Multicenter Randomized Controlled Trials Research Articles

The effectiveness of adding braun anastomosis to standard child reconstruction to reduce delayed gastric emptying after pancreatoduodenectomy: protocol for a multicenter randomized-controlled trial (REMBRANDT) by the Dutch Pancreatic Cancer Group

The effectiveness of adding braun anastomosis to standard child reconstruction to reduce delayed gastric emptying after pancreatoduodenectomy: protocol for a multicenter randomized-controlled trial (REMBRANDT) by the Dutch Pancreatic Cancer Group

HEARING INTERVENTION TO REDUCE COGNITIVE DECLINE: DESIGN AND FINDINGS OF THE ACHIEVE RANDOMIZED CONTROLLED TRIAL

Abstract Epidemiologic data consistently link age-related hearing loss with accelerated cognitive decline and incident dementia in large, population-based studies. Mechanistic pathways that could underlie this association include the effects of distorted peripheral encoding of sound on cognitive load, changes to brain structure/function, and/or reduced social engagement and increased loneliness. Importantly, these pathways may be amenable to comprehensive hearing rehabilitative treatment including hearing assistive technologies (e.g., hearing aids, other integrated hearing assistive devices) and rehabilitative training. To date, however, there has never been a randomized trial that has investigated whether hearing loss treatment could reduce cognitive and other functional decline in older adults without dementia. The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) trial is a multicenter randomized control trial of 977 cognitively intact adults with untreated, mild-to-moderate hearing loss aged 70-84 years at baseline (2018-19) to determine efficacy of best-practices hearing intervention to reduce cognitive decline over 3 years (Clinicaltrials.gov Identifier: NCT03243422). This session, on behalf of the ACHIEVE Collaborative Research Group, will describe the overall design of the ACHIEVE trial including details about recruitment and implementation of both the hearing (amplification, auditory rehabilitation) and successful aging health education control interventions. We will also present the primary findings of the study – the effect of the hearing intervention vs. control on 3-year cognitive decline – as well as the effect of the hearing intervention on several pre-specified outcomes important for the health of older adults, including social engagement, mood disorders and quality of life.

Adjunctive Systemic Corticosteroids for Pulmonary Exacerbations of Cystic Fibrosis.

Rationale: Pulmonary exacerbations (PEx) remain the most common cause of morbidity, recurrent hospitalization, and diminished survival in people with cystic fibrosis (PWCF) and are characterized by excess inflammation. Corticosteroids are potent, widely available antiinflammatory drugs. However, corticosteroid efficacy data from randomized controlled trials in PWCF are limited. Objectives: To determine whether adjunctive systemic corticosteroid therapy is associated with improved outcomes in acute CF PEx. Methods: We performed a secondary analysis of Standardized Treatment of Pulmonary Exacerbations 2 (STOP2), a large multicenter randomized controlled trial of antimicrobial treatment durations for adult PWCF presenting with PEx, that included the use of corticosteroids as a stratification criterion in its randomization protocol. Corticosteroid treatment effects were determined after propensity score matching for covariates including age, sex, baseline forced expiratory volume in 1 second (FEV1), genotype, and randomization arm. The primary outcome measure was the change in percentage predicted FEV1 (ppFEV1). Symptoms, time to next PEx, and the incidence of adverse events (AEs) and serious adverse events (SAEs) were assessed as secondary endpoints. Phenotypic factors associated with the clinical decision to prescribe steroids were also investigated. Results: Corticosteroids were prescribed for 168 of 982 PEx events in STOP2 (17%). Steroid prescription was associated with decreased baseline ppFEV1, increased age, and female sex. Cotreatment with corticosteroids was independent of treatment arm allocation and did not result in greater mean ppFEV1 response, longer median time to next PEx, or more substantial symptomatic improvement compared with propensity-matched PWCF receiving antibiotics alone. AEs were not increased in corticosteroid-treated PWCF. The total number of SAEs-but not the number of corticosteroid-related or PEx-related SAEs-was higher among patients receiving corticosteroids. Conclusions: Empiric, physician-directed treatment with systemic corticosteroids, although common, is not associated with improved clinical outcomes in PWCF receiving antibiotics for PEx. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

A park-based group mobility program for older adults with difficulty walking outdoors: a quantitative process evaluation of the Getting Older Adults Outdoors (GO-OUT) randomized controlled trial

BackgroundProcess evaluations of randomized controlled trials (RCTs) of community exercise programs are important to help explain the results of a trial and provide evidence of the feasibility for community implementation. The objectives of this process evaluation for a multi-centre RCT of outdoor walking interventions for older adults with difficulty walking outdoors, were to determine: 1) implementation fidelity (the extent to which elements of the intervention were delivered as specified in the original protocol) and 2) participant engagement (the receipt of intervention components by the participants) in the Getting Older Adults Outdoors (GO-OUT) trial.MethodsGO-OUT participants attended an active 1-day workshop designed to foster safe, outdoor walking skills. After the workshop, 190 people at 4 sites were randomized to an outdoor walk group (OWG) (n = 98) which met 2x/week for 10 weeks, or the weekly reminders (WR) group (n = 92) which received a phone reminder 1x/week for 10 weeks. The OWG had 5 components – warm-up, continuous distance walk, task-oriented walking activities, 2nd continuous distance walk, and cool-down. Data on implementation fidelity and participant engagement were gathered during the study through site communications, use of standardized forms, reflective notes of the OWG leaders, and accelerometry and GPS assessment of participants during 2 weeks of the OWG.ResultsAll sites implemented the workshop according to the protocol. Participants were engaged in all 8 activity stations of the workshop. WR were provided to 96% of the participants in the WR intervention group. The 5 components of the OWG sessions were implemented in over 95% of the sessions, as outlined in the protocol. Average attendance in the OWG was not high – 15% of participants did not attend any sessions and 64% of participants in the OWG attended > 50% of the sessions. Evaluations with accelerometry and GPS during week 3 and 9 OWG sessions suggest that participants who attended were engaged and active during the OWG.ConclusionsThis process evaluation helps explain the main study findings and demonstrates the flexibility required in the protocol for safe and feasible community implementation. Future research could explore the use of additional behaviour change strategies to optimize attendance for community implementation.Trial registrationClinicalTrials.gov NCT03292510 Date of registration: September 25, 2017.

Transcutaneous electrical acupoint stimulation for prevention of postoperative urinary retention: A systematic review

IntroductionTranscutaneous electrical acupoint stimulation (TEAS) has been proposed for postoperative urinary retention (POUR). This meta-analysis evaluated the effect of TEAS in preventing POUR. MethodsDatabases were searched until February 6, 2023. Randomized controlled trials (RCTs) about TEAS for preventing POUR were included. The primary concern was the incidence of POUR, with post-void residual urine volume as a secondary outcome. ResultsFourteen studies with 2865 participants were identified. TEAS reduced the incidence of POUR (RR = 0.44, 95%CI = 0.33 to 0.58, P < 0.00001) and decreased the post-void residual urine volume (MD = −75.41 mL, 95%CI = −118.76 to −32.06, P = 0.0007). The preventive effect on POUR was found in patients receiving anorectal, gynecologic, orthopedic and biliary surgery, but not urinary surgery. Dilatational- and continuous-wave TEAS had a great outcome in preventing POUR. Intraoperative TEAS, preoperative and intraoperative TEAS, and postoperative TEAS were beneficial, and TEAS was more beneficial when compared with sham TEAS and blank control. It is nevertheless difficult to rule out publication bias. ConclusionsTEAS could prevent POUR. Due to insufficient evidence, multicenter, large-sample and high-quality RCTs should be conducted. (Registration:INPLASY202320095).

Network Meta-analysis of 11 Chinese patent medicines in treatment of dilated cardiomyopathy

Bayesian network Meta-analysis was performed to evaluate the efficacy and safety of different Chinese patent medicines in the treatment of dilated cardiomyopathy. The PubMed, EMbase, Cochrane Library, CNKI, Wanfang, and VIP were searched for the randomized controlled trial(RCT) from the inception to May 2023. The quality of the included RCT was evaluated by the Cochrane risk of bias assessment tool, and the data were analyzed by RStudio 3.6.3 calling the &quot;gemtc&quot; package. A total of 96 RCTs involving 8 452 patients, 11 Chinese patent medicines, and 8 outcome indicators were included. Network Meta-analysis is described as follows.(1)In terms of improving clinical total effective rate, except Yixinshu Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Xinshuai Mixture + conventional western medicine, the other Chinese patent medicines combined with conventional western medicine were superior to conventional western medicine alone, and Shenqi Yiqi Dropping Pills + conventional western medicine had the best effect.(2)In terms of improving left ventricular ejection fraction(LVEF), except Yixinshu Capsules + conventional western medicine and Shensong Yangxin Capsules + conventional western medicine, other Chinese patent medicines combined with conventional western medicine outperformed conventional western medicine alone, and Shexiang Baoxin Pills + conventional western medicine had the best effect.(3)In terms of reducing left ventricular end-diastolic dimension(LVEDD), Getong Tongluo Capsules + conventional western medicine, Xinshuai Mixture + conventional western medicine, Huangqi Mixture + conventional western medicine, Tongxinluo Capsules + conventional western medicine, Wenxin Granules + conventional western medicine, and Qili Qiangxin Capsules + conventional western medicine were better than conventional western medicine alone, and Wenxin Granules + conventional western medicine had the best effect.(4)There was no significant difference in reducing left ventricular end-systolic diameter(LVESD) between Chinese patent medicines combined with conventional western medicine and conventional western medicine alone.(5)In terms of improving 6-minute walking trail(6MWT), Yangxinshi Tablets + conventional western medicine, Yixinshu Capsules + conventional western medicine, Shenqi Yiqi Dropping Pills + conventional western medicine, Wenxin Granules + conventional western medicine, and Qili Qiangxin Capsules + conventional western medicine were superior to conventional western medicine alone, and Shenqi Yiqi Dropping Pills + conventional western medicine had the best effect.(6)In reducing brain natriuretic peptide(BNP), Xinshuai Mixture + conventional western medicine ourperformed conventional western medicine alone.(7)In reducing hypersensitive C-reactive protein(hs-CRP), Shenqi Yiqi Dropping Pills + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine outperformed conventional western medicine alone, and Qili Qiangxin Capsules + conventional western medicine had the best effect.(8)In terms of safety, adverse reactions were reported in both groups. In conclusion, Chinese patent medicine combined with conventional western medicine were more effective in the treatment of dilated cardiomyopathy. The combinations relieve clinical symptoms and improve cardiac function indexes, and thus can be used according to the patients' conditions in clinical practice. However, limited by the quality and sample size of the included studies, the conclusion remains to be verified by multi-center, large-sample, and high-quality RCT in the future.

Clinical Outcomes of Patients Receiving 3 Versus 4 Doses of Methotrexate with Concomitant Anti-Thymocyte Globulin; A Single Center Experience

Background: Four doses of methotrexate (MTX) given on day +1, +3, +6, and +11 after allogeneic stem cell transplant (HSCT) is considered one of the most common graft-versus-host disease (GVHD) prophylaxis regimen. However, mucositis and occasionally transaminitis prohibit safe delivery of the fourth dose of MTX. Prior single institution studies showed conflicting results comparing the outcomes of patients who received 3 vs 4 doses of MTX but to our knowledge, the effect of concomitant anti-thymocyte globulin (ATG) use has not been reported. As both ATG and MTX synergistically prevent GVHD via suppressive effects on T-cells. Our institution uniquely incorporates ATG as part of the conditioning regimen for patients receiving HSCT from 10/10 loci match unrelated donors (MUD) and here we report the clinical outcomes between patients who received 3 versus (vs) 4 doses of MTX. Methods: We retrospectively reviewed the charts of patients who underwent HSCT from MUD between 2009 to 2023 at the University of Iowa Hospital and Clinics. We use rabbit ATG (Thymoglobulin R), given at 0.5 mg/kg on day -3, 2 mg/kg on day -2, and 2.5 mg/kg on day -1. MTX is given at 15 mg/m 2 on day +1 and 10 mg/m 2 on day +3, +6 and +11 per institutional protocol. Statistical Analysis: Time was calculated from transplant to recurrence or death for recurrence-free survival (RFS) and overall survival (OS), respectively. For acute and chronic GVHD (aGVHD and cGVHD), time was calculated from transplant to onset of acute and chronic GVHD. Relapse and death were considered as competing events. For non-relapse mortality (NRM), time was calculated from transplant to death; relapse was considered a competing event. Cox regression and Fine-Gray competing risk models were used to estimate the effect of patient, disease, and treatment characteristics on outcomes Results: We identified 296 patients with various indications of HSCT; the most common was acute myeloid leukemia (45.3%). There were 117 and 179 patients who received 3 doses and 4 doses of MTX respectively. Patients characteristics reported in table 1. Median follow-up was 21.9 months (range 0.6 to 150.8). Patients who received 4 doses of MTX were more frequently male (68.2% vs 49.6%, p&amp;lt;0.01), received a reduced intensity (compared to myeloablative) preparative regimen (38.0% vs 23.1%, p&amp;lt;0.01), were older (median 58 vs 54 years, p=0.01), and underwent transplant at an earlier year (median year of transplant 2014 vs 2018, p&amp;lt;0.01). Severe mucositis was the most common reason for omission of the 4 th dose of MTX. Maximum grade of aGVHD was similar between cohorts (p=0.83). A statistically significant difference was not evidenced between patients receiving 4 versus 3 doses of MTX for the following outcomes: aGVHD (HR 1.11, 95% CI 0.84-1.46), grade 3-4 aGVHD (HR 1.41, 95% CI 0.77-2.60), RFS (HR 1.01, 95% CI 0.66-1.56), NRM (HR 1.33, 95% CI 0.84-2.10) and OS (HR 1.21, 95% CI 0.87-1.69). While significant on univariate analysis, MTX dose was not significantly associated with extensive cGVHD (HR 1.44, 95% CI 0.92-2.26) after adjustment for transplant year. Additionally, the median time to neutrophil engraftment was 14 days in both cohorts. Conclusion: When ATG is used concomitantly, omission of the 4 th dose of MTX does not significantly impact the rate of neutrophil engraftment, cumulative incidence of aGVHD, cGVHD, RFS, NRM, and OS after HSCT from MUD. However, a small sample size and non-randomized nature of this study prompts further confirmation study from a large prospective multicenter randomized control trial.

Comparing Postoperative Pain With Laparoscopic Versus Robotic Sacrocolpopexy

Study ObjectiveTo compare postoperative pain and pain-related outcomes following laparoscopic (LS-MISC) versus robotic minimally invasive sacrocolpopexy (R-MISC). DesignA secondary analysis of an original placebo-controlled randomized-controlled trial (RCT) examining preoperative IV acetaminophen on postoperative pain following MISC. SettingPlanned secondary analysis of multicenter RCT. Patients or ParticipantsWomen undergoing MISC. InterventionsCo-primary outcomes at 24 hours were total opioid use in morphine mg equivalents (MME) and visual analog scale (VAS) pain scores comparing LS-MISC and R-MISC. The secondary outcome was pain scores using a pain diary through seven days post-procedure. Measurements and Main ResultsThe original study was a double blind, multi-center, RCT comparing intravenous acetaminophen to placebo that took place between 2014 and 2017. Given that the original trial was unable to show an impact from the use of intravenous acetaminophen, our analysis focused on the impact of surgical modality. We included 90 subjects undergoing MISC: 65 LS-MISC and 25 R-MISC. Most were Caucasian (97.8%) and postmenopausal (88.9%) with mean age 61.2±7.2 years and BMI 27.6±4.4 kg/m2. IV acetaminophen did not impact pain in the original study and was not different between LS-MISC and R-MISC. Concomitant hysterectomy was performed in 67% (LS-MISC) vs. 60% (R-MISC, p=0.49). LS-MISC underwent more perineorrhaphies (15.4% vs 0%, p=0.04) and posterior repairs (18.5% vs 0%, p=0.02). Operative time was longer with LS-MISC (208.5±57.3 vs 143.6±21.0 minutes, p=<0.01). Length of stay was longer with LS-MISC (0.9±0.4 vs 0.7±0.4 days, p=0.02). Women undergoing LS-MISC consumed more opioid MMEs through 24 hours when including intraoperative opioid's (48.5±25.5 vs 35.1±14.6 MME, p=<0.01). Using linear regression correcting for operative time and concomitant vaginal repairs, this difference disappeared. Likewise, when intraoperative opioids were excluded, there was no difference. There were no differences in 24-hour post-operative VAS scores, opioid use in first week, or quality of life (PROMIS PI-SF, all p<0.05). ConclusionWhen comparing VAS pain scores, MME opioid usage, and quality of life between LS-MISC and R-MISC, there was either no difference or differences disappeared after adjusting for confounders. Overall, opioid use, pain scores, and opioid side effects were low.

HPB P24 Quality assurance within multicentre randomised controlled trials of surgical interventions for pancreatic cancer: a systematic review

Abstract Background Pancreatic cancer surgery is a complex intervention, with numerous studies exploring variations in approach to curative resection with the aim of improving outcomes. Multicentre randomised controlled trials (RCTs) represent the gold standard for evaluating these technical modifications. However, variations in how surgical intervention are delivered across trial sites and individual surgeons can influence results. Surgical quality assurance mechanisms within trial designs attempt to mitigate this by ensuring standardised, high-quality technique and reducing heterogeneity of procedures. This systematic review aimed to identify approaches to quality assurance within multicentre randomised controlled trials of surgical interventions for pancreatic cancer. Methods A systematic review was performed by searching MEDLINE and Embase databases between 1st January 2000 and 18th December 2022. Articles were deemed eligible for inclusion if they were a multicentre RCT and evaluated a surgical intervention, technique modification or variation in approach to surgical resection for pancreatic cancer. Data was extracted from included studies using a semi-structured form, with consideration of four prospectively defined quality assurance domains: i) surgical intervention and co-interventions description, ii) surgical technique standardisation, iii) performance monitoring methods, iv) surgeon/ unit credentialing methods. Results A total of 1970 studies were identified from the initial search, of which 44 trials were deemed eligible for inclusion. Thirty-six RCTs (81.8%) provided description of the intervention and/or co-intervention. Attempts to standardise technique were described in 33 RCTs (75.0%). However, only 4 trials (9.1%) deconstructed the intervention into its constituent components. Twelve studies (27.3%) described methods used to monitor performance and adherence to the intervention. The most common approaches used were intra-operative photographs (n=7; 15.9%), surgeon self-declaration (n=3; 6.8%), and pathological specimen review (n=2; 4.5%). Ten studies (22.7%) used credentialing methods based on unit entry criteria. Conclusions This study provides important data on the utilisation of methods of surgical quality assurance within pancreatic RCTs. With the exception of intervention description, compliance to the remaining domains of quality assurance was low. This may compromise the extent to which observed differences in clinical outcomes are due to the technique being evaluated within these trials. Confidence in the results of future RCTs would be improved by enhanced quality assurance across the four domains described.

Efficacy and safety of vagus nerve stimulation on upper extremity motor function in patients with stroke: A meta-analysis of randomized controlled trials.

In 2021, the U.S. Food and Drug Administration (FDA) approved paired vagus nerve stimulation (VNS) for patients with moderate-to-severe upper extremity motor impairments following chronic ischemic stroke. Previous meta-analyses have shown that VNS may impact stroke rehabilitation, but each has some limitations. PubMed, Ovid, Cochrane Library, ScienceDirect, Web of Science and WHO ICTRP databases were searched until July 14, 2022 for randomized controlled trials (RCTs). We defined primary outcomes as Fugl-Meyer Assessment for Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT). Subgroup analyses included types of VNS, time since onset and long-term effects. Secondary outcomes included adverse events of VNS. Eight RCTs involving 266 patients were analyzed, of which five used direct VNS and three transcutaneous auricular VNS. The results revealed that VNS enhanced upper extremity function via FMA-UE (SMD = 0.73; 95% CI: 0.48 to 0.99; P < 0.00001) and WMFT (SMD = 0.82; 95% CI:0.52 to 1.13; P < 0.00001) in comparison to the control group, but showed no significant change on long-term effects of FMA-UE (SMD = 0.69; 95% CI: - 0.06 to 1.44; P = 0.07). There was no difference in adverse events between the VNS and control groups (RR = 1.16; 95% CI: 0.46 to 2.92; P = 0.74). For stroke victims with upper limb disabilities, VNS paired with rehabilitation was significantly safe and effective. More high-quality multicentric RCTs are needed to validate this conclusion.

Efficacy and safety of veliparib combined with traditional chemotherapy for treating patients with lung cancer: a comprehensive review and meta-analysis

Objective Lung cancer, originating from bronchial mucosa or lung glands, poses significant health risks due to its rising incidence and mortality. This study aimed to assess the efficacy and safety of Veliparib combined with chemotherapy versus pharmacotherapy alone for lung cancer treatment, guiding clinical approaches for this severe disease. Methods Comprehensive searches in PubMed, EMBASE, Cochrane, and Web of Science were conducted to identify randomized controlled trials (RCTs) comparing Veliparib combined with standard chemotherapy to chemotherapy alone in lung cancer treatment, up until December 28, 2022. Two reviewers meticulously selected literature based on inclusion and exclusion criteria. The Cochrane tool was used to assess the bias risk of the included studies, and meta-analysis was performed using Stata 15.0. Results Five RCTs (1,010 participants) were included. The analysis results showed that only Veliparib combinedwith chemotherapy prolonged the progression-free survival (PFS) in small cell lung cancer (SCLC) patients [HR = 0.72, 95% CI = (0.57, 0.90)]. No significant differences were observed in overall survival (OS) and objective response rate (ORR). Veliparib and combined chemotherapy caused some side effects in patients with lung cancer, including leukopenia [RR = 2.12, 95% CI = (1.27, 3.55)], neutropenia [RR = 1.51, 95% CI = (1.01, 2.26)], anemia [RR = 1.71, 95% CI = (1.07, 3.07)], and thrombocytopenia [RR = 3.33, 95% CI = (1.19, 9.30)]. For non-small cell lung cancer (NSCLC) patients, there were no statistically significant differences in PFS, OS, or ORR between the experimental and control groups [HR = 0.97, 95% CI = (0.75, 1.27)]. Conclusion The strategy of combining Veliparib with chemotherapy may, to some extent, prolong the PFS in lung cancer patients. However, this benefit is not observed in OS or ORR. Additionally, there are evident adverse reactions. Due to a limited number of the included studies, additional extensive multicenter RCTs are required to validate these results. PROSPERO registration number: CRD42023411510.

The safety and efficacy of quadruple ultra-low-dose combination (quadpill) for hypertension treatment: a meta-analysis of randomized controlled trials

Abstract Background Hypertension is a significant healthcare burden, with an average global prevalence of 1.28 billion adults aged between 30 -79 years old. Using antihypertensive drug combinations is considered more effective in controlling elevated blood pressure than monotherapy; however, psychological factors of the patients and the physicians’ caution from the drugs' adverse effects are still barriers against antihypertensive drug combinations. Quadpill, a single pill containing a quadruple combination of quarter doses of four antihypertensive agents, has been investigated for hypertension treatment. Purpose We aim to evaluate the efficacy and safety of the quadruple ultra-low-dose combination of antihypertensive drugs (quadpill) in patients with hypertension. Methods We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs) evaluating quadpill versus monotherapy or placebo in patients with hypertension, which were retrieved by systematically searching: PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane through February 17th, 2023. Continuous and dichotomous outcomes were pooled using mean difference (MD) and risk ratio (RR) along with confidence interval (CI), using Revman V. 5.4 software. Results Four RCTs with a total of 781 patients (372 in the quadpill group and 425 in the control group) were included in our analysis. Quadpill was effective in controlling automated systolic blood pressure on the short-term (4-6 weeks) (RR: -13.00 with 95% CI [-17.22, -8.78], P= 0.00001) and on the long-term (12 weeks) (RR: -6.18 with 95% CI [-9.35, -3.01], P= 0.0001). Quadpill was also effective in controlling automated diastolic blood pressure on the short-term (4-6 weeks) (MD: -8.15 with 95% CI [-9.42, -6.89], P= 0.00001) and on the long-term (12 weeks) (MD: -6.35 with 95% CI [-10.37, -2.33], P= 0.002). Moreover, patients in the quadpill group significantly achieved target blood pressure &amp;lt; 140/90 (RR: 1.77 with 95% CI [1.26, 2.51], P= 0.001), compared to the control group. Finally, there was no difference between the quadpill and the control groups regarding the safety outcomes, including the incidence of any adverse events (RR: 1.36 with 95% CI [0.86, 2.15], P= 0.19), any serious adverse events (RR: 1.13 with 95% CI [0.56, 2.25], P= 0.74), and any adverse events leading to drug discontinuation (RR: 0.89 with 95% CI [0.19, 4.11], P= 0.88). Conclusion Quadruple ultra-low-dose combination of antihypertensive drugs (quadpill) was effective and safe for hypertension treatment. However, further large-scale multicenter RCTs are still warranted before endorsement in the clinical practice as current evidence is based on a small number of RCTs and quadpill holds a promising strategy for hypertension treatment.Figure 1Figure 2

Pilot randomized controlled trial of restricted versus liberal crystalloid fluid management in pediatric post-operative and trauma patients

BackgroundIntravenous (IV) fluid therapy is essential in the treatment of critically ill pediatric surgery and trauma patients. Recent studies have suggested that aggressive fluids may be detrimental to patients. Prospective studies are needed to compare liberal to restricted fluid management in these patients. The primary objective of this pilot trial is to test study feasibility—recruitment and adherence to the study treatment algorithm.MethodsWe conducted a two-part pilot randomized controlled trial (RCT) comparing liberal to restricted crystalloid fluid management in 50 pediatric post-operative (1–18 years) and trauma (1–15 years) patients admitted to our pediatric intensive care unit (PICU). Patients were randomized to a high (liberal) volume or low (restricted) volume algorithm using unblinded, blocked randomization. A revised treatment algorithm was used after the 29th patient for the second part of the RCT. The goal of the trial was to determine the feasibility of conducting an RCT at a single site for recruitment and retention. We also collected data on the safety of study interventions and clinical outcomes, including pulmonary, infectious, renal, post-operative, and length of stay outcomes.ResultsFifty patients were randomized to either liberal (n = 26) or restricted (n = 24) fluid management strategy. After data was obtained on 29 patients, a first study analysis was performed. The volume of fluid administered and triggers for intervention were adapted to optimize the treatment effect and clarity of outcomes. Updated and refined fluid management algorithms were created. These were used for the second part of the RCT on patients 30–50. During this second study period, 54% (21/39, 95% CI 37–70%) of patients approached were enrolled in the study. Of the patients enrolled, 71% (15/21, 95% CI 48–89%) completed the study. This met our a priori recruitment and retention criteria for success. A data safety monitoring committee concluded that no adverse events were related to study interventions. Although the study was not powered to detect differences in outcomes, after the algorithm was revised, we observed a non-significant trend towards improved pulmonary outcomes in patients on the restricted arm, including decreased need for and time on oxygen support and decreased need for mechanical ventilation.ConclusionWe demonstrated the feasibility and safety of conducting a single-site RCT comparing liberal to restricted crystalloid fluid management in critically ill pediatric post-operative and trauma patients. We observed trends in improved pulmonary outcomes in patients undergoing restricted fluid management. A definitive multicenter RCT comparing fluid management strategies in these patients is warranted.Trial registrationClinicalTrials.gov, NCT04201704. Registered 17 December 2019—retrospectively registered.

Neoadjuvant PD-1/PD-L1 combined with CTLA-4 inhibitors for solid malignancies: a systematic review and meta-analysis

BackgroundThe effectiveness and safety of neoadjuvant PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors is controversial. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors as neoadjuvant therapy for malignant solid tumors.MethodsThis study has been registered with the number CRD42023407275 on PROSPERO. Systematic searches were conducted in PubMed, Embase, Web of Science and Cochrane Library databases until March 17, 2023. In addition, manual searches were performed. The inclusion criteria encompassed randomized controlled trials (RCTs) that assessed the utilization of neoadjuvant PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors PD-1/PD-L1 inhibitors for patients with solid malignancies. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials (ROB1) were used. Risk ratios (RRs), hazared ratios (HRs) and their respective 95% confidence intervals were calculated using Stata17.0 MP and Review Manager 5.4 software.ResultsA total of 2780 records were identified, and ultimately 10 studies involving 273 patients were included. The meta-analysis showed that the addition of CTLA-4 inhibitors to PD-1/PD-L1 inhibitors did not demonstrate a significant effect on overall response rate, main pathological response, pathological complete response, surgical resection, radical resection, overall survival, progression-free survival, recurrence-free survival, grade 3–4 adverse events, all-cause mortality, and completed treatment (P > 0.05). However, further subgroup analysis indicated that the combination of PD-1 with CTLA-4 inhibitors significantly increased the occurrence of grade 3–4 adverse events in patients (P < 0.05).ConclusionsAs neoadjuvant therapy for malignant solid tumors, the addition of CTLA-4 inhibitors to PD-1/PD-L1 inhibitors does not appear to enhance efficacy.Moreover, there is a potential increase in the risk of grade 3–4 adverse events associated with this combination. However, it is important to note that the studies included in this analysis suffer from limitations such as small samples and single-center designs, which are inherent constrains with the available published literature. Further research involving large-sample and multicenter RCTs are warranted to obtain more reliable results.

Systematic review and Meta-analysis of efficacy and safety of Shufeng Jiedu Capsules in treatment of influenza

This study aims to systematically review the efficacy and safety of Shufeng Jiedu Capsules in the treatment of influenza. The randomized controlled trial(RCT) of Shufeng Jiedu Capsules alone or in combination with conventional western medicine for treating influenza were retrieved from PubMed, EMbase, Cochrane Library, Web of Science, SinoMed, CNKI, VIP, Wanfang, and ClinicalTrails.gov. The data analysis was performed in RevMan 5.4.1. The Cochrane risk of bias assessment tool was used to evaluate the quality of the involved RCT, and GRADEpro GDT to assess the quality of the evidence. A total of 11 RCTs involving 1 836 patients were included in this study. Compared with conventional western medicine, Shufeng Jiedu Capsules/Shufeng Jiedu Capsules + conventional western medicine improved the response rate(RR=1.09, 95%CI[1.03, 1.15], P=0.002), shortened the time to relief of cough, and increased the 3-day sore throat relief rate, whereas there was no significant difference in the time to fever abatement, the time to relief of sore throat, 3-day cough relief rate, or 3-day runny nose relief rate. Subgroup-analysis showed that Shufeng Jiedu Capsules + conventional western medicine improved the response rate(RR=1.11, 95%CI[1.08, 1.15], P&lt;0.000 01), shortened the time to relief of cough, and increased the 3-day relief rate of symptoms(cough, sore throat, and runny nose) compared with conventional western medicine alone, while there was no significant difference in the time to fever abatement or the time to relief of sore throat. Shufeng Jiedu Capsules alone could not improve the response rate(RR=0.97, 95%CI[0.93, 1.02], P=0.19). In addition, Shufeng Jiedu Capsules/Shufeng Jiedu Capsules + conventional western medicine vs conventional western medicine were no significant difference in adverse reactions(RR=0.98, 95%CI[0.57, 1.69], P=0.95). The available evidence suggests that Shufeng Jiedu Capsules is effective and safe in the treatment of influenza, and the combination of Shufeng Jiedu Capsules with conventional western medicine can accelerate the relief of symptoms. However, since the number and quality of the included studies were low, the above findings remained to be further verified by multicenter RCT with large sample sizes.

Multimodal agility-based exercise training (MAT) versus strength and endurance training (SET) to improve multiple sclerosis-related fatigue and fatigability during inpatient rehabilitation: a randomized controlled pilot and feasibility study [ReFEx

BackgroundMultimodal agility-based exercise training (MAT) is a group-based exercise training framework for persons with multiple sclerosis (pwMS) with a potential to impact fatigue and fatigability. In a mixed-methods design, this study evaluated the feasibility of implementing MAT in an inpatient rehabilitation setting and the feasibility of a randomized controlled trial (RCT) study protocol with ‘traditional’ strength and endurance training (SET) as an active control condition. Secondarily, preliminary outcome data was acquired.MethodsPwMS with low to moderate disability and self-reported fatigue were randomly allocated to either MAT or SET when starting inpatient rehabilitation (4–6 weeks). The MAT-participants exercised in a group following a MAT-manual (sessions were gym- (5x/week) and pool-based (3x/week)). SET-participants exercised individually 5x/week on a cycle ergometer, and 3x/week on strength training machines. Feasibility assessments focused on processes, resources, management, time, and scientific domains. Assessed clinical outcomes at admission and discharge included perceived fatigue, motor and cognitive fatigability, cognitive performance, motor function, and balance confidence. Perceived fatigue was reassessed 1, 4, and 12 weeks after discharge. Feasibility was determined regarding predetermined progression criteria.ResultsTwenty-two participants were randomized. Both groups performed the minimum number of sessions (> 18), and retention was adequate (73–91%). SET-participants performed more sessions than MAT-participants (30.8 vs. 22.7) and stayed longer in the facility (34.2 vs. 31.6 days). Non-eligibility of admitted pwMS was high (74% non-eligible), mainly due to high EDSS and inability to attend pool-based sessions. Consequently, recruitment (1.8/month) was slower than the predetermined progression criterium. Baseline assessments took longer than required (only 50% completed within 3 days). Short-term fatigue reduction was similar for both groups. Motor fatigability also improved in both groups, whereas cognitive fatigability deteriorated. In MAT, average improvement in walking endurance (43.9 m) exceeded minimal important change values for individuals (> 26.9 m).ConclusionsProgressing to a definitive RCT necessitates adaptation of eligibility criteria. In the present design it will also be difficult to attain similar dosing of interventions. A multicenter RCT focused only on gym-based MAT might be another option to assess the effect of MAT. The primary outcome measure should be able to measure change in perceived fatigue more robustly.Trial registrationGerman Clinical Trials Register: DRKS00023943, date of registration: 23 September 2021.

Aneuploidy in oocytes from women of advanced maternal age: analysis of the causal meiotic errors and impact on embryo development.

In oocytes of advanced maternal age (AMA) women, what are the mechanisms leading to aneuploidy and what is the association of aneuploidy with embryo development? Known chromosome segregation errors such as precocious separation of sister chromatids explained 90.4% of abnormal chromosome copy numbers in polar bodies (PBs), underlying impaired embryo development. Meiotic chromosomal aneuploidies in oocytes correlate with AMA (>35 years) and can affect over half of oocytes in this age group. This underlies the rationale for PB biopsy as a form of early preimplantation genetic testing for aneuploidy (PGT-A), as performed in the 'ESHRE STudy into the Evaluation of oocyte Euploidy by Microarray analysis' (ESTEEM) randomized controlled trial (RCT). So far, chromosome analysis of oocytes and PBs has shown that precocious separation of sister chromatids (PSSC), Meiosis II (MII) non-disjunction (ND), and reverse segregation (RS) are the main mechanisms leading to aneuploidy in oocytes. Data were sourced from the ESTEEM study, a multicentre RCT from seven European centres to assess the clinical utility of PGT-A on PBs using array comparative genomic hybridization (aCGH) in patients of AMA (36-40 years). This included data on the chromosome complement in PB pairs (PGT-A group), and on embryo morphology in a subset of embryos, up to Day 6 post-insemination, from both the intervention (PB biopsy and PGT-A) and control groups. ESTEEM recruited 396 AMA patients: 205 in the intervention group and 191 in the control group. Complete genetic data from 693 PB pairs were analysed. Additionally, the morphology from 1034 embryos generated from fertilized oocytes (two pronuclei) in the PB biopsy group and 1082 in the control group were used for statistical analysis. Overall, 461/693 PB pairs showed abnormal segregation in 1162/10 810 chromosomes. The main observed abnormal segregations were compatible with PSSC in Meiosis I (MI) (n = 568/1162; 48.9%), ND of chromatids in MII or RS (n = 417/1162; 35.9%), and less frequently ND in MI (n = 65/1162; 5.6%). For 112 chromosomes (112/1162; 9.6%), we observed a chromosome copy number in the first PB (PB1) and second PB (PB2) that is not explained by any of the known mechanisms causing aneuploidy in oocytes. We observed that embryos in the PGT-A arm of the RCT did not have a significantly different morphology between 2 and 6 days post-insemination compared to the control group, indicating that PB biopsy did not affect embryo quality. Following age-adjusted multilevel mixed-effect ordinal logistic regression models performed for each embryo evaluation day, aneuploidy was associated with a decrease in embryo quality on Day 3 (adjusted odds ratio (aOR) 0.62, 95% CI 0.43-0.90), Day 4 (aOR 0.15, 95% CI 0.06-0.39), and Day 5 (aOR 0.28, 95% CI 0.14-0.58). RS cannot be distinguished from normal segregation or MII ND using aCGH. The observed segregations were based on the detected copy number of PB1 and PB2 only and were not confirmed by the analysis of embryos. The embryo morphology assessment was static and single observer. Our finding of frequent unexplained chromosome copy numbers in PBs indicates that our knowledge of the mechanisms causing aneuploidy in oocytes is incomplete. It challenges the dogma that aneuploidy in oocytes is exclusively caused by mis-segregation of chromosomes during MI and MII. Data were mined from a study funded by ESHRE. Illumina provided microarrays and other consumables necessary for aCGH testing of PBs. None of the authors have competing interests. Data were mined from the ESTEEM study (ClinicalTrials.gov Identifier NCT01532284).

The diagnostic accuracy of lung ultrasound to determine PiCCO-derived extravascular lung water in invasively ventilated patients with COVID-19 ARDS

BackgroundLung ultrasound (LUS) can detect pulmonary edema and it is under consideration to be added to updated acute respiratory distress syndrome (ARDS) criteria. However, it remains uncertain whether different LUS scores can be used to quantify pulmonary edema in patient with ARDS.ObjectivesThis study examined the diagnostic accuracy of four LUS scores with the extravascular lung water index (EVLWi) assessed by transpulmonary thermodilution in patients with moderate-to-severe COVID-19 ARDS.MethodsIn this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were enrolled within 48 hours after intubation and underwent LUS and EVLWi measurement on the first and fourth day after enrolment. EVLWi and ∆EVLWi were used as reference standards. Two 12-region scores (global LUS and LUS–ARDS), an 8-region anterior–lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi > 15 mL/kg) was calculated.Results26 out of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 out of 29 patients (83%) at time point 2. The global LUS (r = 0.54), LUS–ARDS (r = 0.58) and anterior–lateral score (r = 0.54) correlated significantly with EVLWi, while the B-line score did not (r = 0.32). ∆global LUS (r = 0.49) and ∆anterior–lateral LUS (r = 0.52) correlated significantly with ∆EVLWi. AUROCC for EVLWi > 15 ml/kg was 0.73 for the global LUS, 0.79 for the anterior–lateral and 0.85 for the LUS–ARDS score.ConclusionsOverall, LUS demonstrated an acceptable diagnostic accuracy for detection of pulmonary edema in moderate–to–severe COVID-19 ARDS when compared with PICCO. For identifying patients at risk of severe pulmonary edema, an extended score considering pleural morphology may be of added value.Trial registration: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020–005447-23.

596P Comparison of neoadjuvant chemoradiotherapy with CAPEOX versus single-agent capecitabine in high-risk locally advanced rectal cancer: Long-term results from a multicenter randomized controlled trial (MONT-R)

596P Comparison of neoadjuvant chemoradiotherapy with CAPEOX versus single-agent capecitabine in high-risk locally advanced rectal cancer: Long-term results from a multicenter randomized controlled trial (MONT-R)

Can Distal First Metatarsal Supination Osteotomy, Varization Osteotomy, or a Combination of Both Improve HV Surgical Outcomes? Preliminary Results of a Multicenter Randomized Control Trial

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: The outcomes of Hallux Valgus (HV) surgical treatment are perfectible. First ray dysmorphia in HV appears to incorporate a first metatarsal (M1) hyperpronation and a valgus deviation of M1 distal articular surface. Those could play a role in first ray destabilization and misalignment in HV. However, we do not know whether correction of these deformities could improve HV surgical treatment outcomes. Therefore, we performed a study to assess the impact of M1 distal supination osteotomy, M1 distal varization osteotomy, and combination of both on HV clinical and radiological outcomes. We hypothesized that M1 distal supination osteotomies would improve surgical outcomes in HV. Methods: We conducted an IRB-approved multicenter randomized control trial. HV with an indication for surgical correction were included. HV requiring surgery of the lesser metatarsals were excluded. Feet were randomly divided into 4 groups corresponding to 4 different types of surgery (Figure): 1. Control, classical M1 distal chevron. 2. Supination M1 distal chevron 3. Varization M1 distal chevron 4. Combination of the latter two. Preoperative evaluation and 6-months follow-up were performed. Demographics, AOFAS score, complications, and patient satisfaction (Likert Scale) were collected. On conventional weight-bearing radiographs before and 6 months after surgery, we measured the Hallux Valgus Angle(HVA), the Intemetatarsal Angle(IMA) the Distal Metatarsal Articular Angle(DMAA), the Okuda's M1 head shape classification(from round to angular) and the sesamoid position according to Hardy and Clapham. Normality of different variables was assessed using the Shapiro-Wilk test. Groups were compared using ANOVA for normal and Kruskall Wallis for nonnormal variables. Post-hoc pairwise analyses were performed with Dunn-Bonferoni’s test. Results: 100 HV were included. 8 were lost to follow-up. The Control (n=24), Supination (n=20), Varization (n=26) and Combination (n=22) groups were comparable on age, gender, BMI, and preoperative radiological parameters. At 6 months, there was no difference on AOFAS improvement (p=0.39) and patients satisfaction (p=0.14) whereas there were significant differences on HVA (p &lt; 0.001), IMA (p &lt; 0.001), DMAA (p &lt; 0.001), Okuda's classifcation (p &lt; 0.001) and sesamoid position (p &lt; 0.001) between groups. We found lower HVA values for Combination VS Control (p &lt; 0.001), Combination VS Varization (p &lt; 0.001), Supination VS Control (p &lt; 0.001) and Supination VS Varization (p = 0.005). Asymptomatic recurrences (HVA&gt;15°) were present in 5 cases in Control (20.8%), and 2 in Varization (7.7%). Asymptomatic Hallux Varus (HVA &lt; 0°) were present in 4 cases in Combination (18.2%), and 1 in Supination (5%). Conclusion: Distal M1 supination osteotomies showed better improvement in radiological parameters without showing clinical benefit. The combination of supination and varization osteotomies could lead to overcorrection while the classic M1 distal chevron could lead to insufficient corrections. Routinely performing a supination osteotomy in HV surgical management may lead to erroneous correction and we recommend an à la carte treatment. These results are preliminary and we recommend more patients and longer follow-up to confirm these findings.