′s institution, showing an increasing trend year by year. During this period, the number of Q1 publications of SJTUSM′s clinical research, publications in top clinical medical journals, clinical studies registered on the United States Clinical Trial Registry website, clinical studies registered on the Chinese Clinical Trial Registry website, clinical guidelines and expert consensus publications, full-time research team members, and newly added national-level talents all showed an overall upward trend. Tumors, cardiovascular and cerebrovascular diseases, major chronic diseases, and mental illnesses were the main research hotspots. A total of 1 308 papers (13.82%) were international collaborative papers. Developed countries/regions such as the United States (733 papers), Australia (137 papers), and the United Kingdom (99 papers) were closely cooperating with SJTUSM. From 2019 to 2023, there was a significant increase in the number of clinical research papers, Q1 publications, publications in top clinical medical journals, and newly added full-time research team members in affiliated hospitals compared to the period from 2015 to 2018 (all P

Abstract This study pooled data from SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD-BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) trial to estimate the treatment effect of intensive BP on stroke prevention, and investigate whether stroke risk score impacted treatment effect. Of all the potential manifestations of the hypertension, the most severe outcomes were stroke or death. A composite endpoint of time to death or stroke (stroke-free survival [SFS]), whichever occurred first, was defined as the outcome of interest. Participants without prevalent stroke were stratified into stroke risk tertiles based on the predicted revised Framingham Stroke Risk Score. The stratified Cox model was used to calculate the hazard ratio (HR) for the intensive BP treatment. 834 (5.92%) patients had SFS events over a median follow-up of 3.68 years. A reduction in the risk for SFS was observed among the intensive BP group as compared with the standard BP group (HR: 0.76, 95% CI: 0.65, 0.89; risk difference: 0.98([0.20, 1.76]). Further analyses demonstrated the significant benefit of intensive BP treatment on SFS only among participants having a high stroke risk (risk tertile 1: 0.76 [0.52, 1.11], number needed to treat [NNT] = 861; risk tertile 2: 0.87[0.65, 1.16], NNT = 91; risk tertile 3: 0.69[0.56, 0.86], NNT = 50). Intensive BP treatment lowered the risk of SFS, particularly for those at high risk of stroke.

Abstract Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients’ muscle transcriptome.

Abstract The use of digital health technologies to measure outcomes in clinical trials opens new opportunities as well as methodological challenges. Digital outcome measures may provide more sensitive and higher-frequency measurements but pose vital statistical challenges around how such outcomes should be defined and validated and how trials incorporating digital outcome measures should be designed and analysed. This article presents eight methodological questions, exploring issues such as the length of measurement period, choice of summary statistic and definition and handling of missing data as well as the potential for new estimands and new analyses to leverage the time series data from digital devices. The impact of key issues highlighted by the eight questions on a primary analysis of a trial are illustrated through a simulation study based on the 2019 Bellerophon INOPulse trial which had time spent in MVPA as a digital outcome measure. These eight questions present broad areas where methodological guidance is needed to enable wider uptake of digital outcome measures in trials.

Abstract This study was designed to investigate the effect of vitamin D and/or synbiotics on the response to treatment, cytokines profile and hormonal biomarkers in breast cancer patients undergoing neoadjuvant therapy. A total of 76 patients were recruited and completed the course of the intervention between 2019 and 2021 in Kerman, Iran. breast cancer patients were randomly enrolled in this study. Patients divided into four groups to receive one of the following regimens: placebo, vitamin D, synbiotics and a combination of vitamin D and synbiotics. clinicopathologic parameters, inflammatory and anti-inflammatory biomarkers and hormonal levels were measured at the baseline and four months after intervention. The study results found no clear link between the interventions and achieving pathological complete response (pCR), and a similar trend was observed in Ki-67 index examination. After neoadjuvant therapy, TNF-α concentrations decreased, with vitamin D supplementation moderating this decline. Vitamin D supplemented groups showed a significant increase in serum IL-6 levels. While IL-10 levels decreased in the placebo group, all intervention groups were protected from this decline. Moreover, there was a notable increase in the anti-inflammatory index, particularly in the group receiving both vitamin D and synbiotic supplementation, suggesting potential synergistic anti-inflammatory effects from their combined administration. The outcomes suggest a potential anti-inflammatory function of this combination. Consequently, more extensive studies with prolonged follow-up periods and substantial sample sizes are warranted to thoroughly evaluate their potential benefits for breast cancer patients.

Abstract Association between metabolic syndrome (MetS) and oxidative stress has been shown in numerous studies. It has been shown that probiotics could be the effective treatment strategy in improving oxidative stress. This study aimed to determine the effects of a new developed synbiotic yogurt on oxidative stress status in adults with MetS. Forty-four individuals were assigned into two groups and given 300 g of synbiotic yogurt containing Lactobacillus plantarum, Lactobacillus pentosus, and Chloromyces marcosianos yeast or regular yogurt for 12 weeks in this randomized, placebo-controlled clinical trial. Before and after the intervention, biochemical parameters were assessed. Daily consumption of synbiotic yogurt in adults with MetS showed a statistically significant improvement in the level of glutathione peroxidase (p = 0.01) and total oxidant status (p = 0.006) compared to the regular yogurt. Total Antioxidant Capacity and superoxide dismutase levels increased significantly (p = 0.002 and p = 0.02, respectively) in the intervention group compared to the baseline levels. In adults with MetS, daily consumption of the synbiotic yogurt containing native strains of Lactobacillus plantarum, Lactobacillus pentosus, and Chloromyces marcosianos yeast for 12 weeks was associated with improvements in oxidative stress status. Trial registration number: Iranian Registry of Clinical Trials (IRCT20220426054667N1) (18/05/2022)

Introduction: Spasticity is a pervasive and debilitating condition. Anti-spastic medications like Baclofen and Diazepam are most commonly used for spasticity management. Objectives: The study aimed to evaluate and compare the efficacy of Baclofen with that of Diazepam in the management of spasticity following acquired spinal cord injuries. Methods: In this randomised open-label study involving 60 patients, 30 patients received 5 mg of oral Baclofen thrice daily and 30 patients received 5 mg of oral Diazepam thrice daily for the management of spasticity. The extent of spasticity was measured by Modified Ashworth Scale (MAS). The efficacy of these drugs was measured with the mean improvement in the above parameters on days 7, 14, 28, 56 and 90 from the start of pharmacotherapy. Results: Baseline muscle spasticity scores were comparable. At the endpoint, mean improvement in tone of right and left hip flexors (1.43 vs. 0.87), hip adductors (1.30 vs. 0.87), knee flexors (0.80 vs. 0.37), ankle plantar flexors (0.80 vs. 0.37) and ankle dorsiflexors (1.23 vs. 0.93) were significantly higher in Baclofen group (p

Abstract Our prototype system designed for clinical data acquisition and recording of studies is a novel electronic data capture (EDC) software for simple and lightweight data capture in clinical research. Existing software tools are either costly or suffer from very limited features. To overcome these shortcomings, we designed an EDC software together with a mobile client. We aimed at making it easy to set-up, modifiable, scalable and thereby facilitating research. We wrote the software in R using a modular approach and implemented existing data standards along with a meta data driven interface and database structure. The prototype is an adaptable open-source software, which can be installed locally or in the cloud without advanced IT-knowledge. A mobile web interface and progressive web app for mobile use and desktop computers is added. We show the software’s capability, by demonstrating four clinical studies with over 1600 participants and 679 variables per participant. We delineate a simple deployment approach for a server-installation and indicate further use-cases. The software is available under the MIT open-source license. Conclusively the software is versatile, easily deployable, highly modifiable, and extremely scalable for clinical studies. As an open-source R-software it is accessible, open to community-driven development and improvement in the future.

Background Postoperative pain can lead to several complications. The effectiveness of different opioids in relieving pain after surgery has been widely studied. However, managing pain in patients with opioid addiction is still challenging. This study aimed to examine the impact of ketamine and methadone on postoperative pain in patients with addiction. Methods This was a non-inferiority randomized clinical trial. All included patients were monitored for morphine use, pain scores, and vital signs every 3 h. The intervention group received 0.5 mg/kg ketamine administered intravenously every 6 h. The control group received 5 mg of methadone intramuscularly every 8 h. The patient received intravenous morphine if their visual analog scale was above 3. All side effects in each group were recorded. Results Two hundred and twenty patients were included in this study. There were 127 men (57.7%) with an average age of 57.1 ± 19.5 and 93 women (42.3%) with an average age of 57.1 ± 21.0. There were no significant differences in demographic characteristics between the groups. There was no significant difference in the dose or frequency of morphine administration between groups. There was no significant difference between the groups in pain scores and vital signs at different time points. Drug side effects, including delirium and gastrointestinal symptoms, did not differ significantly between the methadone and ketamine groups. Conclusions Our clinical data support the hypothesis that ketamine is not inferior to methadone in patients with addiction. Future Randomize Clinical Trials are needed to confirm these observations.

This study offers a detailed analysis of clinical trials conducted in Ecuador from 2010 to 2022 to assess alignment with the country’s disease burden as indicated by the Global Burden of Disease study. Utilizing data from five registries, including ARCSA and Clinicaltrials.gov, we analyzed characteristics and coverage of 75 CTs after removing duplicates and ineligible studies. Findings reveal a 50% research gap across disease groups, with neoplasms being the only category matching disease burden. The scarcity of clinical research highlights the disparity between CTs and prevalent diseases such as cardiovascular and kidney diseases, diabetes, and other non-communicable conditions. Our results underscore the urgent need for increased clinical research investment addressing these critical health challenges in Ecuador.

BackgroundDry eye disease (DED) is commonly caused by excessive tear film evaporation due to Meibomian gland dysfunction (MGD). There is a need for DED treatment options that address tear evaporation and benefit patients across a broad range of demographic and disease characteristics. This study evaluated treatment effects of perfluorohexyloctane ophthalmic drop (formerly NOV03) in the pooled dataset from 2 pivotal clinical trials in patients with DED associated with MGD, both in the overall population and in patient subgroups based on sex, age, and baseline severity of eye dryness.MethodsPooled data from 2 similarly designed, phase 3, randomized controlled trials (GOBI, MOJAVE) were analyzed. Patients aged ≥18 years with DED administered perfluorohexyloctane (n=614) or hypotonic (0.6% solution) saline control (n=603) four times daily for 8 weeks. Primary endpoints were total corneal fluorescein staining (tCFS) score (National Eye Institute scale, 0-15) and eye dryness visual analog scale (VAS) score (0-100). Efficacy was evaluated using analysis of covariance among patient subgroups (male and female, older [≥65 years] and younger [18 to

Resumen: Antecedentes y objetivo: El uso prolongado de metformina puede causar efectos secundarios como deficiencia de vitamina B12. El objetivo de este estudio fue evaluar la seguridad y la eficacia del uso de complejo B intramuscular para mejorar los niveles séricos de vitamina B12 en pacientes con uso prolongado de metformina y niveles subóptimos de vitamina B12. Materiales y métodos: En este estudio de fase IV participaron adultos con diabetes tipo 2, tratados con metformina (de 3 o más años) y vitamina B12 sérica inferior a 300 pg/ml. La intervención consistió en inyecciones intramusculares de complejo B, con seguimiento presencial y telefónico. Resultados: De 201 pacientes evaluados, 40 pacientes en la visita inicial tenían deficiencia de cianocobalamina (19,9%) y de estos, solo 33 (82%) completaron el seguimiento de 6 semanas. Se observo un cambio estadísticamente significativo al comparar los niveles basales de vitamina B12 contra finales (p

Abstract Background Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. Methods In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients’ cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients’ depressive symptoms at baseline and week 2. Results After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p

Shuang Xiao,1 Anthony Androulakis,2 William D Skelton,3 Irene L Quan,4 Jinlian Cheng,1 Yan Wang,1 Xueqi Zhu,1 Haiqun Zhang5 1Office of Drug Clinical Trial Institution, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2School of Public Health, University of South Carolina, Columbia, SC, USA; 3D.AC, The Acupuncture Clinic, Columbia, SC, USA; 4Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 5Trauma Orthopaedics, Beijing Fengsheng Special Hospital of Traditional Medical Traumatology and Orthopaedics, Beijing, People’s Republic of ChinaCorrespondence: Jinlian Cheng, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Art Museum Back Street, Dongcheng District, Beijing, People’s Republic of China, Tel +86-010-87906813, Email cjltitan@126.comAim: The aim of this study is to assess the willingness, motivation, satisfaction levels, and expectations of participants engaged in clinical trials, while also exploring factors that influence compliance from the participants’ standpoint. Furthermore, this research aims to enhance the understanding of all stakeholders involved in clinical trials about the needs of participants and to offer evidence-based and pragmatic recommendations for effectively managing clinical trial participants.Methods: An electronic questionnaire covers various aspects of Traditional Chinese Medicine (TCM) clinical trials. The distribution of the electronic questionnaire was facilitated through WeChat groups, WeChat Moments, and individual interactions. Count data was expressed in terms of frequency (or rate), and subsequent analysis was conducted utilizing the standard chi-squared test. A p value≤ 0.05 was considered significant. By drawing a Pareto chart, the priority of factors influencing participants’ willingness to participate in clinical trials was systematically assessed.Results: 88 participants answered the questionnaire. A decline in education level corresponded to a decreasing comprehension of participants’ grasp of “clinical trial” and “clinical trial participant” (p< 0.05). The primary reason for participants’ reservations about joining clinical trials stems from their inadequate comprehension of clinical trial details. The key factors contributing to participants’ reluctance to engage in clinical trials encompass aspects of trial design, the operational procedures, insufficient understanding of clinical trial particulars, concerns about potential harm to their bodies and opposition from family members. Importantly, these areas of participants’ hesitation and unwillingness to partake in clinical trials mirror the factors participants’ dissatisfaction contributing to.Conclusion: We found four factors significantly influencing participants’ willingness to engage and their overall satisfaction: the participant’s profile, trial design, trial institution setup, and the qualifications of the researchers. Derived from these critical factors, this paper presents a series of constructive measures.Keywords: clinical trial, traditional Chinese medicine, compliance, satisfaction, participants

Background and purpose: One of the main complications of diabetes is psychological problems, such as reduced stamina and psychological well-being. The use of muscle relaxation is a simple, safe, and non-pharmacological method. Therefore, the present study was designed to investigate the effect of Jacobson's muscle relaxation technique on psychological well-being and resilience in patients with type 2 diabetes. Materials and methods: The current study is a two-group randomized clinical trial with a pre-test and post-test design conducted on 40 patients with type 2 diabetes at the Khayyam Diabetes Clinic in 2021. Eligibility criteria included minimum literacy, acceptable hearing, and speaking ability, age between 25 and 65 years, no history of relaxation training, type 2 diabetes for at least 6 months, no smoking and no alcohol, ability to use a computer, poor psychological well-being and resilience (psychological well-being score equal to or less than 63, resilience score equal to or less than 50), and no definite psychiatric disorders. Exclusion criteria included: special medical conditions (such as hospitalization or medical inability to continue treatment), withdrawal from the research, death, unwillingness to cooperate, incomplete completion of questionnaires by members, and failure to perform sedation for more than 4 sessions. The samples were selected using the available methods and then randomly allocated with permutation blocks to two intervention and two control groups. The relaxation technique was then practiced at home by the intervention group once a day for 8 weeks. Rif's psychological well-being questionnaire and Connor's resilience questionnaire were completed by the intervention and control groups at the beginning and end of the intervention. Data were analyzed using the Shapiro-Wilk test for normality, Fisher's exact test, chi-square, and analysis of covariance using SPSS 25 software. Results: The results of the research showed that the two groups were homogeneous in terms of gender, marriage, age, education, history of chronic diseases, history of neuro medications, insulin history, exercise history, peer history, dietary compliance, income, and occupation and there was a statistically significant difference. There was no difference in these variables between the two groups (P>0.05). The results of the covariance test show that the means of the experimental and control groups are the same in terms of patient resilience (P=0.49, eta=0.02). Therefore, it can be concluded that there is no significant difference between the experimental and control groups in terms of patient endurance, controlling for the effect of pre-test means. Also, the means of the experimental and control groups differ in psychological well-being (P=0.00, eta=0.44). Therefore, It can be concluded that there were statistically significant differences between the groups. More specifically, there was a significant difference between the experimental and control groups in terms of psychological well-being, controlling for the effect of pre-test means. Conclusion: Results of the study showed that muscle relaxation training was an effective, practical, and inexpensive method of improving and preventing psychological problems in people with diabetes in the intervention group compared with the control group. (Clinical Trials Registry Number: IRCT20220110053682N1)

Abstract Background Mucosal melanoma (MM) is a rare but devastating subtype of melanoma. Our previous studies have demonstrated robust anti-tumor effects of cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors in head and neck MM (HNMM) patient-derived xenograft models with CDK4 amplification. Herein, we aimed to investigate the efficacy and safety of dalpiciclib (SHR6390), a CDK4/6 inhibitor, in HNMM patients harboring CDK4 amplification. Methods The anti-tumor efficacy of dalpiciclib was assessed by HNMM patient-derived xenograft (PDX) models and patient-derived tumor cells (PDC) in vivo and in vitro. Immunohistochemical analyses and western blot were then performed to assess the markers of cell proliferation and CDK4/6 signaling pathway. For the clinical trial, advanced recurrent and/or metastatic HNMM patients with CDK4 amplification were treated with dalpiciclib 125 mg once daily for 21 consecutive days in 28-day cycles. The primary endpoint was disease control rate (DCR). Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results Dalpiciclib profoundly suppressed growth of HNMM-PDX and PDC with CDK4 amplification, whereas it showed relatively weak suppression in those with CDK4 wild type compared with vehicle. And dalpiciclib resulted in a remarkable reduction in the expression levels of Ki-67 and phosphorylated Rb compared with control group. In the clinical trial, a total of 17 patients were enrolled, and 16 patients were evaluable. The ORR was 6.3%, and the DCR was 81.3%. The estimated median PFS was 9.9 months (95% CI, 4.8-NA), and the median OS was not reached. The rate of OS at 12 months and 24 months was 68.8% (95% CI, 0.494–0.957) and 51.6% (95% CI, 0.307–0.866), respectively. The most frequent adverse events were neutrophil count decrease, white blood cell count decrease, and fatigue. Conclusions Dalpiciclib was well-tolerated and displayed a durable benefit for HNMM patients with CDK4 amplification in this study. Further studies on CDK4 inhibitors and its combination strategy for MM are worth further exploration. Trial registration ChiCTR2000031608.

Abstract Pre-clinical and clinical studies have shown that PEGPH20 depletes intratumoral hyaluronic acid (HA), which is linked to high interstitial fluid pressures and poor distribution of chemotherapies. 29 patients with metastatic advanced solid tumors received quantitative magnetic resonance imaging (qMRI) in 3 prospective clinical trials of PEGPH20: HALO-109-101 (NCT00834704), HALO-109-102 (NCT01170897), and HALO-109-201 (NCT01453153). Apparent Diffusion Coefficient of water (ADC), T1, k trans , v p , v e , and iAUC maps were computed from qMRI acquired at baseline and ≥ 1 time point post-PEGPH20. Tumor ADC and T1 decreased, while iAUC, k trans , v p , and v e increased, on day 1 post-PEGPH20 relative to baseline values. This is consistent with HA depletion leading to a decrease in tumor extracellular water content and an increase in perfusion, permeability, extracellular matrix space, and vascularity. Baseline parameter values predictive of pharmacodynamic responses were: ADC > 1.46 × 10−3 mm2/s (Balanced Accuracy (BA) = 72%, p 0.54 s (BA = 82%, p

Aim. Effectiveness and safety of levosalbutamol metered dose inhaler (MDI) in comparison with placebo and salbutamol. Materials and methods. In this multicenter, randomized, placebo-controlled, 3-period crossover study, all asthma patients (n=91) received levosalbutamol (90 mcg), salbutamol (180 mcg), and placebo using standard MDI. Pulmonary function testing – forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) – was performed 45 and 15 minutes before and 5, 10, 15, 30, 60, 90, 120, 180, 240, 300 and 360 minutes after dosing. The primary efficacy endpoint was the baseline-corrected area under FEV1 curve from 0 to 6 hours (AUC(0–6h)). Secondary endpoints were the baseline adjusted FEV1 and FVC peak values, as well as the onset of drug action. Results. The FEV1 AUC0–6 hours analysis confirmed similar bronchodilatory levosalbutamol and salbutamol effect (p=0.595), significantly improved compared with placebo (p0.001). The peak values of FEV1 and FVC after levosalbutamol or salbutamol dosing were similar (p=0.643) and significantly higher compared with placebo group (p0.001). The active therapy effect was observed 5 minutes after dosing and throughout the entire observation period up to 6 hours, however, there was some tendency towards a longer duration of action of levosalbutamol compared to salbutamol. Levosalbutamol was well tolerated by patients; after levosalbutamol dosing twiсе fewer adverse reactions were observed compared to salbutamol. Conclusion. Levosalbutamol at a 90-mcg dose showed efficacy similar to that of salbutamol at a dose of 180 mcg, assosiated with a good safety profile.

Abstract Access to Hepatis C treatment in Sub-Saharan Africa is a clinical, public health and ethical concern. The multi-country open-label trial TAC ANRS 12311 allowed assessing the feasibility, safety, efficacy of a specific care model of HCV treatment and retreatment in patients with hepatitis C in Sub Saharan Africa. Between November 2015 and March 2017, with follow-up until mid 2019, treatment-naïve patients with HCV without decompensated cirrhosis or liver cancer were recruited to receive 12 week-treatment with either sofosbuvir + ribavirin (HCV genotype 2) or sofosbuvir + ledipasvir (genotype 1 or 4) and retreatment with sofosbuvir + velpatasvir + voxilaprevir in case of virological failure. The primary outcome was sustained virological response at 12 weeks after end of treatment (SVR12). Secondary outcomes included treatment adherence, safety and SVR12 in patients who were retreated due to non-response to first-line treatment. The model of care relied on both viral load assessment and educational sessions to increase patient awareness, adherence and health literacy. The study recruited 120 participants, 36 HIV-co-infected, and 14 cirrhotic. Only one patient discontinued treatment because of return to home country. Neither death nor severe adverse event occurred. SVR12 was reached in 107 patients (89%): (90%) in genotype 1 or 2, and 88% in GT-4. All retreated patients (n = 13) reached SVR12. HCV treatment is highly acceptable, safe and effective under this model of care. Implementation research is now needed to scale up point-of-care HCV testing and SVR assessment, along with community involvement in patient education, to achieve HCV elimination in Sub-Saharan Africa.

Abstract Background Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC. Methods In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy. Results Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6–51.9) and 90.3% (56/62, 95% CI, 80.1–96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8–not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7–94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients. Conclusions Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC. Trial registration ClinicalTrials.gov (NCT 04401800).

Abstract Glycogen storage disease type Ib (GSD-Ib) is a rare inborn error of glycogen metabolism caused by mutations in SLC37A4. Patients with GSD-Ib are at high risk of developing inflammatory bowel disease (IBD). We evaluated the efficacy of empagliflozin, a renal sodium‒glucose cotransporter protein 2 (SGLT2) inhibitor, on colonic mucosal healing in patients with GSD-associated IBD. A prospective, single-arm, open-label clinical trial enrolled eight patients with GSD-associated IBD from Guangdong Provincial People's Hospital in China from July 1, 2022 through December 31, 2023. Eight patients were enrolled with a mean age of 10.34 ± 2.61 years. Four male and four female. The endoscopic features included deep and large circular ulcers, inflammatory hyperplasia, obstruction and stenosis. The SES-CD score significantly decreased at week 48 compared with before empagliflozin. Six patients completed 48 weeks of empagliflozin therapy and endoscopy showed significant improvement or healing of mucosal ulcers, inflammatory hyperplasia, stenosis, and obstruction. One patient had severe sweating that required rehydration and developed a urinary tract infection. No serious or life-threatening adverse events. This study suggested that empagliflozin may promote colonic mucosal healing and reduce hyperplasia, stenosis, and obstruction in children with GSD-associated IBD.

Abstract Background Rimegepant orally disintegrating tablet (ODT), an oral small-molecule calcitonin gene-related peptide receptor antagonist, is indicated for acute and preventive treatment of migraine in the United States and other countries. Previously, a large clinical trial assessed the efficacy and safety of rimegepant ODT 75 mg for the acute treatment of migraine in adults living in China or South Korea. A post hoc subgroup analysis of this trial was performed to evaluate the efficacy and safety of rimegepant for acute treatment of migraine in adults living in China. Methods Eligible participants were ≥ 18 years of age and had a ≥ 1-year history of migraine, with 2 to 8 attacks of moderate or severe pain intensity per month and

Abstract Cyclin-dependent kinase 7 (CDK7) serves as a pivotal regulator in orchestrating cellular cycle dynamics and gene transcriptional activity. Elevated expression levels of CDK7 have been ubiquitously documented across a spectrum of malignancies and have been concomitantly correlated with adverse clinical outcomes. This review delineates the biological roles of CDK7 and explicates the molecular pathways through which CDK7 exacerbates the oncogenic progression of breast cancer. Furthermore, we synthesize the extant literature to provide a comprehensive overview of the advancement of CDK7-specific small-molecule inhibitors, encapsulating both preclinical and clinical findings in breast cancer contexts. The accumulated evidence substantiates the conceptualization of CDK7 as a propitious therapeutic target in breast cancer management.

Background Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission ( 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods. Conclusions The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. Registration PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)

Stroke has become the leading cause of death in China, and rational diet is an important primary prevention strategy, but the optimal dietary pattern remains to be studied. Based on this, this paper reviews the progress of epidemiological studies on the correlation of Mediterranean Diet (MD) , Dietary Approaches to Stop Hypertension (DASH) pattern, Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, Japanese dietary pattern and Chinese diet pattern with cerebrovascular diseases, and suggests that MD pattern, DASH pattern and Japanese dietary pattern have protective effects on cerebrovascular disease; however, the relationship between MIND pattern and cerebrovascular disease remains uncertain. There is a lack of large-scale randomized controlled trials to examine the effect of traditional Chinese dietary pattern on cerebrovascular diseases. In the future, active efforts in exploring the healthy dietary patterns in line with local dietary habits are needed for providing a Chinese strategy for primary stroke prevention.

Abstract To evaluate the impact of using ion-releasing liners on the 3-year clinical performance of posterior resin composite restorations after selective caries excavation with polymer burs. 20 patients were enrolled in this trial. Each patient had two deep carious lesions, one on each side of the mouth. After selective caries removal using polymer bur (PolyBur P1, Komet, Brasseler GmbH Co. KG, Lemgo, Germany), cavities were lined with bioactive ionic resin composite (Activa Bioactive Base/Liner, Pulpdent, Watertown, MA, USA) or resin-modified glass ionomer liner (Riva Light Cure, SDI, Bayswater, Victoria, Australia). All cavities were then restored with nanofilled resin composite (Filtek Z350XT, 3M Oral Care, St. Paul, MN, USA). All the tested materials were placed according to the manufacturers’ instructions. Clinical evaluation was accomplished using World Dental Federation (FDI) criteria at baseline and after 6 months, 1, 2, and 3 years. Data were analyzed using Mann–whitney U and Friedman tests (p 0.05). Resin composite restorations showed acceptable clinical performance over 3 years either lined with bioactive ionic or resin-modified glass ionomer liners after selective caries excavation preserving pulp vitality. After the 3-year follow-up period, Activa Bioactive and Riva Light Cure liners were clinically effective and they exhibited with the overlying composite restorations successful clinical performance. Trial registration number: NCT05470959. Date of registration: 22/7/2022. Retrospectively registered.

Informed consent is a foundation of the ethical conduct of research involving human participants. Based on the ethical principle of respect for persons, the goal of informed consent is to ensure that participants are aware of the risks and potential benefits and make a voluntary decision about participating in clinical trial research. The extraordinary scientific advances happening globally, have demonstrated the potential of regenerative therapies in transforming the health of the nation by providing a therapeutic option for diseases that were previously considered incurable. These therapies, which include cells and gene therapy (GT) labeled as Advanced Therapeutic Medicinal Products globally, have complex mechanisms of action. Owing to their highly personalized and intricate nature of these therapies, developing the latter often presents unique challenges above and beyond those encountered for small molecule drugs. We recently looked through some cell and GT clinical trials and realized the lacunae in the informed consent form (ICF) provided by the investigators. Especially in a country like India, where the general understanding and perception of patients is limited regarding clinical trials, it is felt that any lapses in the consent process may jeopardize the informed decision-making and safety of the participants and tarnish the reputation of India globally. The present article highlights the need for appropriate patient and public education on the various aspects of cell and gene therapies and aims to address all the elements of ICF in light of the challenges associated with these innovative therapies.

Abstract Background Health care routinely fails Indigenous peoples and anti-Indigenous racism is common in clinical encounters. Clinical training programs aimed to enhance Indigenous cultural safety (ICS) rely on learner reported impact assessment even though clinician self-assessment is poorly correlated with observational or patient outcome reporting. We aimed to compare the clinical impacts of intensive and brief ICS training to control, and to assess the feasibility of ICS training evaluation tools, including unannounced Indigenous standardized patient (UISP) visits. Method Using a prospective parallel group three-arm randomized controlled trial design and masked standardized patients, we compared the clinical impacts of the intensive interactive, professionally facilitated, 8- to10-h Sanyas ICS training; a brief 1-h anti-bias training adapted to address anti-Indigenous bias; and control continuing medical education time-attention matched to the intensive training. Participants included 58 non-Indigenous staff physicians, resident physicians and nurse practitioners from family practice clinics, and one emergency department across four teaching hospitals in Toronto, Canada. Main outcome measures were the quality of care provided during UISP visits including adjusted odds that clinician would be recommended by the UISP to a friend or family member; mean item scores on patient experience of care measure; and clinical practice guideline adherence for NSAID renewal and pain assessment. Results Clinicians in the intensive or brief ICS groups had higher adjusted odds of being highly recommended to friends and family by standardized patients (OR 6.88, 95% CI 1.17 to 40.45 and OR 7.78, 95% CI 1.05 to 58.03, respectively). Adjusted mean item patient experience scores were 46% (95% CI 12% to 80%) and 40% (95% CI 2% to 78%) higher for clinicians enrolled in the intensive and brief training programs, respectively, compared to control. Small sample size precluded detection of training impacts on clinical practice guideline adherence; 100% of UISP visits were undetected by participating clinicians. Conclusions Patient-oriented evaluation design and tools including UISPs were demonstrated as feasible and effective. Results show potential impact of cultural safety training on patient recommendation of clinician and improved patient experience. A larger trial to further ascertain impact on clinical practice is needed. Trial registration Clinicaltrials.org NCT05890144. Retrospectively registered on June 5, 2023.

Abstract Background Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. Methods All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded. Results In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018). Conclusion The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

Background: The Measles–Rubella Microarray Patch (MR-MAP) is an important technology that is expected to reduce coverage and equity gaps for measles-containing vaccines (MCVs), reach zero-dose children, and contribute to elimination of measles and rubella. MR-MAPs are anticipated to be easier to deploy programmatically and could be delivered by lesser-trained health workers, thereby increasing immunization coverage. The most advanced MR-MAP has reached clinical proof-of-concept through a Phase I/II trial in the target population of infants and young children. The World Health Organization (WHO) and partners have developed the Phase III clinical trial framework for MR-MAPs presented in this article. Objectives and Methods: The purpose of such framework is to inform the considerations, design and approach for the pivotal clinical trial design, while considering the anticipated data requirements to inform regulatory approval, WHO prequalification, and policy decision. Results: The proposed Phase III trial would compare the immunogenicity and safety of an MR-MAP with MR vaccine delivered subcutaneously in 9- to 10-month-old infants. An analysis of non-inferiority (NI) of immunogenicity would occur six weeks after the first dose. Should regulatory agencies or policy makers require, a proportion of infants could receive a second dose of either the same or alternate MR vaccine presentation six months after the first dose, with those children returning six weeks after the second dose for a descriptive assessment of immunogenicity, and then followed up six months after the second dose for evaluation of safety and immunogenicity. It is anticipated that this proposed pivotal Phase III trial framework would generate the required clinical data for regulatory licensure and WHO prequalification (PQ) of MR-MAPs. However, the trial design would need to be reviewed and confirmed by a national regulatory authority (NRA) that will assess the product for regulatory licensure and the WHO PQ team. Additional research will likely be required to generate data on concomitant vaccine delivery, the safety and immunogenicity of MR-MAPs in other age groups such as children 1–5 years and infants younger than 9 months of age, and the impact of MR-MAPs on coverage and equity. Such studies could be conducted during or after clinical MR-MAP development.

Protective antibodies in the upper respiratory tract prevent the spread of COVID-19 in the community. Intranasal vaccines could raise the specific secretory IgA and IgG levels. This is a single-center, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and immunogenicity of Razi Cov Pars (RCP) intranasal recombinant protein subunit COVID-19 vaccine as a booster in adults. We compared specific IgG and IgA levels in the intranasal RCP group (n = 97) versus placebo (n = 96) in serum, saliva, and nasal mucosal secretions on days 0 and 14 and reported their Geometric Mean Ratios (GMR) and 95% confidence intervals (CI). We showed significant increases in IgA and IgG anti-RBD in the nasal mucosa in the RCP group, but their increase was not detectable in the serum and saliva. Anti-spike IgA in the nasal mucosa also increased in the RCP group compared to the placebo. This increase against the COVID-19 variant Omicron was also similar to that of the Wuhan. We detected no serious adverse reactions or anaphylaxis and all adverse events resolved completely during the follow-up period and were similar in both groups. Intranasal RCP is safe, stimulates the respiratory mucosal immunity, and could be a booster on various COVID-19 vaccines and be effective against new virus variants.

Background Paget’s disease of bone is characterised by focal abnormalities of bone turnover resulting in various complications. It often presents at an advanced stage with irreversible bone damage. At this point, the symptomatic benefits of treatment are blunted. Paget’s disease of bone has a strong genetic component and the most important susceptibility gene is SQSTM1. Carriers of SQSTM1 mutations have more severe disease with an earlier age of onset than non-carriers and about 80% develop Paget’s disease of bone by the seventh decade. Objectives The primary objective was to determine if zoledronic acid could prevent new Paget’s disease of bone-like bone lesions in SQSTM1 mutation carriers. Secondary objectives were to assess if zoledronic acid could: modify existing Paget’s disease of bone lesions, markers of bone turnover, quality of life, bone pain, anxiety, depression or the risk of complications. Design This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires. Setting This was a multicentre trial that was conducted at 27 secondary care referral centres for bone disease in 7 countries. All the visits were conducted within a secondary healthcare setting. Participants Interventions Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo. Main outcome measures The study’s primary outcome measure was defined as the total number of participants who developed new bone lesions on radionuclide bone scans with the characteristics of PDB between the baseline visit and the final end-of-study visit. The secondary outcomes included the number of new PDB bone lesions on radionuclide bone scans, change in the activity of existing PDB bone lesions at the end of study assessed by radionuclide scans; changes in plasma type I collagen C-telopeptides (CTX); plasma procollagen type I amino-terminal propeptide (PINP); serum bone-specific alkaline phosphatase (BAP); quality of life assessed by SF-36, BPI, HADS questionnaires; the presence and severity of localized bone pain assessed by the BPI pain manikin; and the development of PDB-related skeletal events (PDRSE) in SQSTM1 mutation carriers including new lesions, complications (fractures, deformity), or the need for treatment of PDB. Methods This was a multicentre, double-blind placebo-controlled trial. Genetic screening of the SQSTM1 gene was offered to people with a family history of Paget’s disease of bone, identifying 222 mutation carriers who consented to participate. At baseline, a radionuclide bone scan was performed; biochemical markers of bone turnover were measured and questionnaires on pain, quality of life and mental health were completed. Participants were randomly allocated to receive a single infusion of the bisphosphonate zoledronic acid 5 mg or an identical placebo. Participants completed annual biochemical markers measurements and questionnaires. Adverse events were recorded on a continuous basis. At the end of study, the bone scan was repeated, along with biochemical markers and questionnaires. Results At baseline, 21/222 individuals (9.5%) had evidence of Paget’s disease of bone on bone scans. In the placebo group, 2/90 individuals (2.2%) developed new bone lesions compared with 0/90 (0%) in the zoledronic acid group (odds ratio 0.41, 95% confidence interval 0.00 to 3.43; p = 0.25). Eight participants in the placebo group had a poor outcome (new/unchanged/progressing lesions) compared with none in the zoledronic acid group (odds ratio 0.08, 95% confidence interval 0.00 to 0.42; p = 0.003). With placebo, 1/29 (3.4%) lesions disappeared compared with 13/15 (86.6%) with zoledronic acid (p

Background African children with cerebral malaria and seizures caused Plasmodium falciparum are at greater risk of poor outcomes including death and neurological sequelae. The agonal events are severe hypoventilation and respiratory arrest often triggered by seizures. We hypothesised that prophylactic anti-seizure medication (ASM) could avert ‘spikes’ of intracranial pressure during or following seizures and that adequate ventilation could be supported by biphasic Cuirass Ventilation (BCV) which requires no intubation. Methods A Phase I trial conducted in Kilifi, Kenya designed to provide data on safety, feasibility and preliminary data on seizure control using prophylactic ASM (levetiracetam) and BCV as non-invasive ventilatory support in children with cerebral malaria. Children aged 3 months to 12-years hospitalised with P falciparum malaria (positive rapid diagnostic test or a malaria slide), a Blantyre Coma Score ≤2 and a history of acute seizures in this illness are eligible for the trial. In a phased evaluation we will study i) BCV alone for respiratory support (n=10); ii) prophylactic LVT: 40mg/kg loading dose then 30mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10) and; iii) prophylactic LVT: 60mg/kg loading dose then 45mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10). Primary outcome measure: cumulative time with a clinically detected seizures or number of observed seizures over 36 hours. Secondary outcomes will be assessed by feasibility or ability to implement BCV, and recovery from coma within 36 hours. Safety endpoints include: aspiration during admission; death at 28 days and 180 days; and de-novo neurological impairments at 180 days. Conclusions This is a Phase I trial largely designed to test the feasibility, tolerability and safety of using non-invasive ventilatory support and LVT prophylaxis in cerebral malaria. Registration ISRCTN76942974 (5.02.2019); PACTR202112749708968 (20.12.2021).

BackgroundLower limb motor recovery, including abnormal muscle synergies, occurs mainly within the first 5–8 weeks after a stroke. This suggests the importance of delivering impairment-focused therapies, such as therapeutic robots that promote symmetric gait, during this time-sensitive period, following the principle of “the earlier, the better.”ObjectiveFirst, to compare early robotic training (ERT) with usual care (UC) against UC alone on restoring intralimb muscle synergies and interlimb symmetry during functional tasks; Second, to investigate whether ERT is superior to delayed robotic training (DRT) starting after the proposed time-sensitive period.MethodsThis observer-blinded, randomized pilot trial with crossover design involved 19 nonambulatory adults included within 14 days poststroke. Those allocated to ERT (N = 10) received immediately 4 weeks of training (16 sessions, 4× /week) with the Ekso GT® above UC and were compared with the DRT group (N = 9) who received UC alone at this point. Thereafter a 3-week UC period followed to investigate sustainability of ERT and the interventional roles were exchanged; at about week 8 poststroke DRT subjects started the same experimental robotic protocol and ERT subjects continued UC as controls. Outcomes included changes in Fugl-Meyer lower extremity scores (FM-LE) reflecting muscle synergies, weight-bearing asymmetry (WBA), and dynamic control asymmetry (DCA) during quiet standing. Functional ambulation category (FAC) was used to classify walking independence (cut-off ≥4).ResultsA trend toward earlier reacquisition of walking independence favoring ERT with UC over UC was not accompanied by differences in FM-LE, WBA, or DCA (first objective). Thereafter, DRT with UC did not yield any significant changes relative to UC, such that no between-group differences were found favoring restorative effects of ERT over DRT (second objective).ConclusionThis pilot trial shows the feasibility of investigating a wearable exoskeleton as an adjunct therapy in subacute stroke. Nevertheless, our preliminary findings suggest that motor recovery of lower limb muscle synergies was not enhanced by 4 weeks of robotic training to reduce compensations with the less-affected side, irrespective of the timing of application.Trial registrationClinicalTrials.gov, identifier: NCT03727919.