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Background: Anti-angiogenic, VEGF inhibitors (VEGFi) increase progression-free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi, the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with a hazard ratio (HR) for PFS of 0.56. The aim of the VALTIVE1 study is to validate the utility of plasma Tie2 as a vascular response biomarker and to optimise the Tie2-definition of vascular response so that the subsequent randomised discontinuation VALTIVE2 study can be powered optimally. Methods: VALTIVE1 is a multi-centre, single arm, non-interventional biomarker study, with a sample size of 205 participants (176 bevacizumab-treated participants + 29 participants receiving bevacizumab and olaparib/PARPi), who are 16 years or older, have FIGO stage IIIc/IV ovarian cancer on treatment with first-line platinum-based chemotherapy and bevacizumab. Their blood plasma samples will be collected before, during, and after treatment and the concentration of Tie2 will be determined. The primary objective is to define the PFS difference between Tie2-defined vascular responders and Tie2-defined vascular non-responders in patients receiving bevacizumab for high-risk Ovarian Cancer. Secondary objectives include defining the relationship between Tie2-defined vascular progression and disease progression assessed according to RECIST 1.1 criteria and assessing the impact of PARPi on the plasma concentration of Tie2 and, therefore, the decision-making utility of Tie2 as a vascular response biomarker for bevacizumab during combined bevacizumab-PARPi maintenance. Discussion: There is an urgent need to establish a test that tells patients and their doctors when VEGFi are working and when they stop working. The data generated from this study will be used to design a second trial aiming to prove conclusively the value of the Tie2 test. Trial registration: ClinicalTrials.gov identifier: NCT04523116. Registered on 21 Aug 2020. [ABSTRACT FROM AUTHOR]

Introduction: Smartphone app interventions based on cognitive-behavioral therapy (CBT) are promising scalable alternatives for treating mental disorders, but the evidence of their efficacy for postpartum depression is limited. We assessed the efficacy of Motherly, a standalone CBT-based smartphone app, in reducing symptoms of postpartum depression. Methods: Women aged 18–40 with symptoms of postpartum depression were randomized either to intervention (Motherly app) or active control (COMVC app). The primary outcome was symptoms of depression measured by the Edinburgh Postnatal Depression Scale (EPDS) at post-treatment. Secondary outcomes were anxiety symptoms, parental stress, quality of sleep, behavioral activation, availability of response-contingent positive reinforcement, and clinical improvement at post-treatment and 1-month follow-up. Exploratory analyses were performed to investigate if app engagement was associated with treatment response. Results: From November 2021 to August 2022, 1,751 women volunteered, of which 264 were randomized, and 215 provided primary outcome data. No statistically significant differences were found between groups at post-treatment: intervention: mean (SD): 12.75 (5.52); active control: 13.28 (5.32); p = 0.604. There was a statistically significant effect of the intervention on some of the secondary outcomes. Exploratory analyses suggest a dose-response relationship between Motherly app engagement and outcomes. Conclusion: Our standalone app intervention did not significantly reduce postnatal depression symptoms when compared to active control. Exploratory findings suggest that negative findings might be associated with insufficient app engagement. Consistent with current literature, our findings suggest that standalone app interventions for postpartum depression are not ready to be implemented in clinical practice. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions This scoping review aims to expansively review the reporting of Indigenous status, ethnicity, culture, language and country of birth in Australian paediatric clinical studies.Scoping review of Australian clinical studies, including randomised controlled trials, non‐randomised controlled trials, cluster randomised controlled trials and quasi‐experimental studies, with paediatric participants (<18 years) or mixed adult and paediatric participants. PubMed, Cumulated Index to Nursing and Allied Health Literature and Embase databases were searched for clinical studies published 1 January 2018 to 28 November 2022.Of the 2717 studies identified in the search, 209 clinical studies were included. Overall, 131 (62.7%) clinical studies captured in this review did not report any of the variables of interest. When reported, terms used by study authors varied extensively and subsequently five study‐defined categories emerged ‘Indigenous status’, ‘race’, ‘race and ethnicity’, ‘ethnicity’, or ‘natural skin colour’. ‘Indigenous status’ was most reported (n = 37, 17.7%), followed by ‘ethnicity and/or cultural background’ (n = 15, 7.2%), ‘race and ethnicity’ (n = 4, 1.9%), race (n = 1, 0.5%) and ‘natural skin colour’ (n = 1, 0.5%). Furthermore, language used at home was reported in 27 studies (12.9%) and country of birth in 23 studies (11.0%).This review demonstrated very low reporting of Indigenous status, ethnicity, culture, language and country of birth in Australian paediatric clinical studies. Poor reporting has raised concerns surrounding generalisability of findings from these trials in addition to equity. The recent international shift encompassing improved clinical trial reporting requirements, for ethnicity and race, require prompt establishment in the Australian clinical trial domain. [ABSTRACT FROM AUTHOR]

Introduction: Accurately predicting a patient’s prognosis is an important component of decision-making in intracerebral hemorrhage (ICH). We aimed to determine clinicians’ ability to predict survival, functional recovery, and return to premorbid activities in patients with ICH. Methods: Pre-specified secondary analysis of the third intensive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3), an international, multicenter, stepped-wedge cluster randomized controlled trial. Clinician perspectives on prognosis were collected at hospital admission and Day 7 (or before discharge). Prognosis questions were the likelihood of (i) survival at 48 h and 6 months, (ii) favorable functional outcome (recovery walking and self-care), and (iii) return to usual activities at 6 months. Clinician predictions were compared with actual outcomes. Results: Most clinician participants were from neurosurgery (75%) with a median of 8 working years (IQR 5–14) of experience. Of the 6,305 randomized patients who survived 48 h, 213 (3.4%) were predicted to die (positive predictive value [PPV] 0.99, 95% confidence interval [CI] 0.99–0.99). Of 5,435 patients who survived 6 months, 209 (3.8%) were predicted to die (PPV 0.93, 95% CI: 0.92–0.93). Predictions on the favorable functional outcome (PPV 0.54, 95% CI: 0.52–0.56) and satisfied ability to return to usual activities (PPV 0.50, 95% CI: 0.49–0.52) were poor. Prediction accuracy varied by working years and region of practice. Conclusions: In patients with ICH, clinician estimates of death are very good but conversely they are poor in predicting higher levels of functional recovery and activities. [ABSTRACT FROM AUTHOR]

Aims Materials and Methods Results Conclusions Life expectancy is reduced in people with obesity and is further reduced in those with concomitant type 2 diabetes. The aim of the study was to assess whether a 2‐year delay in diabetes development influences life expectancy in people with obesity.Participants from the Swedish Obese Subjects study without diabetes at baseline and known diabetes status at the 2‐year follow‐up were included: bariatric surgery (n = 1471) and usual obesity care (n = 1392). Median follow‐up was 26.1 years (interquartile range: 22.7–28.7 years). The Swedish Cause of Death Register, case sheets and autopsy reports were assessed to determine the direct cause of death. Analyses were adjusted for preselected risk factors: inclusion year, sex, baseline age, body mass index (BMI) and smoking.Across both study arms, 146 participants were newly diagnosed with type 2 diabetes at the 2‐year examination, whereas 2717 remained diabetes‐free. Most participants diagnosed with diabetes (n = 140) were from the usual care control group. During the follow‐up, there were 18.3 deaths per 1000 person‐years (95% confidence interval [CI]:14.1–23.9) in the group with diagnosed diabetes at the 2‐year follow‐up and 10.9 deaths per 1000 person‐years (95% CI:10.2–11.8) in the group that remained diabetes‐free (adjusted hazard ratio [HRadj] 1.60, 95% CI: 1.19–2.15, p = 0.002). The adjusted median life expectancy in the diabetes group was 3.7 years (95% CI: 1.4–6.0, p = 0.002) shorter than in the diabetes‐free group. Specifically, cardiovascular mortality was higher in the group with diabetes (adj sub‐hazard ratio [sub‐HR] 1.74 [95% CI: 1.09–2.77], p = 0.021).A 2‐year delay in diabetes development may be linked to increased life expectancy, possibly due to a reduction in cardiovascular mortality. Future studies should confirm these findings. [ABSTRACT FROM AUTHOR]

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is linked to high mortality, primarily through an intense inflammatory response. Diacerein has emerged as a potential therapy for COVID-19 due to its potential impact in decreasing the inflammasome activation and coronavirus replication. This study aims to explore diacerein's influence in inhibiting both viral replication and the inflammatory response after SARS-CoV-2 infection. Methods: Human peripheral blood mononuclear cells (PBMCs) were obtained from healthy volunteers and infected in vitro with SARS-CoV-2. Additionally, we carried out a pilot randomized, double-blind, placebo-controlled study with 14 participants allocated to diacerein (n = 7) or placebo (n = 7) therapies every 12 h for 10 days. The primary endpoint was change in plasma markers of inflammasome activation (NLRP3, caspase-1, and gasdermin-D). Results: In vitro protocols have shown that rhein, diacerein's primary metabolite, decreased IL-1ß secretion caused by SARS-CoV-2 infection in human PBMCs (p < 0.05), and suppressed viral replication when administered either before or after the virus incubation (p < 0.05). This later effect was, at least partially, attributed to its inhibitory effect on 3-chymotrypsin-like protease (SARS-CoV-2 3CLpro) and papain-like protease in the SARS-CoV-2 (SARS-CoV-2 PLpro) virus and in the phosphorylation of proteins related cytoskeleton network (p < 0.05). Diacereintreated COVID-19 patients presented a smaller area under the curve for NLRP3, caspase-1 and GSDM-D measured on days 2, 5, and 10 after hospitalization compared to those receiving a placebo (p < 0.05). Conclusion: The indicated mechanisms of action of diacerein/rhein can reduce viral replication and mitigate the inflammatory response related to SARS-CoV-2. These findings are preliminary and require confirmation in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Traditional medical research infrastructures relying on the Centers of Excellence (CoE) model (an infrastructure or shared facility providing high standards of research excellence and resources to advance scientific knowledge) are often limited by geographic reach regarding patient accessibility, presenting challenges for study recruitment and accrual. Thus, the development of novel, patient-centered (PC) strategies (e.g., the use of online technologies) to support recruitment and streamline study procedures are necessary. This research focused on an implementation evaluation of a design innovation with implementation outcomes as communicated by study staff and patients for CoE and PC approaches for a randomized controlled trial (RCT) for patients with vasculitis. Methods: In-depth qualitative interviews were conducted with 32 individuals (17 study team members, 15 patients). Transcripts were coded using the Consolidated Framework for Implementation Research (CFIR). Results: The following CFIR elements emerged: characteristics of the intervention, inner setting, characteristics of individuals, and process. From the staff perspective, the communication of the PC approach was a major challenge, but should have been used as an opportunity to identify one "point person" in charge of all communicative elements among the study team. Study staff from both arms were highly supportive of the PC approach and saw its promise, particularly regarding online consent procedures. Patients reported high self-efficacy in reference to the PC approach and utilization of online technologies. Local physicians were integral for making patients feel comfortable about participation in research studies. Conclusions: The complexity of replicating the interpersonal nature of the CoE model in the virtual setting is substantial, meaning the PC approach should be viewed as a hybrid strategy that integrates online and face-to-face practices. Trial registrations: 1) Name: The Assessment of Prednisone In Remission Trial – Centers of Excellence Approach (TAPIR). Trial registration number: ClinicalTrials.gov NCT01940094. Date of registration: September 10, 2013. 2) Name: The Assessment of Prednisone In Remission Trial – Patient Centric Approach (TAPIR). Trial registration number: Clinical Trials.gov NCT01933724. Date of registration: September 2, 2013. [ABSTRACT FROM AUTHOR]

Background: Robotic exoskeletons have changed rehabilitation care available to people after spinal cord injury (SCI). Yet, the current evidence base is insufficient to identify the optimal dose and neurophysiological mechanism of robotic exoskeleton gait training (RGT) as an effective rehabilitation approach. This study will (1) examine whether the frequency of RGT after motor incomplete SCI impacts function and health outcomes, (2) analyze the neuroplastic effects of RGT dose, and (3) evaluate the safety, tolerability, and feasibility of delivering RGT. Methods: We will enroll 144 participants with motor incomplete SCI admitted to inpatient rehabilitation within 6 months of SCI. Participants will be randomized based on injury severity and level into one of 3 RGT frequency groups (high, moderate, low) or none/usual care only. Participants will complete 24 RGT sessions and be assessed at admission and discharge to inpatient rehabilitation, post-RGT intervention, 1-month post-RGT, and 9-month post-SCI. Outcomes include Walking Index for Spinal Cord Injury-II, health outcomes (gait speed, Spinal Cord Independence Measure, pain, fatigue, spasticity, general health, quality of life, physical activity), and motor evoked potential amplitudes obtained using transcranial magnetic stimulation. Discussion: Successful completion of this study will provide an evidence-based intervention, specifically tailored to meet the unique needs of people with SCI, which supports walking recovery; maximizing health, function, and ultimately participation. The intervention will further support widespread clinical implementation of exoskeleton use during acute rehabilitation. Trial registration: ClinicalTrials.gov NCT05218447. Registered on June 23, 2022. [ABSTRACT FROM AUTHOR]

Abstract.Adaptive designs for clinical trials address the ethical requirement of allocating fewer patients to the inferior treatment as the trial progresses. We present here a generic strategy partly motivated by play-the-winner heuristic for reducing the variability of such designs. It is shown through simulations from a real clinical setting that employing this strategy improves the safety and the performance of some standard response adaptive designs. A closely related alternate strategy amenable to a theoretical analysis is also proposed with the same objective of lower variability. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusions This study examined the efficacy of AST‐001 for the core symptoms of autism spectrum disorder (ASD) in children.This phase 2 clinical trial consisted of a 12‐week placebo‐controlled main study, a 12‐week extension, and a 12‐week follow‐up in children aged 2 to 11 years with ASD. The participants were randomized in a 1:1:1 ratio to a high‐dose, low‐dose, or placebo‐to‐high‐dose control group during the main study. The placebo‐to‐high‐dose control group received placebo during the main study and high‐dose AST‐001 during the extension. The a priori primary outcome was the mean change in the Adaptive Behavior Composite (ABC) score of the Korean Vineland Adaptive Behavior Scales II (K‐VABS‐II) from baseline to week 12.Among 151 enrolled participants, 144 completed the main study, 140 completed the extension, and 135 completed the follow‐up. The mean K‐VABS‐II ABC score at the 12th week compared with baseline was significantly increased in the high‐dose group (P = 0.042) compared with the placebo‐to‐high‐dose control group. The mean CGI‐S scores were significantly decreased at the 12th week in the high‐dose (P = 0.046) and low‐dose (P = 0.017) groups compared with the placebo‐to‐high‐dose control group. During the extension, the K‐VABS‐II ABC and CGI‐S scores of the placebo‐to‐high‐dose control group changed rapidly after administration of high‐dose AST‐001 and caught up with those of the high‐dose group at the 24th week. AST‐001 was well tolerated with no safety concern. The most common adverse drug reaction was diarrhea.Our results provide preliminary evidence for the efficacy of AST‐001 for the core symptoms of ASD. [ABSTRACT FROM AUTHOR]

Rationale: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors enable an additional 54–75% reduction in low-density lipoprotein cholesterol (LDL-C) in statin-treated patients, demonstrating plaque regression in coronary artery disease. However, the impact of achieving an extremely low level of LDL-C with PCSK9 inhibitors (e.g. Evolocumab) on symptomatic intracranial atherosclerosis remains unexplored. Aim and hypothesis: To determine whether combining Evolocumab and statins achieves a more significant symptomatic intracranial plaque regression than statin therapy alone. Sample size estimates: With a sample size of 1000 subjects, a two-sided α of 0.05, and 20% lost to follow-up, the study will have 83.3% power to detect the difference in intracranial plaque burden. Methods and design: This is an investigator-initiated multicenter, randomized, open-label, outcome assessor-blinded trial, evaluating the impact of combining Evolocumab and statins on intracranial plaque burden assessed by high-resolution magnetic resonance imaging at baseline in patients undergoing a clinically indicated acute stroke or transient ischemic attack due to intracranial artery stenosis, and after 24 weeks of treatment. Subjects (n = 1000) were randomized 1:1 into two groups to receive either Evolocumab 140 mg every 2 weeks with statin therapy or statin therapy alone. Study outcomes: The primary endpoint is the change in intracranial plaque burden assessed by high-resolution magnetic resonance imaging, performed at baseline and at the end of the 24-week treatment period. Discussion: This trial will explore whether more significant intracranial plaque regression is achievable with the treatment of combining Evolocumab and statins, providing information about efficacy and safety data. Trial registration number: ChiCTR2300068868; https://www.chictr.org.cn/ [ABSTRACT FROM AUTHOR]

Cellular immunotherapy exploits the capacity of the human immune system in self-protection and surveillance to achieve the anti-tumor effects. Natural killer (NK) cells are lymphocytes of innate immune system and they display a unique inherent ability to identify and eliminate tumor cells. In this review, we first introduce the basic characteristics of NK cells in the physiological and pathological milieus, followed by a discussion of their effector function and immunosuppression in the tumor microenvironment. Clinical strategies and reports regarding NK cellular therapy are analyzed in the context of tumor treatment, especially against solid tumors. Given the widely studied T-cell therapy in the recent years, particularly the chimeric antigen receptor (CAR) T-cell therapy, we compare the technical features of NK- and T-cell based tumor therapies at the clinical front. Finally, the technical challenges and potential solutions for both T and NK cell-based immunotherapies in treating tumor malignancies are delineated. By overviewing its clinical applications, we envision the NK-cell based immunotherapy as an up-and-comer in cancer therapeutics. [ABSTRACT FROM AUTHOR]

ABSTRACT In covariate‐adaptive or response‐adaptive randomization, the treatment assignment and outcome can be correlated. Under this situation, the re‐randomization test is a straightforward and attractive method to provide valid statistical inferences. In this paper, we investigate the number of repetitions in tests. This is motivated by a group sequential design in clinical trials, where the nominal significance bound can be very small at an interim analysis. Accordingly, re‐randomization tests lead to a very large number of required repetitions, which may be computationally intractable. To reduce the number of repetitions, we propose an adaptive procedure and compare it with multiple approaches under predefined criteria. Monte Carlo simulations are conducted to show the performance of different approaches in a limited sample size. We also suggest strategies to reduce total computation time and provide practical guidance in preparing, executing, and reporting before and after data are unblinded at an interim analysis, so one can complete the computation within a reasonable time frame. [ABSTRACT FROM AUTHOR]

In response to the coronavirus disease 2019 (COVID-19) pandemic, vaccines were quickly and successfully developed and deployed, saving millions of lives globally. While first-generation vaccines are safe and effective in preventing disease caused by SARS-CoV-2, next-generation vaccines have the potential to improve efficacy and safety. Vaccines delivered by a mucosal route may elicit greater protective immunity at respiratory surfaces, thereby reducing transmission. Inclusion of viral antigens in addition to the spike protein may enhance protection against emerging variants of concern. Next-generation vaccine platforms with a new mechanism of action may necessitate efficacy trials to fulfill regulatory requirements. The Biomedical Advanced Research and Development Authority (BARDA) will be supporting Phase 2b clinical trials of candidate next-generation vaccines. The primary endpoint will be improved efficacy in terms of symptomatic disease relative to a currently approved COVID-19 vaccine. In this paper, we discuss the planned endpoints and potential challenges to this complex program. [ABSTRACT FROM AUTHOR]

Background: Hypertensive disorders of pregnancy (HDP) pose significant risks to maternal and fetal health, with substantial mortality and morbidity rates globally, particularly in developing countries. Pre-eclampsia (PE) accounts for a notable portion of maternal morbidity and mortality, with varied prevalence across regions within countries like India. Despite advancements, disparities in healthcare access persist, influencing outcomes. PE not only affects maternal health during pregnancy but also predisposes women to long-term cardiovascular complications, emphasizing the need for early screening and preventive measures. Methods: This prospective randomized double-blind clinical trial aims to compare the efficacy and safety of 75 mg versus 150 mg aspirin for preventing preterm pre-eclampsia in high-risk women. Screen-positive women aged 18–45 years with singleton pregnancies between 12 and 16 weeks of gestational age will be enrolled. They will be randomized in a 1:1 ratio to receive either 75 mg or 150 mg of aspirin nightly until 37 weeks of pregnancy or earlier if preterm pre-eclampsia develops. Feto-maternal outcomes, including preterm pre-eclampsia incidence and neonatal and maternal complications, will be assessed. The sample size calculation based on expected proportions of preterm pre-eclampsia in both groups indicates a total of 370 participants (185 per group) accounting for 20% attrition. Discussion: This prospective randomized double-blind clinical trial aims to compare the effectiveness and safety of two doses of aspirin (75 mg vs 150 mg) in preventing preterm pre-eclampsia in high-risk women. The potential implications of this study are significant, including the optimization of aspirin prophylaxis, the development of evidence-based guidelines, and comprehensive assessment of maternal and fetal outcomes. In conclusion, the results of this study have the potential to significantly impact clinical practice by enhancing maternal and perinatal health outcomes and contributing to evidence-based obstetric care. Trial registration: Clinical Trials Registry-India CTRI/2023/12/060983. Trial was registered prospectively on 29 December 2023. Acknowledgement Number REF/2023/12/076358. https://acrobat.adobe.com/id/urn:aaid:sc:AP:15870322-f1f4-4460-900c-6e056ab83a44. [ABSTRACT FROM AUTHOR]

Background: Balance and mobility deficits are major concerns in stroke rehabilitation. Virtual reality (VR) training and Swiss-ball training are commonly used approaches to improve balance and mobility. However, no study has compared the efficacy of VR training, Swiss-ball training, and their combination in improving balance and mobility function or investigated cortical activation and connectivity in individuals with stroke. Methods: A prospective, single-blinded, parallel-armed, multi-center randomized controlled trial with factorial design will be conducted. Seventy-six participants aged 30–80 years with stroke will be recruited. Participants will be allocated to one of the four groups: (A) the VR training + Swiss-ball training + conventional physical therapy group; (B) the Swiss-ball training + conventional physical therapy group; (C) the VR training + conventional physical therapy group; or (D) the conventional physical therapy group. All participants will receive 50 min of training per day, 5 times per week, for a total of 4 weeks. The primary outcomes will be balance and mobility measures. Secondary outcomes will include the 10-min walk test, dynamic gait index, and cortical activation. Outcomes will be measured on three occasions: at baseline, after the training, and at the 4-week follow-up. Discussion: This trial will provide evidence to determine whether there are differences in clinical outcomes and cortical activation following two different types of exercise programs and their combination, and to elucidate the recovery mechanisms of balance and mobility function in individuals with stroke. Trial registration: Chinese Clinical Trial Registry reference: www.chictr.org.cn (No. ChiCTR2400082135). Registered on May 24, 2024. [ABSTRACT FROM AUTHOR]

While the macronutrient content of a ketogenic diet specifically utilized for childhood epilepsy is clearly defined in the literature, variations among other ketogenic diets exhibit substantial heterogeneity. Furthermore, studies utilizing ketogenic diets contain several confounders with notable impacts on outcomes, thereby rendering both their findings and those of the meta-analyses less reliable. The objective of this meta-epidemiological assessment was to scrutinize existing clinical trials that investigated the effects of ketogenic diets on patients with obesity and diabetes, thereby determining the feasibility of conducting a meta-analysis. The Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched from 1946 to 24 September 2024. Of the studies reviewed, none met the predefined inclusion criteria. However, seven articles met these criteria very closely. In the future, studies investigating the effects of ketogenic diets containing significant confounding factors should adopt a single definition of a ketogenic diet. Additionally, accurate measurement of actual macronutrient and caloric intake, along with regularly monitored nutritional ketosis, will be essential to highlight the true effects of a ketogenic diet. [ABSTRACT FROM AUTHOR]

Background: Acute ischemic stroke (AIS) is an acute brain injury caused by sudden occlusion of a blood vessel. Endovascular therapy is the most effective way to restore blood flow. However, despite the restoration of blood flow in some patients, their clinical prognosis often remains unsatisfactory. Albumin has shown neuroprotective effects in animal models of AIS. Therefore, this study aims to evaluate the safety, feasibility, and efficacy of local arterial infusions of 20% human serum albumin solution as an adjuvant therapy after endovascular therapy in patients with AIS. Methods: This study is a prospective, therapeutic exploratory, non-randomized, open-label, phase 1 clinical trial testing the use of 20% human serum albumin solution injected via the artery immediately after successful reperfusion in patients with AIS. The study is divided into two stages. In the first stage, a single- dose-finding will explore the maximum safe dose according to the 3 + 3 dose escalation principle;, with the maximum dose being 0.60 g/kg. After recanalizing the occluded blood vessel, human serum albumin solution will be injected into the internal carotid artery region through a guiding catheter for 30 min. The second stage involves an albumin adjuvant therapy cohort (AT) and an endovascular treatment lonely cohort (ET). The AT cohort will encompass at least 15 additional participants to complete safety trials at the maximum safe dose determined in the first stage. The ET cohort will include well-matched patients receiving endovascular therapy alone, derived from a contemporaneous prospective registry, who will be excluded from having cardiopulmonary disorders and from receiving any neuroprotective therapy. The primary outcome of this study will be symptomatic intracranial hemorrhage. Efficacy outcomes will include the proportion of patients with the progression of cerebral infarction volume, a modified Rankin Scale of 0–2 on day 90 after randomization. An exploratory secondary outcome will be the analysis of thromboinflammatory and neuroprotective molecule profiles. Conclusion: This pilot trial aims to explore the safety and efficacy of arterial infusion of an albumin solution after occlusive vessel opening in AIS. The results will provide data parameters for subsequent tests on the arterial infusion of albumin solutions. [ABSTRACT FROM AUTHOR]

Background: Burn wounds require optimal medical management due to associated psycho-emotional and socioeconomic impacts and severe pain. The use of synthetic and biological dressings improves healing and reduces burn wound complications. The present study aimed to compare the outcomes of using human amniotic membrane (hAM) dressings and conventional silver sulfadiazine (SSDZ) ointment dressings in the management of second-degree burn wounds. Methods: Fifty patients who participated in this clinical trial were divided into two groups via simple randomization. All the enrolled patients, who had burnt in the last 24 h, had thermal damage mechanisms and were suffering from less than 20% second-degree heat-burn wounds on the skin surface. The target group (n = 25) was treated with hAM, and the control group (n = 25) was treated with SSDZ ointment. The researcher-designed checklist was used to determine the clinical performance in the follow-up assessments on days 7, 14, and 30. Results: No significant differences were detected in terms of sex, age, or percentage of burn wounds (p > 0.05). Wound epithelialization at days 7, 14, and 30, scar formation, wound pigmentation, pain severity, analgesia requirements, and hospital stay length (on day 30) were significantly lower in the target group (treated with hAM) than in the control group (treated with SSDZ ointment) (p < 0.05). However, treatment costs in the target group ($170) were significantly higher than those in the control group ($71) (p < 0.001). Conclusion: Despite its higher cost, hAM, as a technology-based therapy dressing, demonstrates superiority over SSDZ ointment in terms of wound healing and pain management. [ABSTRACT FROM AUTHOR]

Background: SHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects. Methods: Two randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18–45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55–80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg). Results: Sixty-two (part 1/2, n = 50/12; age range, 18–42/55–63 years) and 30 subjects (age range, 18–42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2–60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed. Conclusions: A single intravenous dose of SHR-1707 at 2–60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development. Trial registration: NCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Aims Materials and Methods Results Conclusions The aim was to evaluate the effect of extended use of the Omnipod® 5 automated insulin delivery (AID) system in adults with type 2 diabetes and suboptimal glycaemic control.Following an 8‐week single‐arm, multicentre, outpatient trial of AID in adults with type 2 diabetes and baseline ≥ 64 mmol/mol, participants were given the opportunity to continue use of the AID system in a 26‐week (~6 month) extension phase. The primary safety endpoints were percentage of time with sensor glucose ≥ 250 mg/dL and < 54 mg/dL. Additional glycaemic measures, including percentage of time in range (TIR) (70–180 mg/dL) and HbA1c, were evaluated. The use of non‐insulin anti‐hyperglycaemic medications was permitted throughout the entire study.During the initial 8‐week study, participants (N = 22) achieved a decrease in percentage of time ≥ 250 mg/dL from 27.4% ± 21.0% to 10.5% ± 8.8% (p < 0.0001), which further decreased to 9.7% ± 9.2% during the extension phase (p = 0.0002 vs. standard therapy). Percentage of time < 54 mg/dL remained low from standard therapy through extension (median [interquartile range] 0.00% [0.00%, 0.06%] vs. 0.02% [0.00%, 0.05%], p > 0.05). HbA1c decreased by 1.6% ± 1.2% (15.5 ± 13.1 mmol/mol, p < 0.0001) and TIR increased by 22.4% ± 19.2% (p < 0.0001) from standard therapy through extension with no significant change in body mass index and without an observed increase in total daily insulin requirements.These longer‐term findings of Omnipod 5 AID system use demonstrate the potential value of AID in helping people with type 2 diabetes reach glycaemic targets. [ABSTRACT FROM AUTHOR]

Originally devised for cancer control, mRNA vaccines have risen to the forefront of medicine as effective instruments for control of infectious disease, notably their pivotal role in combating the COVID-19 pandemic. This review focuses on fundamental aspects of the development of mRNA vaccines, e.g., tumor antigens, vector design, and precise delivery methodologies, - highlighting key technological advances. The recent, promising success of personalized mRNA vaccines against pancreatic cancer and melanoma illustrates the potential value for other intractable, immunologically resistant, solid tumors, such as glioblastoma, as well as the potential for synergies with a combinatorial, immunotherapeutic approach. The impact and progress in human cancer, including pancreatic cancer, head and neck cancer, bladder cancer are reviewed, as are lessons learned from first-in-human CAR-T cell, DNA and dendritic cell vaccines targeting glioblastoma. Going forward, a roadmap is provided for the transformative potential of mRNA vaccines to advance cancer immunotherapy, with a particular focus on the opportunities and challenges of glioblastoma. The current landscape of glioblastoma immunotherapy and gene therapy is reviewed with an eye to combinatorial approaches harnessing RNA science. Preliminary preclinical and clinical data supports the concept that mRNA vaccines could be a viable, novel approach to prolong survival in patients with glioblastoma. [ABSTRACT FROM AUTHOR]

Background: White matter lesions(WML) is an important cause of mild cognitive impairment(MCI). Ginkgo biloba extracts (GBTs) are widely used to treat cognitive dysfunctions. But the treatment of MCI is still limited. Shenqingtongqiao Decoction(SQTQD), as a clinical empirical formula, has received good feedback in treating MCI of WML. However, there was a lack of solid clinical research on SQTQD in treating MCI. The purpose of this study is to evaluate the efficacy of SQTQD in the MCI patients of WML. Methods: This is a randomized, double-blind, double-dummy, parallel-controlled trial. 80 participants will be assigned to receive SQTQD granules plus GBTs mimetics or SQTQD mimetic granules plus GBTs in a 1:1 ratio. The trial will last 24 weeks, including a 12-week intervention and 12-week follow-up. The primary outcome is MoCA and AVLT. The secondary outcome is a neuropsychological battery (including MMSE, SCWT, TMT, DST, SDMT, BNT, VFT, and CDT), quality of life(BI, ADL, and FAQ scores), emotion assessment(PHQ-9, GAD-7 score) , Fazekas and ARWMCs scale, and fMRI. Researchers will record any adverse events throughout the trial. Discussion: This study will provide evidence to evaluate the efficacy and safety of SQTQD for MCI of WML compared with GBTs. Trial registration: The trial is registered at Chinese Clinical Trial Registry: Chinese Clinical Trial Registry (Number: ChiCTR2300068552). [ABSTRACT FROM AUTHOR]

AbstractA clinical trial aims to uncover high-quality evidence for both efficacy and safety for an experimental treatment. Traditionally, statisticians evaluate the two aspects marginally, where, for example, efficacy considers the proportion of patients cured and safety considers the proportion of patients not showing adverse events. However, separate analyses could end up with misleading results, as the cumulative nature of clinical outcomes and the correlation between efficacy and safety endpoints are neglected. The desirability of outcome ranking (DOOR) method addresses such issues and provides a patient-centric approach to benefit:risk evaluation. A patient’s outcome is ranked based on pre-specified clinical criteria, where the most desirable rank represents a good outcome with no side effects and the least desirable rank is the worst possible clinical outcome. As the DOOR outcome is a temporal state that can have repeated measures, we propose a longitudinal approach that estimates and infers the temporal treatment effects. We develop a methodology for constructing simultaneous confidence bands by accounting for the correlations across time points. Additionally, we propose a weighted Mann-Whitney-U statistic to evaluate the treatment effect over the entire trial period. The performance of the proposed methodologies is examined through simulations and an application to a COVID-19 trial. [ABSTRACT FROM AUTHOR]

Background: Poor patient accrual can delay reporting of clinical trials and, consequently, the development of new treatments. For reducing the risk of additional resource requirements, a method for setting planned accrual periods with minimal deviation from the actual accrual periods is desirable. Risk factors for poor patient accrual and the appropriate method of estimating the required accrual period for timely completion of clinical trials were evaluated using the data of trials conducted by the Japan Clinical Oncology Group. Methods: The study included 199 trials that started patient accrual between January 1, 1990, and June 30, 2021. The explanatory variables included factors that could be evaluated prior to trial commencement. We also evaluated whether the estimation methods for accrual pace could lead to completion within the planned accrual period. Results: Approximately 23.6% of trials were completed within the planned accrual period. The risk factors for trial extension included planned accrual periods > 3 years (reference group: ≤ 3 years, odds ratio [OR] 0.37, 95% confidence interval [CI]: 0.15–0.92, P = 0.033) and stratified trial design (reference group: nonrandomized phase II trials, nonrandomized phase III trial [OR: 3.28, 95% CI: 0.99–10.9, P = 0.051], randomized phase II trial [OR: 3.91, 95% CI: 0.75–20.30, P = 0.105], and randomized phase III trial [OR: 9.29, 95% CI: 3.39–25.40, P < 0.001]). The method of estimating the accrual pace based on past clinical trials facilitated timely completion of the trial (OR: 3.51; 95% CI: 1.73–7.10, P < 0.001), unlike the estimation method based on survey evaluation of the accrual pace for participating institutions (OR: 1.12, 95% CI: 0.56–2.26, P = 0.751). Furthermore, the discrepancy between planned and actual accrual periods was minimal when using the methods of considering the accrual pace of past clinical trials. Conclusions: Considering the accrual pace of past clinical trials is useful for estimating the required accrual period if data from past trials are available. When conducting a survey, it is necessary to be cautious of overestimating the cases at each facility. [ABSTRACT FROM AUTHOR]

Background and Objective: Cytisine serves as an affordable smoking cessation aid with acceptable safety profile. However, data comparing its efficacy and safety to standard therapies are limited. We aimed to examine efficacy and safety of cytisine compared to nortriptyline, which is the only approved smoking‐cessation medication in Thailand. Methods: A 12‐month, multicentre, randomized, double‐blinded, placebo‐controlled trial was conducted. Participants aged ≥20 years who smoked ≥10 cigarettes/day were randomly assigned to receive a 25‐day cytisine or a 12‐week nortriptyline treatment course. Brief interventions (BI) for smoking cessation were provided to all participants. The primary outcome was biochemically verified continuous abstinence rate (CAR) at 12 months. Additionally, self‐reported abstinence, verified by exhaled carbon monoxide (CO) ≤ 10 ppm, was collected at 2 weeks, 1, 3, 6 and 12 months to assess both CAR and 7‐day point prevalence abstinence rate (PAR). Results: A total of 1086 participants were recruited and randomized into cytisine (n = 540) and nortriptyline (n = 546) groups. The 12‐month CAR was 12.22% for cytisine and 9.52% for nortriptyline. The relative difference was 0.03 (95% confidence interval [CI]; −0.01 to 0.06) and the relative risk was 1.28 (95% CI; 0.91–1.81). No differences were observed in secondary outcomes between both groups. The incidence of adverse effects from cytisine appeared to be lower than that of nortriptyline. Conclusion: At 12 months, cytisine plus BI was as effective as nortriptyline plus BI for smoking cessation. The adverse events for both cytisine and nortriptyline were minimal and well‐tolerated. [ABSTRACT FROM AUTHOR]

Background The standard of care for Lassa fever is the use of ribavirin with supportive therapy. There is little information on the course of viremia and its relationship with clinical outcomes in patients treated with ribavirin. Methods We conducted a retrospective analysis of virologic and clinical parameters of 152 reverse transcription polymerase chain reaction–confirmed Lassa fever cases admitted and treated with ribavirin therapy. We describe the Lassa virus RNA kinetics in blood in relation to the clinical course of the patients. Results The overall mortality was 9%. The median duration (interquartile range [IQR]) of illness before admission was 8 (5–12) days. Median (IQR) Ct values on admission (t0) were lower among patients who died (21 [20–27]) than in those who survived (34 [30–37]; P <.01). The receiver operating characteristics curve of the association between outcome and Ct value at t0 had a high classification performance, with an AUC of 0.92 (95% CI, 0.86–0.98). The median time to viral clearance (IQR) was 10 (5–15) days. The viral load decreased steadily with the duration of treatment, and all survivors achieved viral clearance within 25 days of hospitalization. Conclusions Our study demonstrates that the Ct value on admission has prognostic value and Lassa fever patients treated with ribavirin typically clear the virus within 3–4 weeks of hospitalization. This kinetics has implications for the design of clinical case management and future clinical trial protocols. [ABSTRACT FROM AUTHOR]

Background Immunogenicity studies suggest that recombinant influenza vaccine (RIV) may provide better protection against influenza than standard-dose inactivated influenza vaccines (SD IIV). This randomized trial evaluated the relative vaccine effectiveness (VE) and immunogenicity of RIV versus SD IIV in frontline workers and students aged 18–64 years. Methods Participants were randomized to receive RIV or SD IIV and followed for reverse-transcription polymerase chain reaction (RT-PCR)–confirmed influenza during the 2022–2023 influenza season. Sera were collected from a subset of participants before and at 1 and 6 months postvaccination and tested by hemagglutination inhibition for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria and against cell-grown vaccine reference viruses for A/H1N1 and A/H3N2. Results Overall, 3988 participants were enrolled and vaccinated (25% of the trial sample size goal); RT-PCR–confirmed influenza occurred in 20 of 1963 RIV recipients and 28 of 1964 SD IIV recipients. Relative VE was 29% (95% confidence interval [CI], −26% to 60%). In the immunogenicity substudy (n = 118), the geometric mean titer ratio (GMTR) comparing RIV to SD IIV at 1 month was 2.3 (95% CI, 1.4–3.7) for cell-grown A/H1N1, 2.1 (95% CI, 1.3–3.4) for cell-grown A/H3N2, 1.1 (95% CI,.7–1.6) for B/Victoria, and 1.4 (95% CI,.9–2.0) for B/Yamagata. At 6 months, GMTRs were >1 against A/H1N1, A/H3N2, and B/Yamagata. Conclusions Relative VE of RIV compared to SD IIV did not reach statistical significance, but RIV elicited more robust humoral immune responses to 2 of 4 vaccine viruses at 1 month and 3 of 4 viruses at 6 months after vaccination, suggesting possible improved and sustained immune protection from RIV. Clinical Trials Registration. NCT05514002. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Introduction: Bipolar disorder is a recurrent mental health disorder with a prevalence rate of 1.4%. On average, there can be a delay of 9.5 years from the initial presentation of symptoms to a confirmed diagnosis. Individuals living with bipolar disorder have a reduced life expectancy. There is limited evidence regarding the effectiveness of antidepressants in treating bipolar disorder. The ASCEnD clinical trial will test the clinical and cost‐effectiveness of the aripiprazole/sertraline combination in comparison with quetiapine for the treatment of bipolar depression (individuals who suffer from depressive episodes in bipolar disorder) and will include a nested qualitative study. Methods: The qualitative study will use semi‐structured interviews to explore pilot trial participants' and clinicians' perspectives on recruitment procedures, the acceptability of the intervention, the management of bipolar disorder and attitudes to medication combinations. Conclusion: Findings will inform recruitment strategies and optimise training for the participating sites in the ASCEnD full trial. They will also help to illuminate the lived experience of people with bipolar disorder and the clinicians who work with people with bipolar disorder. The discussion will explore perspectives on the delay in diagnosis, having a diagnosis, the impact of living with bipolar disorder and attitudes to treatment, including drug combinations. Patient or Public Contribution: A Lived Experience Advisory Panel (LEAP) has been convened with the support of the McPin Foundation, which will contribute to the ASCEnD trial and its nested qualitative study to provide input on the design and delivery of the trial and qualitative study, analysis of qualitative data and dissemination of findings. [ABSTRACT FROM AUTHOR]

Background and Objectives: This survey study aimed to (1) identify patient/family research priorities in pediatric-onset multiple sclerosis (POMS), and (2) delineate optimized methods for research study/clinical trials design, engagement, and implementation. Methods: Participants were as follows: (1) parents of a child (<18 years) with POMS enrolled in a national registry, (2) adolescents (13–17 years) with POMS in the registry, and (3) adults (18–40 years) with POMS receiving care at a registry affiliated clinic. Of 293 eligible participants, 192 completed surveys. Results: Experiences with health care and medications were generally positive but there remain areas of priority improvement. Incentives to participate in clinical trials included medications previously tested and in pill form, bloodwork/study visits required ⩾ every 3 months, cognitive testing ⩽1 hour, compensation for travel and time, ability to continue current multiple sclerosis (MS) medication, option to take study medication if on placebo, and individualized study feedback. Priorities for clinical research were (1) psychosocial impact, (2) cognitive/academic impact, (3) environmental risk, and (4) nutrition. Conclusions: Results highlighted the importance of a holistic approach to study design and a focus on the impact of disease on daily life to best engage patients and families in POMS clinical trials and research. [ABSTRACT FROM AUTHOR]

Objective: We aimed to compare the results of phase III and IV clinical trials examining drugs to treat multiple sclerosis (MS) registered at ClinicalTrials.gov to those published in peer-reviewed journals. Methods: After identifying trials registered at ClinicalTrials.gov, consecutive searches were conducted in PubMed, EMBASE and Google Scholar for matching publications. Information regarding participants and efficacy and safety results was extracted and compared. The degree of consistency was classified as 'concordant', 'discrepant' or 'not comparable'. The Kaplan–Meier method was used to model time to reporting. Results: In total, 65 trials were appraised. The median time from completion to reporting was shorter for ClinicalTrials.gov (16.4 vs 27.3 months; p = 0.010). Information availability was generally higher in journals except for serious adverse events (SAEs) (86.2% vs 100.0%, p = 0.029) and their description (78.2% vs 100.0%, p < 0.001). However, 45 trials had at least one reporting discrepancy (69.2%). Three studies omitted one or more primary outcomes in the matching journal publication. Regarding safety results, the lowest consistencies were found for causes of death (60.0%) and description of SAEs (27.9%). Conclusion: Consulting both ClinicalTrials.gov and journals increases the accessibility to MS clinical trial results. Some data were frequently missing or disagreed between sources, raising concerns about transparency and generalizability of results. [ABSTRACT FROM AUTHOR]

Background Chikungunya is a serious and debilitating viral infection with a significant disease burden. VLA1553 (IXCHIQ®) is a live-attenuated vaccine licensed for active immunization for prevention of disease caused by chikungunya virus (CHIKV). Methods Immunogenicity following a single dose of VLA1553 was evaluated in healthy adults aged ≥18 years in two Phase 3 trials [ N  = 656 participants (per protocol analysis set)]. Immunogenicity data to 180 days post-vaccination [geometric mean titres (GMTs), seroresponse rate, seroconversion rate] were pooled for the two trials. A comparison of subgroups based on age, sex, body mass index (BMI), race and baseline seropositivity was included. All analyses were descriptive. Results Most participants were aged 18–64 years (N  = 569/656 [86.7%]), there were slightly more females (N  = 372/656 [56.7%]), most were not Hispanic/Latino (N  = 579/656 [88.3%]), and most were White (N  = 517/656 [78.8%]). In baseline seronegative participants, GMT peaked at Day 29 post-vaccination, and subsequently declined slightly but remained elevated until Day 180. At Days 29, 85 and 180, seroresponse rate was 98.3, 97.7 and 96.4% and seroconversion rate was 98.5, 98.4 and 98.2%. There were no differences in seroresponse rate in participants aged 18–64 years or ≥65 years at Day 29 (98.1 vs 100%), Day 85 (97.4 vs 100%) and Day 180 (96.3 vs 96.5%) nor based on sex, BMI, ethnicity or race. An immune response was shown in a small heterogenous population of baseline seropositive participants, with GMTs showing the same trend as baseline seronegative participants. Conclusions A single dose of VLA1553 elicited a very strong immune response by Day 29 that remained elevated at Day 180 in both baseline seronegative and seropositive participants in a combined evaluation of two Phase 3 trials. The vaccine was similarly immunogenic in participants aged ≥65 years and 18–64 years, and there were no differences based on subgroup analyses for sex, BMI, ethnicity or race. [ABSTRACT FROM AUTHOR]

Background: In a previously reported Phase I trial, we observed therapy‐associated declines in circulating myeloid‐derived suppressor cells (MDSCs) with the administration of white button mushroom (WBM) tablets in prostate cancer (PCa) patients. These observations led us to hypothesise that WBM could mitigate PCa progression by suppressing MDSCs. Methods: We performed bidirectional translational research to examine the immunomodulatory effects of WBM consumption in both syngeneic murine PCa models and patients with PCa participating in an ongoing randomised Phase II trial (NCT04519879). Results: In murine models, WBM treatment significantly suppressed tumour growth with a reduction in both the number and function of MDSCs, which in turn promoted antitumour immune responses mediated by T cells and natural killer (NK) cells. In patients, after consumption of WBM tablets for 3 months, we observed a decline in circulating polymorphonuclear MDSCs (PMN‐MDSCs), along with an increase in cytotoxic CD8+ T and NK cells. Furthermore, single immune cell profiling of peripheral blood from WBM‐treated patients showed suppressed STAT3/IRF1 and TGFβ signalling in circulating PMN‐MDSCs. Subclusters of PMN‐MDSCs presented transcriptional profiles associated with responsiveness to fungi, neutrophil chemotaxis, leukocyte aggregation, and regulation of inflammatory response. Finally, in mouse models of PCa, we found that WBM consumption enhanced the anticancer activity of anti‐PD‐1 antibodies, indicating that WBM may be used as an adjuvant therapy with immune checkpoint inhibitors. Conclusion: Our results from PCa murine models and patients provide mechanistic insights into the immunomodulatory effects of WBM and provide a scientific foundation for WBM as a nutraceutical intervention to delay or prevent PCa progression. Highlights: White button mushroom (WBM) treatment resulted in a reduction in pro‐tumoural MDSCs, notably polymorphonuclear MDSCs (PMN‐MDSCs), along with activation of anti‐tumoural T and NK cells.Human single immune cell gene expression profiling shed light on the molecular alterations induced by WBM, specifically on PMN‐MDSCs.A proof‐of‐concept study combining WBM with PD‐1 blockade in murine models revealed an additive effect on tumour regression and survival outcomes, highlighting the clinical relevance of WBM in cancer management. [ABSTRACT FROM AUTHOR]

Background Succinylcholine is commonly used as a neuromuscular blocker during electroconvulsive therapy (ECT), but it can induce myalgia in patients. Dexmedetomidine, an alpha-2 adrenergic agonist, may mitigate this side effect. This study investigates the efficacy of dexmedetomidine in reducing succinylcholine-induced myalgia in ECT patients. Materials and Methods We conducted a randomized, double-blind clinical trial involving 100 patients scheduled for ECT. Participants were divided into two groups: the dexmedetomidine group (n=50) received 1 µg/kg dexmedetomidine prior to succinylcholine administration, while the control group (n=50) received a placebo. Myalgia was assessed using a numerical rating scale (0-10) 24 hours post-ECT. Results The dexmedetomidine group reported a significantly lower incidence of myalgia (20%) compared to the control group (48%) (p < 0.01). The mean myalgia score in the dexmedetomidine group was 2.1 ± 1.3, while the control group had a mean score of 4.8 ± 2.5 (p < 0.01). No significant adverse effects were noted in either group. Conclusion Dexmedetomidine significantly reduces the incidence and severity of succinylcholine-induced myalgia in patients undergoing ECT. This finding supports the use of dexmedetomidine as a premedication option in this population. [ABSTRACT FROM AUTHOR]

Objective To analyze the international status and level of clinical trial quality in China, and explore the advantages and value of scientific regulation of clinical research quality in China. Methods The data is sourced from the relevant reports publicly released by the National Medical Products Administration (NMPA), the inspection reports and announcements published by the Center for Food and Drug Inspection of the NMPA, the inspection data displayed on the official website of the U.S. Food and Drug Administration (FDA), as well as clinical diagnosis and treatment guidelines issued by the National Comprehensive Cancer Network (NCCN) of United States and the Chinese Society of Clinical Oncology (CSCO) (data as of July 21, 2023). This data provides an analysis of the regulatory status of the implementation of clinical drug trials in China, inspection data, and the approval and market entry of new oncology drugs and feedback from their practical application. Results The clinical trial quality inspection systems of China and the United States are generally aligned, with similar inspection subjects, focus areas, and public disclosure pathways. However, each has its characteristics in terms of inspection targets and types. The quality of clinical trial data in China has been continuously improving. Between 2009-2015 and 2016-July 2023, China underwent 25 and 20 FDA Bioresearch Monitoring (BIMO) inspections, respectively. The inspection results showing "No Action Indicated" (NAI) improved from 48.0% to 85.0%, while "Voluntary Action Indicated" (VAI) decreased from 44.0% to 15.0%. Official Action Indicated (OAI) measures were required in 2009 and 2012. Compared to the 2009-2015 period, there has been a clear upward trend in the quality of clinical trial data since 2016. From 2016 to July 2023, the number of new oncology drugs developed by Chinese pharmaceutical companies and included in professional guidelines has steadily increased. Specifically, 37 drugs (58.7%) were included in the 2022 edition of the CSCO guidelines, and 15 drugs (23.8%) were included in the 2023 edition of the NCCN guidelines, with 10 of these drugs featured in both guidelines. Conclusions The implementation quality of clinical trials in China has gained a certain level of international recognition and competitiveness. This progress is attributed to national macro-level guidance, a unique institutional model, and clinical practices aligned with international standards. In the future, it will be necessary to further strengthen the scientific regulatory system and enhance clinical research capabilities to continue advancing the high-quality development of clinical trials. [ABSTRACT FROM AUTHOR]

Aim: To explore parental perceptions of the consenting process and understanding of the study in a pilot randomised controlled trial wherein extremely premature infants (<29 weeks' gestation) were recruited either antenatally or by 4 h of life. Methods: We prospectively surveyed parents who had consented, declined consent or were eligible infants in the Positioning Preterm Infants for Neuroprotection study, a low‐risk intervention study in the first 72 h of life. Structured interview questions explored the process and acceptability of the consenting approach by the parents and their knowledge of the study. Additional comments made by the parents were transcribed verbatim. Results: Sixty‐two parents participated in the surveys; of those, 41 had provided their consent, 8 declined consent and 13 were parents of missed eligible infants. Overall, most parents reported they understood the study well before providing their consent and approaching them for consenting did not create a burden for them. A verbal explanation of the study by the study team, especially by the medical practitioners, was viewed as beneficial. Where consent was obtained in the birthing unit (imminent births and within 4 h of birthing), it was suggested that the 4‐h period for obtaining post‐natal consent may be too short. A deferred consent with a follow‐up opportunity for obtaining informed consent could be a suitable alternative. Conclusion: Parents found the consenting process acceptable and indicated they had sufficient understanding of the study to provide an informed consent. Deferred consent should be explored for future, low‐risk intervention studies as an alternative to prospective consent where extremely preterm infants need to be recruited in the immediate neonatal period. [ABSTRACT FROM AUTHOR]

Monitoring chimeric antigen redirected (CAR) T-cells post-infusion in clinical trials is a specialized application of flow cytometry. Unlike the CAR T-cell monitoring for individual patients conducted in clinical laboratories, the data generated during a clinical trial will be used not only to monitor the therapeutic response of a single patient, but determine the success of the therapy itself, or even of an entire class of therapeutic compounds. The data, typically acquired at multiple testing laboratories, will be compiled into a single database. The data may also be used for mathematical modeling of cellular kinetics or to identify predictive biomarkers. With the expanded context of use, a robust, standardized assay is mandatory in order to generate a valuable and reliable data set. Hence, the requirements for assay validation, traceable calibration, technology transfer, cross-instrument standardization and regulatory compliance are high. [ABSTRACT FROM AUTHOR]

Simple Summary: Established in 2002, the Korean Gynecologic Oncology Group (KGOG) has presented improved clinical outcomes based on multi-center clinical trials. To date, KGOG has approved 156 studies and published 68 KGOG-led studies. The organization aims to advance gynecologic cancer research through sustained efforts and international collaboration. The Korean Gynecologic Oncology Group (KGOG) was established in 2002 and is the only organization in Korea conducting multi-center clinical trials for gynecologic cancers. Since its re-establishment as a non-profit organization in 2021, KGOG has grown significantly, now including 207 gynecologic oncology specialists from 76 hospitals. This growth is a testament to the dedication and hard work of all those involved in the organization. KGOG is committed to maximizing the activation of multi-center clinical research through policies that support patients with rare diseases and gynecologic cancer research, focusing on strengthening institutional capacity, equalizing participation opportunities, and enhancing information sharing. A significant milestone for KGOG was becoming a member of the US Gynecologic Oncology Group (GOG) in 2005, allowing participation in GOG clinical trials. KGOG later joined the Gynecologic Cancer InterGroup (GCIG) and strengthened its capabilities by hosting the first Endometrial Cancer Consensus Conference—Clinical Research (ECCC-CR) in 2023. KGOG holds biannual meetings and symposia, as well as 224 operating committee meetings annually to review the discussions of the Tumor Site Committee. KGOG has conducted 156 investigator-initiated trial (IIT) or sponsor-initiated trial (SIT) studies as KGOG-led or participated in research. Currently, 18 studies are registered, and 10 are in preparation. To date, 68 papers have been published. KGOG conducts six national projects and collaborates with external organizations such as the NRG Oncology Foundation, Gynecologic Oncology Group Partners (GOG-P), GCIG, East Asian Gynecologic Oncology Trial group (EAGOT), and the Japanese Gynecologic Oncology Group (JGOG). Through collaboration with renowned international research institutions, KGOG has significantly expanded the scope of its research, achieving noteworthy clinical outcomes. This report not only introduces the history and recent status of KGOG but also presents the exciting future direction of the organization, filled with potential breakthroughs and advancements in gynecologic oncology research. [ABSTRACT FROM AUTHOR]

Background: Cochlear implants and hearing aids may facilitate the development of listening and spoken language (LSL) in deaf/hard of hearing young children, but they require aural rehabilitation therapy—often unavailable outside urban areas—for optimal outcomes. This trial assessed the relative effectiveness of LSL therapy delivered either in person or by interactive video. The hypothesis was that telehealth service delivery would be noninferior to in-person therapy. Methods: Most parents refused randomization of their children to telehealth or in-person conditions; therefore, randomization was impossible. In consultation with the funder (NIDCD), the study design was modified. Parents were allowed to select their preferred study condition, and the study team was blinded to group membership. Forty-two families were in the in-person group and 35 in telehealth (40 and 30, respectively, after attrition). Primary endpoints were total score, auditory comprehension, and expressive communication on the Preschool Language Scale, 5th edition. There were several secondary speech, hearing, and language outcome measures. Assessments occurred at baseline and at follow-up after 6 months of LSL therapy. Results: Propensity scores were used to create two matched groups. At baseline, groups did not differ on PLS-5 scores. Change from baseline to F/U on age-equivalents for all three scores was nearly identical for both groups, although the telehealth group was younger, on average, than the in-person group. Discussion: Telehealth was noninferior to in-person services for all primary endpoints. For secondary outcomes, neither group demonstrated a significant advantage. Magnitudes of estimated group differences were small, suggesting nonsignificant differences not predominantly because of sample size. The telehealth group showed greater improvement on 15/24 of secondary language outcome measures. The findings provide evidence that telehealth is equivalent to in-person care for providing LSL therapy to young children with cochlear implants and hearing aids. [ABSTRACT FROM AUTHOR]

Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks. [ABSTRACT FROM AUTHOR]

Purpose/objectives: NRG/RTOG 0436 evaluated cetuximab added to chemoradiation (CRT) for non-operative esophageal cancer management. PRO objectives assessed improvement in the FACT-Esophageal cancer subscale (ECS), version 4, with cetuximab, and if improved ECS correlated with clinical complete response (cCR). Materials/methods: Patients were randomized to cisplatin/paclitaxel/radiation ± cetuximab. Overall survival (OS) was the primary endpoint, with a 420 patient target, which also provided 82% power to detect ≥ 15 increase in the proportion of cetuximab patients with ECS improvement from baseline to 6–8 weeks post-CRT; α = 0.05, using a χ2 test. Improvement in ECS and its Swallowing and Eating Indices (SI, EI) was defined as 5, 4 and 2 point increases, respectively, from baseline to 6–8 weeks post-CRT. Univariate logistic regression assessed if cCR was associated with improved ECS. Results: This study was stopped early for not meeting a pre-specified OS endpoint and did not show survival benefit. Of 420 planned patients, 344 enrolled and 281 consented to PROs. ECS was completed by 261 (93%) at baseline, 173 (66%) 6–8 weeks post-CRT, and 117 (64%) at 1 year. At 6–8 weeks, patients receiving CRT + Cetuximab didn't have improved ECS; they experienced a lower proportion of improvement compared to standard CRT (37% vs. 53%; P = 0.04). The proportion of CRT patients with improvement in SI was 9% higher than with cetuximab, but not statistically significant (39% vs. 30%, P = 0.22). There was no association between treatment and EI. When examining ECS scores at 1 year by cCR vs. residual disease, a higher proportion of cCR patients improved, but not statistically significant (48% vs. 45%, P = 0.74). Conclusions: The addition of cetuximab to CRT for the nonoperative management of esophageal cancer did not improve PROs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A phase 1b study was conducted to evaluate the safety and feasibility of ciprofloxacin and etoposide combination treatment in subjects with relapsed and refractory acute myeloid leukemia. Eleven subjects were enrolled in the study. Utilizing the standard '3 + 3' design, escalating ciprofloxacin doses (750 mg, 1000 mg) twice daily on D1-D10 in combination with a fixed dose (200 mg) of etoposide on D2-D8 were administered. Maximum tolerated dose was determined to be 1000 mg of ciprofloxacin in combination with 200 mg of etoposide. Serious adverse events occurred in 54.5% (n = 6) subjects and 91% (n = 10) subjects reported ≥ grade 3 toxicities. Nine subjects completed treatment, one had a dose-limiting toxicity, and one withdrew. One subject achieved complete remission with a duration of 111 days and one subject achieved morphologic leukemia-free state after cycle 1. While the combination demonstrated safety and an acceptable toxicity profile, only modest hematologic and clinical benefits were observed. This trial was registered at as #NCT02773732. [ABSTRACT FROM AUTHOR]

Background: The Otago Exercise Programme is an effective intervention for falls prevention. However, there is limited evidence in relation to studies that compare efficacy for falls prevention when delivered Otago Exercise Programme in a group or individual format in a primary care context. Objective: To compare the Otago Exercise Programme delivered as a group vs. individual format for community dwelling older adults, over a one year period. The hypothesis was that neither format would be inferior to the other. Methods: Design: A four-year multicentre, randomized, non-inferiority clinical trial, with two arms— Otago Exercise Programme group training and individual Otago exercise training. Setting(s): 21 primary healthcare centers. Participants: A sample size of 728 participants was established. Participants were aged between 65 and 80 years; living in the community; able to walk independently; and agreed to take part in the study and provided signed informed consent. Intervention: The Otago Exercise Programme was delivered mainly by nurses in primary care, with five face to face sessions, and a reinforcement 6 months later. Participants were encouraged to exercise at home between face to face sessions. Data collection: at baseline and after 6 and 12 months from October 2017 to 2020. Primary outcome: people who reported at least one fall. Secondary outcomes: number of falls, cause of falls, consequences and assistance, adherence and satisfaction. Group allocation was blinded to the researchers involved in analysis. Reporting: Consolidated Standards of Reporting Trials recommendations for the Statement for Randomized Trials of Nonpharmacologic Treatments. Results: Eight hundred twenty-seven participants were randomized (226 were allocated in group training and 272 in individual training). The analysis of the proportion of people who reported at least one fall and number of falls showed no differences between individual and group training. Assessment of the equivalence between the interventions at 12 months showed that the confidence interval for the difference of people who reported at least one fall was found to be within the equivalence limit of 10% considered. However, in those participants with a previous history of falls, group format showed potentially greater benefit. The participants in individual training presented higher scores on the Exercise Adherence Rating Scale test. No differences were found in satisfaction between the groups. Conclusions: The group Otago Exercise Programme is equivalent to individually delivered Otago Exercise Programme in terms of prevention of falls over a 12-month follow up. Adherence was higher in individual training. Implications: Healthcare professionals could offer either Otago Exercise Programme format dependent on patient preference and be confident that that standardized intervention provides patient benefit. Trial Registration: ClinicalTrials.gov (NCT03320668). Data registration 31/10/2017. [ABSTRACT FROM AUTHOR]

CADASIL is the most frequent hereditary cerebral small vessel disease worldwide. The disease is responsible for a slow and progressive accumulation of cerebral ischemic insults that lead to disabling cognitive and motor symptoms at late age. Although there is currently no cure for this condition, future therapies may concern subjects only at early stage of the disease. This will raise the question of the participation of asymptomatic carriers of pathogenic NOTCH3 gene mutation in future clinical trials, which will presuppose acceptance of presymptomatic genetic diagnosis. In this study, we questioned the population at risk of CADASIL who had not undergone a diagnostic procedure yet. Based on a questionnaire survey carried out by an independent team of sociologists, we analyzed what underlies the choice of people at risk to undergo or not to undergo a genetic test, and what could constitute the tipping point that could lead people who were initially not interested in their diagnosis to have recourse to it. Our results suggest that, far from being a simple, unequivocal path, the decision-making process leading to the choice of diagnosis is initially slowed down by the need to distance oneself from the disease so that it doesn't take over one's life, and then evolves under the influence of a complex tangle between advancing age, the presence of early symptoms, and the personal relationship with uncertainty. It cannot be ruled out that the real and imminent prospect of therapy may also modify responses to this type of survey. [ABSTRACT FROM AUTHOR]

Objective Design Setting Participant Main outcome measures Results Conclusions The objective of this study is to determine if there are differences in outcome for patients diagnosed with multiple myeloma in a rural setting compared to a metropolitan setting and which factors influence these outcomes.Retrospective cohort study.Illawarra Shoalhaven Local Health District.A total of 391 patients diagnosed with multiple myeloma between 2000 and 2022.Treatment and survival outcomes of these patients.Patients being treated in a rural cancer care centre had lower overall survival compared to those treated at a metropolitan cancer care centre (median OS = 44.4 months vs. 80.2 months, p = 0.002), despite access to similar treatments by the same group of haematologists. There was a significantly higher rate of upfront autologous transplantation (38% vs. 20%, p = 0.001) and higher rate of inclusion in clinical trials (16% vs. 7%, p = 0.021) in patients treated at a metropolitan cancer care centre compared to the rural cancer care centre.Multiple myeloma patients treated at a rural centre had shorter survival compared to patients treated at a metropolitan centre, and this may be related to lower rates of autologous transplantation and inclusion in clinical trials. [ABSTRACT FROM AUTHOR]

Aims/BackgroundDesign/MethodsResultsConclusionRoutine third-trimester ultrasonography is increasingly conducted to screen for foetal growth restriction (FGR) and reduce adverse perinatal and child neurodevelopmental outcomes using timely obstetric management. While it did not reduce adverse perinatal outcomes in previous trials, evidence regarding its association with child neurodevelopmental outcome is absent. We examined whether routine third-trimester ultrasonography is positively associated with child developmental and behavioural/emotional outcomes compared to usual care.Dutch mothers with a low-risk pregnancy participating in a subsample (n = 1070) of a nationwide cluster-randomised trial reported infant (age 6 months) and toddler (age 28 months) developmental milestones (Ages and Stages Questionnaire) and toddlers’ internalising and externalising problems (Child Behavior Checklist). Usual care (n = 380) comprised selective ultrasonography. The intervention strategy (n = 690) included two routine third-trimester ultrasounds next to usual care. Both strategies applied the same interdisciplinary protocol for FGR detection and management.Adjusted linear mixed-level regressions revealed that routine third-trimester ultrasonography was positively but modestly related to z-standardised infant developmental milestones at 6-month follow-up, B = 0.20, 95%CI [0.07; 0.32], p = 0.003, compared to usual care. At 28-month follow-up, these strategies did not differ in child developmental outcome and internalising and externalising problems.Routine third-trimester ultrasonography was positively but modestly associated with infant development. In toddlerhood, routine ultrasonography was not related to child developmental and behavioural/emotional outcomes. Overall, these findings do not support the implementation of routine third-trimester ultrasonography for low-risk pregnant women for reasons concerning children’s early neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

Aims: To provide an overview of the primary outcomes and key clinical implications of the CANVAS Program and CREDENCE trial, which were event‐driven, double‐blind randomized controlled trials that established the efficacy and safety of canagliflozin in those with type 2 diabetes (T2D) and high cardiovascular risk (CV) or albuminuric chronic kidney disease (CKD). Methods and Results: The CANVAS programme (CANVAS and CANVAS‐R trials) randomized 10 142 people with T2D and high CV risk to canagliflozin or placebo and followed them for a median of 126 weeks. The primary efficacy outcome was met, with canagliflozin treatment associated with a 14% reduction in major adverse CV events (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.75 to 0.97; p < 0.001) as compared to placebo. The CREDENCE trial randomized 4401 individuals with T2D and albuminuric CKD to canagliflozin or placebo and followed them for 109 weeks. The CREDENCE trial also met its primary endpoint; canagliflozin treatment was associated with a 30% reduction in the composite of kidney failure, sustained doubling of serum creatinine level, or death from kidney or CV causes (HR 0.70, 95% CI 0.59 to 0.82; p < 0.001). Substantial reductions in hospitalization for heart failure (CANVAS: HR 0.67, 95% CI 0.52 to 0.87; CREDENCE: HR 0.61, 95% CI 0.47 to 0.80) and other key CV and kidney outcomes were also identified. Relative clinical benefits were consistent across subgroups defined by baseline age, sex, kidney function and history of CV disease but absolute benefits were greatest in those at highest baseline risk. Total serious adverse events were less common with canagliflozin treatment. Concerns about amputation and fracture risk observed in the CANVAS Program were not seen in CREDENCE and appear to have been spurious chance findings. Conclusion: Canagliflozin reduced important CV, kidney and mortality outcomes in those with T2D and high CV risk or CKD across diverse patient groups, with a good safety profile. Taken together with the other sodium‐glucose cotransporter‐2 inhibitor CV and renal outcomes trials, these landmark findings have changed the treatment landscape for patients worldwide. [ABSTRACT FROM AUTHOR]