The challenge of running trials in advanced angiosarcoma: A systematic review of the literature from EORTC/STBSG to guide the development of angiosarcoma-specific trials.

INTRODUCTION: While available systemic treatments have modest long term efficacy in advanced angiosarcoma, immunotherapy represents an interesting new therapeutic opportunity. To establish its benefit, it is required to conduct a clinical trial assessing its efficacy and toxicity compared to standard treatments. MATERIAL AND METHODS: This is a literature review from PubMed search. RESULTS: Several systemic treatments (chemotherapy and TKI) are currently used in advanced angiosarcoma with ORR ranging from 12.5 to 68 % and PFS from 2 to 7 months. However, few randomized trials, mainly phase II, has been conducted to compare these treatments. While most centers propose doxorubicin containing regimens or paclitaxel in 1st or 2nd line, a high heterogeneity of regimens administered in this setting is observed even across sarcoma specialized centers with no consensual standard treatment. Encouraging signals of immunotherapy activity have been reported in angiosarcoma from several retrospective and phase II studies assessing anti-PD1 either alone or in combination with anti CTLA4 or TKI. Although cutaneous and head and neck location seems to benefit more from immunotherapy, response may be observed in any angiosarcoma subtype. In sarcoma in general and AS in particular, no biomarker has been clearly established to predict the efficacy of immunotherapy: high tumor mutational burden and presence of tertiary lymphoid structures are under assessment. DISCUSSION: Even essential, developing a randomized clinical trial in AS struggles with the heterogeneity of the disease, the lack of consensual standard regimen, the uncertainty on optimal immunotherapy administration and the absence of established predictive biomarkers. CONCLUSION: International collaboration is essential to run randomized trial in advanced AS and asses the efficacy of immune therapy in this rare and heterogeneous disease.

Nutrition guidance within a multimodal intervention improves diet quality in prodromal Alzheimer's disease: Multimodal Preventive Trial for Alzheimer's Disease (MIND-ADmini).

BACKGROUND: Multimodal lifestyle interventions can benefit overall health, including cognition, in populations at-risk for dementia. However, little is known about the effect of lifestyle interventions in patients with prodromal Alzheimer's disease (AD). Even less is known about dietary intake and adherence to dietary recommendations within this population making it difficult to design tailored interventions for them. METHOD: A 6-month MIND-ADmini pilot randomized controlled trial (RCT) was conducted among 93 participants with prodromal AD in Sweden, Finland, Germany, and France. Three arms were included in the RCT: 1) multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management, and social stimulation); 2) multimodal lifestyle intervention + medical food product; and 3) regular health advice (control group). Adherence to dietary advice was assessed with a brief food intake questionnaire by using the Healthy Diet Index (HDI) and Mediterranean Diet Adherence Screener (MEDAS). The intake of macro- and micronutrients were analyzed on a subsample using 3-day food records. RESULTS: The dietary quality in the intervention groups, pooled together, improved compared to that of the control group at the end of the study, as measured with by HDI (p = 0.026) and MEDAS (p = 0.008). The lifestyle-only group improved significantly more in MEDAS (p = 0.046) and almost significantly in HDI (p = 0.052) compared to the control group, while the lifestyle + medical food group improved in both HDI (p = 0.042) and MEDAS (p = 0.007) during the study. There were no changes in macro- or micronutrient intake for the intervention groups at follow-up; however, the intakes in the control group declined in several vitamins and minerals when adjusted for energy intake. CONCLUSION: These results suggest that dietary intervention as part of multimodal lifestyle interventions is feasible and results in improved dietary quality in a population with prodromal AD. Nutrient intakes remained unchanged in the intervention groups while the control group showed a decreasing nutrient density. TRIAL REGISTRATION: ClinicalTrials.gov NCT03249688, 2017-07-08.

Pediatric dentistry systematic reviews using the GRADE approach: methodological study.

BACKGROUND: To assess the reporting of the certainty of the evidence using the GRADE approach in systematic reviews of interventions in pediatric dentistry. METHODS: The inclusion criteria were systematic reviews of randomized clinical trials (RCTs) and non-randomized studies of interventions (NRSIs) in pediatric dentistry that reported the certainty of the evidence through the GRADE approach. Paired independent reviewers screened the studies, extracted data, and appraised the methodological quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR 2) tool. The certainty of the evidence was extracted for each outcome. A descriptive analysis was conducted. RESULTS: Around 28% of pediatric dentistry reviews of interventions used the GRADE approach (n = 24). Twenty reviews reported 112 evidence outcomes from RCTs and 13 from NRSIs using GRADE evidence profile tables. The methodological quality was high (16.7%), moderate (12.5%), low (37.5%), and critically low (33.3%), fulfilling the majority of the AMSTAR 2 criteria. The certainty of the evidence for outcomes generated from RCTs and NRSIs was very low (40.2% and 84.6%), low (33.1% and 7.7%), moderate (17.8% and 7.7%), and high (9.8% and 0.0%). The main reasons to downgrade the certainty were due to (for RCTs and NRSIs, respectively): risk of bias (68.8% and 84.6%), imprecision (67.8% and 100.0%), inconsistency (18.8% and 23.1%), indirectness (17.8% and 0.0%), and publication bias (7.1% and 0.0%). CONCLUSION: The proportion of systematic reviews assessing the certainty of the evidence using the GRADE approach was considered small, considering the total initial number of published pediatric dentistry reviews of intervention. The certainty of the evidence was mainly very low and low, and the main problems for downgrading the certainty of evidence were due to risk of bias and imprecision. REGISTRATION: PROSPERO database #CRD42022365443.

Electroacupuncture for slow flow/no-reflow phenomenon in patients with acute myocardial infarction undergoing percutaneous coronary intervention: protocol for a pilot randomized controlled trial.

Background: Slow flow/no-reflow (SF-NR) during percutaneous coronary intervention (PCI) is associated with poor prognosis of patients with acute myocardial infarction (AMI). Currently, effective treatment is not available for SF-NR. Electroacupuncture (EA) has shown significant efficacy as an adjuvant therapy for many cardiovascular diseases by improving microcirculation and reducing ischemia-reperfusion injury. However, its effects on SF-NR in the AMI patients during PCI are not clear. This pilot trial aims to determine the efficacy of intraoperative EA in alleviating SF-NR in AMI patients undergoing PCI. Methods: This prospective, single-center, randomized controlled, pilot trial will recruit 60 AMI patients scheduled for PCI at the Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, China. The patients will be randomized in a 1:1 ratio into the EA or the control groups. Patients in the control group will undergo standard PCI. Patients in the EA group will undergo intraoperative electroacupuncture while undergoing standard PCI. Incidence of SF-NR is the primary outcome for this study. This study will also assess secondary outcomes including cardiac biomarkers, inflammatory biomarkers, pain and anxiety scores, electrocardiography parameters, traditional Chinese medicine (TCM) symptom score, and major adverse cardiovascular and cerebrovascular events (MACCE). All the included patients will undergo laboratory tests including routine blood tests, levels of electrolytes, as well as liver and renal function tests. Patients will be followed up for 1 month after the procedure. Discussion: This pilot trial will provide evidence for the potential benefits of intraoperative EA in improving microvascular perfusion and preventing or alleviating SF-NR during PCI in patients with AMI. If proven effective, intraoperative EA will provide a new and effective strategy against SF-NR and provide evidence for subsequent multicenter trials. Clinical Trial Registration: ClinicalTrials.gov, identifier (ChiCTR2300072265). Registered on 8 June 2023.

How much could anemia-related interventions reduce the HIV disparity in adverse birth outcomes?

Women and other people of childbearing potential living with HIV (WLHIV) have a higher risk of adverse birth outcomes than those without HIV (WWHIV). A higher risk of anemia in WLHIV could partially explain this disparity. Using a birth outcomes surveillance study in Botswana, we emulated target trials corresponding to currently available or feasible interventions on anemia. The first target trial evaluated two interventions: initiate multiple micronutrient supplementation (MMS), and MMS or iron and folic acid supplementation by 24 weeks gestation. The remaining target trials evaluated the interventions: eliminate anemia before pregnancy; and jointly eliminate anemia before pregnancy and initiate MMS. We estimated the observed disparity in adverse birth outcomes between WLHIV and WWHIV and compared the observed disparity measure (ODM) to the counterfactual disparity measure (CDM) under each intervention. Of 137,499 individuals (22% WLHIV), the observed risk of any adverse birth outcome was 26.0% in WWHIV and 34.5% in WLHIV (ODM, 8.5% [95% CI, 7.9-9.1%]). CDMs (95% CIs) ranged from 6.6% (4.8-8.4%) for the intervention to eliminate anemia and initiate MMS to 8.4% (7.7-9.1%) for the intervention to eliminate anemia only. Preventing anemia and expanding MMS may reduce HIV disparities in birth outcomes, but interventions with greater impact should be identified.

Aggressive hydration with lactated Ringer's solution versus plasma solution for the prevention of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (ALPS study): protocol for a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) plays an indispensable role in treating pancreato-biliary diseases but carries a risk of post-ERCP pancreatitis (PEP). Despite advances in the prevention strategies, prevention of PEP remains imperfect, necessitating more refined hydration methods. This study investigates the effectiveness of lactated Ringer's solution versus plasma solution in preventing PEP. METHOD AND ANALYSIS: This multicentre, double-blind, randomised controlled trial, will be initiated by the investigator-sponsor, and conducted in three tertiary centres in South Korea. The aim of this study is to assess the effectiveness of hydration in preventing PEP in patients with naïve papillae. It will target patients with naïve papillae, focusing on those at medium to high risk of PEP. Patients aged ≤18 years and those with serious comorbidities, acute/chronic pancreatitis and various other medical conditions will be excluded. Eligible participants will be randomly assigned into two arms in equal numbers: (1) PEP prevention using lactated Ringer's solution and (2) PEP prevention using plasma solution. The primary outcome of this study will be the occurrence of PEP, and secondary outcomes will be additional risk factors and potential adverse events related to ERCP. With a total enrolment of 844 patients, the study will be able to detect significant differences between the intervention arms. ETHICS AND DISSEMINATION: Ethical approval is obtained from each institution (Asan Medical Centre, 2023-0382; Seoul National University Hospital, H-2302-05-1404; Samsung Medical Centre, SMC 2023-02-001-009). All participants provided informed consent following clear explanation of the study procedures. The results of the study will be disseminated in peer-reviewed journals and research conferences. TRIAL REGISTRATION NUMBER: NCT05832047. PROTOCOL VERSION: Ver 4.1 (2023).

Impact of tonsillectomy on the efficacy of Alt-RAMEC/PFM treatment protocols in children with class III malocclusion and tonsillar hypertrophy: protocol for a cluster randomised controlled trial.

INTRODUCTION: Orthodontic treatment using face mask protraction combined with an alternate rapid maxillary expansion and constriction/protraction face mask (Alt-RAMEC/PFM) protocol is effective in the early treatment of patients with class III malocclusion, but the stability of treatment outcomes represents a major concern. Previous studies have suggested that tonsillar hypertrophy can be a risk factor for class III malocclusion and tonsillectomy may prompt the normalisation of dentofacial growth. However, these studies had a low-to-moderate level of evidence. This study was designed to identify the impact of tonsillectomy before orthodontic treatment on the efficacy and stability of Alt-RAMEC/PFM protocols and the sleep quality and oral health in children with anterior crossbite and tonsillar hypertrophy. METHODS AND ANALYSIS: This is a two-arm, parallel-group, superiority cluster randomised controlled trial, with four clinics randomly assigned to the surgery-first arm and the orthodontic-first arm in a 1:1 ratio. The Alt-RAMEC protocol involves alternate activation and deactivation of the expander's jet screw over 6 weeks to stimulate maxillary suture distraction. Patients will be instructed to wear the PFM for a minimum of 14 hours per day. The primary outcomes are changes in Wits appraisal and the degree of maxillary advancement from baseline to the end of orthodontic treatment. Lateral cephalometric radiographs, polysomnography, Obstructive Sleep Apnoea-18 questionnaire and Oral Health Impact Profile-14 questionnaire will be traced, collected and measured. We will recruit 96 patients intofor the study. To assess differences, repeated multilevel linear mixed modelling analyses will be used. ETHICS AND DISSEMINATION: This study has been granted ethical approval by the Ethics Committee of the School & Hospital of Stomatology, Wuhan University (approval No. 2023-D10). Written informed consent will be obtained from the participants and their guardians. The results of the trial will be disseminated through academic conferences and journal publications. TRIAL REGISTRATION NUMBER: ChiCTR2300078833.

INfluenza VaccInation To mitigate typE 1 Diabetes (INVITED): a study protocol for a randomised, double-blind, placebo-controlled clinical trial in children and adolescents with recent-onset type 1 diabetes.

INTRODUCTION: Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving ß-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer ß-cell protection. This study aims to assess the effect of influenza vaccination on preserving ß-cell function in children and adolescents with recent-onset T1D. METHODS AND ANALYSIS: The INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7-17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual ß-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D. ETHICS AND DISSEMINATION: Ethical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.

Infant formula supplemented with milk fat globule membrane compared with standard infant formula for the cognitive development of healthy term-born formula-fed infants: protocol for a randomised controlled trial.

INTRODUCTION: Milk fat globule membrane (MFGM) is a complex lipid-protein structure in mammalian milk and human milk that is largely absent from breastmilk substitutes. The objective of this trial is to investigate whether providing infant formula enriched with MFGM versus standard infant formula improves cognitive development at 12 months of age in exclusively formula-fed full-term infants. METHODS AND ANALYSIS: This is a randomised, controlled, clinician-blinded, researcher-blinded and participant-blinded trial of two parallel formula-fed groups and a breastfed reference group that were recruited in the suburban Adelaide (Australia) community by a single study centre (a medical research institute). Healthy, exclusively formula-fed, singleton, term-born infants under 8 weeks of age were randomised to either an MFGM-supplemented formula (intervention) or standard infant formula (control) from enrolment until 12 months of age. The reference group was not provided with formula. The primary outcome is the Cognitive Scale of the Bayley Scales of Infant Development, Fourth Edition (Bayley-IV) at 12 months. Secondary outcomes are the Bayley-IV Cognitive Scale at 24 months, other Bayley-IV domains (language, motor, emotional and behavioural development) at 12 and 24 months of age, infant attention at 4 and 9 months of age, parent-rated language at 12 and 24 months of age, parent-rated development at 6 and 18 months of age as well as growth, tolerance and safety of the study formula. To ensure at least 80% power to detect a 5-point difference in the mean Bayley-IV cognitive score, >200 infants were recruited in each group. ETHICS AND DISSEMINATION: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/19/WCHN/140). Caregivers gave written informed consent prior to enrolling in the trial. Findings of this study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ACTRN12620000552987; Australian and New Zealand Clinical Trial Registry: anzctr.org.au.

Assessing the efficacy of a brief universal family skills programme on child behaviour and family functioning in Gilgit-Baltistan, Pakistan: protocol for a feasibility randomised controlled trial of the Strong Families programme.

PURPOSE: The global burden of mental health difficulties among children underscores the importance of early prevention. This study aims to assess the efficacy, feasibility and acceptability of the Strong Families programme in enhancing child behaviour and family functioning in low-resource settings in Gilgit-Baltistan, Pakistan. METHODS AND ANALYSIS: This is a two-arm, multisite feasibility randomised controlled trial with an embedded process evaluation in three districts of Gilgit-Baltistan, namely Gilgit, Hunza and Skardu. 90 families living in these challenged settings, comprising a female primary caregiver aged 18 or above, and at least one child aged 8-15 years, will participate. Participants will be randomly assigned to either receive the Strong Families programme or to the waitlist group. Strong Families is a 7-hour family skills group intervention programme attended by children and their primary caregivers over 3 weeks. The waitlist group will be offered the intervention after their outcome assessment. Three raters will conduct blind assessments at baseline, 2 and 6 weeks postintervention. The primary outcome measures include the feasibility of Strong Families, as determined by families' recruitment and attendance rates, and programme completeness (mean number of sessions attended, attrition rates). The secondary outcomes include assessment of child behaviour, parenting practices, parental adjustment and child resilience. Purposefully selected participants, including up to five caregivers from each site, researchers and facilitators delivering the intervention, will be interviewed. Descriptive statistics will be used to analyse primary and secondary outcomes. The process evaluation will be conducted in terms of programme context, reach, fidelity, dose delivered and received, implementation, and recruitment. ETHICS AND DISSEMINATION: This study has been approved by the UNODC Drug Prevention and Health Branch in the Headquarters office of Vienna and the National Bioethics Committee of Pakistan. Findings will be disseminated through publication in reputable journals, newsletters and presentations at conferences. TRIAL REGISTRATION NUMBER: NCT05933850.

Study protocol for ADAPT-TDM: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring.

INTRODUCTION: Critically ill patients are at risk of suboptimal beta-lactam antibiotic (beta-lactam) exposure due to the impact of altered physiology on pharmacokinetics. Suboptimal concentrations can lead to treatment failure or toxicity. Therapeutic drug monitoring (TDM) involves adjusting doses based on measured plasma concentrations and individualising dosing to improve the likelihood of improving exposure. Despite its potential benefits, its adoption has been slow, and data on implementation, dose adaptation and safety are sparse. The aim of this trial is to assess the feasibility and fidelity of implementing beta-lactam TDM-guided dosing in the intensive care unit setting. METHODS AND ANALYSIS: A beta-lactam antibiotic Dose AdaPtation feasibility randomised controlled Trial using Therapeutic Drug Monitoring (ADAPT-TDM) is a single-centre, unblinded, feasibility randomised controlled trial aiming to enroll up to 60 critically ill adult participants (≥18 years). TDM and dose adjustment will be performed daily in the intervention group; the standard of care group will undergo plasma sampling, but no dose adjustment. The main outcomes include: (1) feasibility of recruitment, defined as the number of participants who are recruited from a pool of eligible participants, and (2) fidelity of TDM, defined as the degree to which TDM as a test is delivered as intended, from accurate sample collection, sample processing to result availability. Secondary outcomes include target attainment, uptake of TDM-guided dosing and incidence of neurotoxicity, hepatotoxicity and nephrotoxicity. ETHICS AND DISSEMINATION: This study has been approved by the Alfred Hospital human research ethics committee, Office of Ethics and Research Governance (reference: Project No. 565/22; date of approval: 22/11/2022). Prospective consent will be obtained and the study will be conducted in accordance with the Declaration of Helsinki. The finalised manuscript, including aggregate data, will be submitted for publication in a peer reviewed journal. ADAPT-TDM will determine whether beta-lactam TDM-guided dose adaptation is reproducible and feasible and provide important information required to implement this intervention in a phase III trial. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry, ACTRN12623000032651.

Photobiomodulation therapy for chronic knee pain in obese patients in pre-rehabilitation for bariatric surgery: randomised, placebo-controlled, double-blinded, clinical trial protocol.

INTRODUCTION: Obesity has become a worldwide public health problem and is directly linked to loss of quality of life, complications and comorbidities. One of them is chronic pain, especially in the knees, which increases significantly and proportionally with weight gain. In patients with severe obesity, with indication for bariatric surgery, the presence of chronic pain disables and often prevents their participation in a pre-surgical rehabilitation programme. As an analgesic therapy, photobiomodulation (PBM) has been studied with safety, efficacy, well-tolerated used and low costs. Thus, this study aims to evaluate the use of PBM for the treatment of chronic knee pain in obese patients undergoing a pre-surgical rehabilitation programme for bariatric surgery. METHODS AND ANALYSES: This is a double-blinded, randomised, placebo-controlled clinical, superiority, trial protocol. The PBM will be applied in bilateral knees and lumbar paraspinal points levels referring to the roots of innervation of the knee. The outcomes evaluated will be pain intensity, functionality, quality of life and clinical signs of neurological sensitization of chronic knee pain pathways. ETHICS AND DISSEMINATION: This protocol has already been approved by the Comitê de Ética em Pesquisa do Hospital das Clínicas da Universidade Federal de Goiás/EBSERH-Ethics Committee and it is following SPIRIT guidelines. The results will be statistically analysed and subsequently published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Clinical Trials Platform (https://clinicaltrials.gov/) with the number NCT05816798.

Results of the RVA Breathes randomized controlled trial.

OBJECTIVE: This study tested a randomized controlled trial of RVA Breathes, a community asthma program, in reducing asthma-related healthcare utilization among children living in an area with a high poverty rate. METHODS: Participants included 250 caregivers (78% African American/Black; 73.3% household income<$25,000/year) and their children with asthma (5-11 years). Inclusion criteria included an asthma-related emergency department (ED) visit, hospitalization, unscheduled doctor's visit, or systemic steroids in the past 2 years. Families were randomized to a full active intervention (asthma education with community health workers [CHWs], home remediation with home assessors, and a school nurse component; n = 118), partial active intervention (asthma education and home remediation; n = 69), or a control group (n = 63) for 9 months. Measures on healthcare utilization and asthma-related factors were collected. Follow-up assessments occurred across a 9-month period. RESULTS: Although we did not find any significant effects, there was a trend toward significance for a group by time effect with objective healthcare utilization as the outcome (F4,365 = 2.28, p = .061). The full intervention group experienced a significant decrease from baseline to 9-month follow-up compared with the other groups (p < .001). Only the full intervention group experienced a significant increase in reported asthma action plans across time (no significant group effect). CONCLUSIONS: In the context of the unprecedented COVID-19 pandemic, which led to a substantial global decrease in healthcare utilization, the study's main hypotheses were not supported. Nevertheless, findings support the benefit of community asthma programs that integrate care across multiple settings and connect families with CHWs.

Efficacy and safety of Lianhua Qingwen granule combined with azithromycin for mycoplasma pneumoniae pneumonia in children: a systematic review with meta-analysis and trial sequential analysis.

Background: Lianhua Qingwen (LHQW) granule, a botanical drug preparation, is frequently utilized as an adjuvant treatment for mycoplasma pneumoniae pneumonia (MPP). Nevertheless, the clinical efficacy and safety of this treatment remain uncertain. Purpose: This study aims to evaluate the efficacy and safety of LHQW granule combined with azithromycin (AZM) in treating MPP in children. Method: To identify all randomized controlled trials (RCTs) of LHQW granule plus AZM, a search was conducted in eight Chinese and English databases (CNKI, Wan Fang, VIP, Sinomed, PubMed, Embase, Web of Science, and Cochrane Library) from their inception until 25 December 2023. Meta-regression and subgroup analysis were employed to investigate heterogeneity. Sensitivity analysis and trial sequential analysis (TSA) were conducted to assess the robustness of the findings. Additionally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was utilized to evaluate the quality of evidence. Results: A total of 15 RCTs involving 1909 participants were included in this study. The meta-analysis results indicated combination therapy of LHQW granule and AZM is significant different from AZM alone in both efficacy and safety, which are specifically observed in the following outcomes: response rate (RR = 1.17, 95% CI: 1.12 to 1.22, p < 0.01), antipyretic time (MD = -1.32, 95% CI: -1.66 to -0.98, p < 0.01), cough disappearance time (MD = -1.76, 95% CI: -2.47 to -1.05, p < 0.01), pulmonary rale disappearance time (MD = -1.54, 95% CI: -2.06 to -1.02, p < 0.01), c-reactive protein (CRP) (MD = -5.50, 95% CI: -6.92 to -4.07, p < 0.01), procalcitonin (PCT) (MD = -0.31, 95% CI: -0.38 to -0.24, p < 0.01), interleukin 6 (IL-6) (MD = -5.97, 95% CI: -7.39 to -4.54, p<0.01), tumor necrosis factor α (TNF-α) (MD = -5.74, 95% CI: -7.44 to -4.04, p < 0.01), forced vital capacity (FVC) (SMD = 0.48, 95% CI: 0.34 to 0.62, p < 0.01), forced expiratory volume in the first second (FEV1) (SMD = 0.55, 95% CI: 0.44 to 0.67, p < 0.01), FEV1/FVC (SMD = 0.49, 95% CI: 0.32 to 0.67, p < 0.01), CD4+ T lymphocyte (CD4+) (MD = 4.04, 95% CI: 3.09 to 4.98, p < 0.01), CD8+ T lymphocyte (CD8+) (MD = -3.32, 95% CI: 4.27 to 2.38, p < 0.01) and adverse events (RR = 0.65, 95% CI: 0.43 to 0.96, p < 0.01). Conclusion: The combination therapy of LHQW granule and AZM may be a better strategy to treat MPP in children. However, the clinical efficacy and safety of LHQW granule require further validation. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/.

Efficacy and safety of alpha-pinene capsule in the management of functional dyspepsia and eradication of helicobacter pylori: a randomized clinical trial.

Aim: Our objective was to assess the efficacy and safety of adding alpha-pinene (a herbal terpenoid) to quadruple therapy compared to a placebo in improving symptoms and Helicobacter pylori (H. pylori) eradication rates in Functional dyspepsia (FD) patients. Background: FD is a prevalent upper gastrointestinal condition, and no definitive pharmacological treatment is available for its management. Methods: We conducted a randomized, double-blinded, placebo-controlled trial on FD patients diagnosed with H. pylori infection. We collected baseline demographic data and assessed FD symptoms in the participants. Patients were randomly allocated to receive either standard quadruple therapy with α-pinene capsules (0.25 mg/day) or quadruple therapy with a placebo for two weeks. We employed a validated questionnaire, the Short Form Leeds Dyspepsia Questionnaire (SF-LDQ), to evaluate FD symptoms. The eradication rate of H. pylori was compared between the two groups one month after completing the treatment regimens. Any reported adverse drug reactions (ADRs) were documented throughout the trial. Results: Over four months, a total of 66 patients completed the trial. Notably, there were no significant differences in baseline SF-LDQ scores between the two groups (p=0.83); however, a significant divergence emerged at the trial's conclusion (p=0.03). The H. pylori eradication rates did not show notable differences between the two treatment arms (p=0.43). Importantly, there were no dropouts from the trial due to ADRs. Among reported ADRs, participants experienced abdominal pain, headache, diarrhea, and a metallic taste, with no significant variance in incidence rates observed between the two groups (p=0.62). Conclusion: These findings suggest that α-pinene could be an effective and safe agent for reducing FD symptoms.

Safety and efficacy of nintedanib as second-line therapy for patients with differentiated or medullary thyroid cancer progressing after first-line therapy. A randomized phase II study of the EORTC Endocrine Task Force (protocol 1209-EnTF).

Background: Nintedanib is a triple-angiokinase inhibitor with potential activity in patients with advanced thyroid cancers, as radioiodine refractory differentiated thyroid cancer (RAIR DTC) and medullary thyroid cancer (MTC). Design: EORTC-1209 (NCT01788982) was a double-blind randomized (2:1 ratio) placebo-controlled phase II, multi-cohort study exploring the efficacy and safety of nintedanib in patients with progressive, locally advanced, and/or metastatic RAIR DTC and MTC. The primary endpoint was progression-free survival (PFS) in the per-protocol (PP) population for both cohorts. Secondary endpoints included response rate, duration of response, overall survival (OS), and safety. Results: RAIR DTC cohort: Seventy out of the 75 planned patients with RAIR DTC (median age, 66 years; 39 women) who had progressed after one (76%) or two lines (24%) of previous systemic therapy were randomized to receive either nintedanib (N = 45) or placebo (N = 25). Of these, 69 patients started treatment and 56 met all inclusion criteria (PP). At data cutoff, the median duration of follow-up was 26.3 months in the nintedanib arm and 19.8 months in the placebo arm. In the PP population, the median PFS was 3.7 months [80% confidence interval (CI), 1.9-6.5] in the nintedanib arm and 2.9 months (80% CI, 2.0-5.6) in the placebo arm (HR = 0.65; 80% CI, 0.42-0.99; one-sided log-rank test P = 0.0947). No objective response was observed. The median OS was 29.6 months [80% CI, 15.2-not reached (NR)] in the nintedanib arm and not reached in the placebo arm. Grade 3-4 adverse events of any attribution occurred in 50% of patients receiving nintedanib and in 36% of patients receiving placebo. MTC cohort: Thirty-one out of the 67 planned patients with MTC (median age, 57 years; eight women) who had progressed after one (68%) or two (32%) lines of previous systemic therapy were randomized to receive either nintedanib (N = 22) or placebo (N = 9). Of these, 20 patients (15 in the nintedanib arm and five in the placebo arm) started treatment and met all inclusion criteria (PP). The median PFS was 7.0 months (80% CI, 1.9-8.7) in the nintedanib arm and 3.9 months (80% CI, 3.0-5.5) in the placebo arm (HR = 0.49; 95% CI, 0.16-1.53). No objective response was reported. The median OS was 16.4 months (80% CI, 12.1-24.9) in the nintedanib arm and 12.3 months (80% CI, 7.1-NR) in the placebo arm. Grade 3-4 adverse events of any attribution during the blinded period occurred in 59.1% of patients receiving nintedanib and in 33.3% of patients receiving placebo. Conclusion: This study did not suggest a clinically significant improvement of PFS with nintedanib over placebo in patients with pretreated RAIR DTC and MTC.

Ruyi Zhenbao Tablet and Baimai Ointment Therapy in Acute Ischemic Stroke: A Study Protocol for a Multi-Center, Randomized, Double-blinded, and Parallel-Controlled Trial.

Introduction: Stroke is characterized by high incidence, recurrence rate, and mortality. Patients with acute ischemic stroke (AIS) who are ineligible for acute revascularization therapy require more effective medication treatments. A previous clinical study showed that Ruyi Zhenbao tablets and Baimai ointments might be effective against AIS; however, high-quality clinical evidence supporting their application in AIS is lacking. To explore the efficacy of the two classic Tibetan medicines in the treatment of AIS, a randomized clinical trial will be conducted in patients with AIS who are not eligible for thrombolytic treatment. Methods: A prospective, randomized, multiple-center, double-blinded, placebo-controlled, and parallel-group trial will be conducted. We shall randomize 480 eligible participants to either the intervention or the control group. The distribution ratio of each group will be 1:1:1:1, including 120 patients each in the dual-medication group, the Baimai ointment group, the Ruyi Zhenbao tablet group, and the placebo group. Participants will be treated with medication for 8 weeks, and they will receive three follow-up visits: at 4 weeks (D29), 8 weeks (D56), and 90 days (D90) after commencing treatment. The primary outcome will be D90 change in the simplified Fugl-Meyer score from baseline to posttreatment. The secondary outcomes are as follows: D29 change of simplified Fugl-Meyer score from baseline to posttreatment; proportion of participants whose D29 NIHSS scores decreased by four or more points from baseline D90 proportion of subjects with mRS score of 0-2 (inclusive); D90 proportion of subjects with Barthel index score ≥95; D90 incidence of cardiovascular and cerebrovascular events. Safety endpoint includes mortality within 90 days; proportion of subjects with adverse events/serious adverse events within 90 days. Conclusion: This research protocol lays a solid groundwork for its practical execution. This study is poised to serve as a reference for other Tibetan medicine researchers, contributing to the reduction of stroke-related expenditures globally and, in turn, benefiting a broader population of stroke patients.

Systems-level computational modeling in ischemic stroke: from cells to patients.

Ischemic stroke, a significant threat to human life and health, refers to a class of conditions where brain tissue damage is induced following decreased cerebral blood flow. The incidence of ischemic stroke has been steadily increasing globally, and its disease mechanisms are highly complex and involve a multitude of biological mechanisms at various scales from genes all the way to the human body system that can affect the stroke onset, progression, treatment, and prognosis. To complement conventional experimental research methods, computational systems biology modeling can integrate and describe the pathogenic mechanisms of ischemic stroke across multiple biological scales and help identify emergent modulatory principles that drive disease progression and recovery. In addition, by running virtual experiments and trials in computers, these models can efficiently predict and evaluate outcomes of different treatment methods and thereby assist clinical decision-making. In this review, we summarize the current research and application of systems-level computational modeling in the field of ischemic stroke from the multiscale mechanism-based, physics-based and omics-based perspectives and discuss how modeling-driven research frameworks can deliver insights for future stroke research and drug development.

Precision cancer medicine platform trials: Concepts and design of AcSé-ESMART.

Precision cancer medicine brought the promise of improving outcomes for patients with cancer. High-throughput molecular profiling of tumors at treatment failure aims to direct a patient to a treatment matched to the tumor profile. In this way, improved outcome has been achieved in a small number of patients whose tumors exhibit unique targetable oncogenic drivers. Most cancers, however, contain multiple genetic alterations belonging to and of various hallmarks of cancer; for most of these alterations, there is limited knowledge on the level of evidence, their hierarchical roles in oncogenicity, and utility as biomarkers for response to targeted treatment(s). We developed a proof-of-concept trial that explores new treatment strategies in a molecularly-enriched tumor-agnostic, pediatric population. The evaluation of novel agents, including first-in-child molecules, alone or in combination, is guided by the available understanding of or hypotheses for the mechanisms of action of the diverse cancer events. Main objectives are: to determine 1) recommended phase 2 doses, 2) activity signals to provide the basis for disease specific development, and 3) to define new predictive biomarkers. Here we outline concepts, rationales and designs applied in the European AcSé-ESMART trial and highlight the feasibility but also complexity and challenges of such innovative platform trials.