Multicenter Randomized Clinical Trial Research Articles

Use of the Win Ratio for Analysis of Stroke Trials: Description, Illustration, and Planned Use in the Second European Carotid Surgery Trial (ECST-2).

Randomized trials in stroke often focus on outcomes beyond a single clinical event. Trials of stroke prevention commonly use composite outcomes that include multiple components (eg, death, stroke, or myocardial infarction). A major limitation is that all events count equally but may differ markedly in terms of clinical severity. Trials in acute stroke often use ordinal outcomes or scale scores. Limitations include the requirement for statistical assumptions and the difficulty of handling the competing risk of death. We introduce the win ratio as an alternative method. It works by placing components of a composite into a hierarchy, whereby clinically more important outcomes take priority over less important ones. We illustrate how it works using data from 2 major stroke trials: the ICSS (International Carotid Stenting Study, a trial in stroke prevention) and the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). Potential benefits of the win ratio approach include the possibility to (1) emphasize the clinically most important outcomes, (2) combine components of different outcome types into a composite (eg, a mixture of time-to-event, continuous, and categorical), and (3) naturally handle the competing risk of death in analyses of quantitative outcomes. The win ratio will be used in the upcoming analysis of the ECST-2 (Second European Carotid Surgery Trial), which has a hierarchical primary outcome of (1) time to perioperative death, fatal stroke, or fatal myocardial infarction (most important); (2) time to nonfatal stroke; (3) time to nonfatal myocardial infarction (excluding silent infarcts); and (4) new silent cerebral infarct on brain imaging (least important). The win ratio provides a useful clinically relevant method for analyzing trial outcomes. It has some advantages over conventional methods, and we recommend its wider application in future stroke trials.

Outcome and Risk of Poststroke Pneumonia in Patients with Acute Ischemic Stroke After Endovascular Thrombectomy: A Post Hoc Analysis of the DIRECT-MT Trial.

In this study, we aimed to investigate the risk factors and impact of poststroke pneumonia (PSP) on mortality and functional outcome in patients with acute ischemic stroke (AIS) after endovascular thrombectomy (EVT). This was a post hoc analysis of a prospective randomized trial (Direct intraarterial thrombectomy in order to revascularize AIS patients with large-vessel occlusion efficiently in Chinese tertiary hospitals: a multicenter randomized clinical trial). Patients with AIS who completed EVT were evaluated for the occurrence of PSP during the hospitalization period and their modified Rankin Scale (mRS) scores at 90days after AIS. Logistic regression analysis was conducted to investigate the independent predictors of PSP. Propensity score matching was conducted for the PSP and non-PSP groups by using the covariates resulting from the logistic regression analysis. The associations between PSP and outcomes were analyzed. The outcomes included 90-day poor functional outcome (mRS scores > 2), 90-day mortality, and early 2-week mortality. A total of 639 patients were enrolled, of whom 29.58% (189) developed PSP. Logistic regression analysis revealed that history of chronic heart failure (unadjusted odds ratio [OR] 2.011, 95% confidence interval [CI] 1.026-3.941; P = 0.042), prethrombectomy reperfusion on initial digital subtraction angiography (OR 0.394, 95% CI 0.161-0.964; P = 0.041), creatinine levels at admission (OR 1.008, 95% CI 1.000-1.016; P = 0.049), and National Institutes of Health Stroke Scale at 24h (OR 1.023, 95% CI 1.007-1.039; P = 0.004) were independent risk factors for PSP. With propensity scoring matching, poor functional outcome (mRS > 2) was more common in patients with PSP than in patients without PSP (81.03% vs. 71.83%, P = 0.043) at 90days after EVT. The early 2-week mortality of patients with PSP was lower (5.74% vs. 12.07%, P = 0.038). But there was no statistically significant difference in 90-day mortality between the PSP group and non-PSP group (22.41% vs. 14.94%, P = 0.074). The survivorship curve also shows no statistical significance (P = 0.088) between the two groups. Nearly one third of patients with AIS and EVT developed PSP. Heart failure, higher creatinine levels, prethrombectomy reperfusion, and National Institutes of Health Stroke Scale at 24h were associated with PSP in these patients. PSP was associated with poor 90-day functional outcomes in patients with AIS treated with EVT.

Effects of mixed nuts as part of a Brazilian Cardioprotective diet on LDL-cholesterol in adult patients after myocardial infarction: a multicenter randomized controlled clinical trial

BackgroundNuts consumption is related to cardioprotective effects on primary cardiovascular prevention, but studies conducted in secondary prevention are small, scarce and controversial. The objective of this trial was to evaluate the effects of a regional and sustainable cardioprotective diet added or not with an affordable mixed nuts on cardiometabolic features in patients with previous myocardial infarction.MethodsDICA-NUTS study is a national, multi-center, and superiority-parallel randomized clinical trial. Males and females over 40 years old diagnosed with previous myocardial infarction in the last 2 to 6 months were included. Patients were allocated into two groups: the Brazilian Cardioprotective diet (DICA Br) supplemented with 30 g/day of mixed nuts (10 g of peanuts; 10 g of cashew; 10 g of Brazil nuts) (intervention group, n = 193); or only DICA Br prescription (control group, n = 195). The primary outcome was low-density lipoprotein cholesterol means (in mg/dL) after 16 weeks. Secondary outcomes were other lipid biomarkers, glycemic and anthropometric data and diet quality.ResultsAfter adjustment for baseline values, participating study site, time since myocardial infarction and statin treatment regimen (high potency, moderate and low potency/no statins), no significant difference was found between the groups in low-density lipoprotein cholesterol concentrations (intervention-control difference: 3.48 mg/dL [-3.45 to 10.41], P = 0.32). Both groups improved their overall diet quality at the end of the study without differences between them after 16 weeks (intervention-control difference: 1.05 (-0.9 to 2.99); P = 0.29). Other lipids, glycemic profile and anthropometrics were also not different between study groups at the end of the study.ConclusionAdding 30 g/day of mixed nuts to the DICA Br for 16 weeks did not change lipid, glycemic and anthropometric features in the post-myocardial infarction setting.Trial registrationThis study is registered on ClinicalTrials.gov website under number NCT03728127 and its World Health Organization Universal Trial Number (WHO-UTN) is U1111-1259–8105.

Effect of high-dose N-acetylcysteine on exacerbations and lung function in patients with mild-to-moderate COPD: a double-blind, parallel group, multicentre randomised clinical trial.

Evidence for the treatment of patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) is limited. The efficacy of N-acetylcysteine (an antioxidant and mucolytic agent) for patients with mild-to-moderate COPD is uncertain. In this multicentre, randomised, double-blind, placebo-controlled trial, we randomly assigned 968 patients with mild-to-moderate COPD to treatment with N-acetylcysteine (600 mg, twice daily) or matched placebo for two years. Eligible participants were 40-80 years of age and had mild-to-moderate COPD (forced expiratory volume in 1 second [FEV1] to forced vital capacity ratio <0.70 and an FEV1 ≥ 50% predicted value after bronchodilator use). The coprimary outcomes were the annual rate of total exacerbations and the between-group difference in the change from baseline to 24 months in FEV1 before bronchodilator use. COPD exacerbation was defined as the appearance or worsening of at least two major symptoms (cough, expectoration, purulent sputum, wheezing, or dyspnoea) persisting for at least 48 hours. Assessment of exacerbations was conducted every three months, and lung function was performed annually after enrolment. The difference between the N-acetylcysteine group and the placebo group in the annual rate of total exacerbation were not significant (0.65 vs. 0.72 per patient-year; relative risk [RR], 0.90; 95% confidence interval [CI], 0.80-1.02; P = 0.10). There was no significant difference in FEV1 before bronchodilator use at 24 months. Long-term treatment with high-dose N-acetylcysteine neither significantly reduced the annual rate of total exacerbations nor improved lung function in patients with mild-to-moderate COPD. Chinese Clinical Trial Registration: ChiCTR-IIR-17012604.

Protocol for a feasibility multi-centre randomised controlled trial of a pre-operative two-week very low-calorie diet to reduce steatosis prior to liver resection (RESOLVE)

BackgroundHepatic steatosis (HS) increases morbidity and mortality associated with liver surgery (LS). Furthermore, patients with HS are more likely to require a blood transfusion, which is associated with worse short and long-term outcomes. Patients with HS requiring LS receive no specific dietary treatment or advice. A very low-calorie diet (VLCD) is commonly used before gallbladder and bariatric surgery to reduce liver volumes and associated intraoperative morbidity. These diets typically provide 800–1200 kcal/day over a 2–4-week period. Limited evidence suggests that a VLCD in patients with LS may result in better outcomes.MethodsThis study aims to test the feasibility of delivering a multi-centre randomised clinical trial to compare a dietary intervention (VLCD plus motivational instructions) versus treatment as usual (TAU) in people with HS having LS. This study will provide high-quality data to estimate screening rates, recruitment, randomisation, retention, and intervention adherence. The study will also determine the definitive trial’s most clinically relevant primary outcome. The study will also estimate resource use and costs associated with the delivery of the intervention. Seventy-two adults ≥ 18 who are scheduled to undergo elective LS and have a magnetic resonance imaging (MRI) identified HS will be recruited. Acceptability to the dietary intervention will be evaluated with food diaries and focus groups. Clinical and patient-reported outcomes will be collected at baseline, pre- and post-surgery, day of discharge, plus 30- and 90-day follow-up.DiscussionThis feasibility study will provide data on the acceptability and feasibility of a dietary intervention for patients with HS having LS. The intervention has been developed based on scientific evidence from other clinical areas and patient experience; therefore, it is safe for this patient group. Patients with experience of LS and VLCDs have advised throughout the development of the study protocol. The findings will inform the design of a future definitive study.Trial registrationISRCTN Number 19701345. Date registered: 20/03/2023. URL: https://www.isrctn.com/ISRCTN19701345.

From pain level to pain experience: redefining acute pain assessment to enhance understanding of chronic postsurgical pain

BackgroundChronic postsurgical pain (CPSP) significantly impairs quality of life and poses a substantial healthcare burden, affecting up to a quarter of patients undergoing surgery. Although acute pain is recognised as a predictor for CPSP development, the role of patient experience remains underexplored. This study examines the predictive value of patient experience alongside traditional risk factors for CPSP after orthopaedic surgery. MethodsAn exploratory analysis was conducted on 294 patients from a multicentre randomised clinical trial comparing continuous perineural analgesia and single-injection nerve block in ambulatory orthopaedic surgeries. Patient experience was assessed using the Evaluation du Vecu de l’Anesthésie Générale (EVAN-G) validated questionnaire. Factors associated with CPSP at 90 days after surgery were identified through univariate and multivariate analyses, incorporating patient-reported outcomes and classical variables. ResultsOut of 219 patients with complete data, 63 (29%) developed CPSP at day 90. Multivariate analysis revealed a poor pain experience, as assessed by the pain dimension of EVAN-G on postoperative day 2, as an independent predictor of CPSP (odds ratio 6.45, 95% confidence interval 1.65–25.26, P<0.01). Poor pain experience was associated with an augmented risk of CPSP. ConclusionsThis study underscores the role of patient-reported outcomes, specifically the pain experience dimension captured by the EVAN-G scale, in prediction of CPSP 90 days after surgery. It suggests a shift from conventional assessments of pain intensity to a comprehensive understanding of pain experience, advocating for tailored pain management approaches that could reduce chronic pain, thereby improving patient quality of life and functional recovery.

Lung Recruitment Before Surfactant Administration in Extremely Preterm Neonates

A multicenter randomized clinical trial (RCT) showed a lung recruitment maneuver using high-frequency oscillatory ventilation just before surfactant administration (ie, intubate-recruit-surfactant-extubate [IN-REC-SUR-E]) improved the efficacy of treatment compared with the standard intubate-surfactant-extubate (IN-SUR-E) technique without increasing the risk of adverse neonatal outcomes. To examine follow-up outcomes at corrected postnatal age (cPNA) 2 years of preterm infants previously enrolled in an RCT and treated with IN-REC-SUR-E or IN-SUR-E in 35 tertiary neonatal intensive care units. This was a follow-up study of infants recruited into the primary RCT from 2015 to 2018 at 35 tertiary neonatal intensive care units (NICUs) in Italy. Follow-up examinations included neurodevelopmental, growth, and respiratory outcomes of these children at cPNA 2 years. Participants included spontaneously breathing extremely preterm neonates (24 0/7 to 27 6/7 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 hours of life. Data were analyzed from April 2023 to January 2024. Infants were randomly assigned (1:1) to IN-REC-SUR-E or IN-SUR-E and then followed up. The primary outcome was the occurrence of death after discharge or major disability at cPNA 2 years. Secondary outcomes were neurodevelopmental outcomes (major disability, cerebral palsy, cognitive impairment, visual deficit, or auditory deficit), anthropometric measurements (weight, length, and head circumference), and recurrent respiratory infections and hospitalizations because of respiratory causes at 2y cPNA. A total of 137 extremely preterm infants (median [IQR] gestational age, 26.5 [25.3-27.5] weeks and 75 [54.7%] female), initially enrolled in the original RCT, were followed up at cPNA 2 years, including 64 infants in the IN-SUR-E group and 73 infants in the IN-REC-SUR-E group. There were no significant differences in the occurrence of death after discharge or major disability at cPNA 2 years (IN-SUR-E: 13 children [20.3%] vs IN-REC-SUR-E: 10 children [13.7%]; P = .36). There were no significant differences in incidence of disability, cerebral palsy, or cognitive impairment in the IN-REC-SUR-E group compared with the IN-SUR-E group. There were no significant differences in anthropometric measurements (weight, length, and head circumference) between groups. There were no significant differences in the incidence of recurrent respiratory infections or in hospitalizations because of respiratory causes between groups. In this RCT of lung recruitment before surfactant vs standard care there were no significant differences between the 2 groups in death, neurodevelopmental outcomes, anthropometric measurements, or recurrent respiratory infections at the 2-year follow-up. These findings can aid clinicians in decision-making for the best strategy to administer surfactant, considering long-term outcomes.

Benefits and Harms of Hepatocellular Carcinoma Screening Outreach in Patients with Cirrhosis: A Multi-Center Randomized Clinical Trial.

The value of hepatocellular carcinoma (HCC) screening is defined by the balance of benefits from early tumor detection vs harms due to false positive results. We evaluated the value of a mailed outreach strategy for HCC screening in patients with cirrhosis. We conducted a multi-center pragmatic randomized clinical trial comparing mailed outreach for HCC screening (n = 1436) and usual care with visit-based screening (n = 1436) among patients with cirrhosis at three health systems from March 2018 to September 2021. Outcomes of interest were early-stage HCC detection (ie, screening benefit) and diagnostic evaluation for false positive or indeterminate results (ie, screening harm). Screening harm was categorized as mild, moderate, and severe based on number and type of diagnostic exams. All patients were included in intention-to-screen analyses. Of 125 patients diagnosed with HCC (67 outreach and 58 usual care), 71.2% were found at an early stage per the Milan Criteria. Early tumor detection did not significantly differ between the outreach and usual care arms (64.2% vs 79.3%, p = .06). The proportion of patients with physical harms also did not differ between the outreach and usual care arms (10.8% vs 10.7%, p = .95) with 5.9% in both arms having mild harms, 4.0% and 3.8% respectively with moderate harms, and 0.9% and 1.0% respectively with severe harms. Most patients enrolled in HCC screening were detected at an early stage, and a minority experienced physical harms. A mailed outreach strategy did not significantly increase early HCC detection or physical harms compared to usual care. NCT02582918 and NCT03756051.

Sevoflurane in the Acute Phase of Severe Traumatic Brain Injury

The aim of the study was to evaluate the usefulness and safety of sevoflurane in patients in the acute phase of severe traumatic brain injury (TBI).Materials and methods. A prospective, randomized, pilot clinical trial was conducted at the Sklifosovsky Research Institute for Emergency Medicine (Moscow) in adults with acute severe TBI, aged 18 years and older, undergoing intensive intracranial pressure (ICP)-guided therapy. To achieve the desired sedative effect, the inhaled anesthetic sevoflurane was administered in the main group, and standard doses of intravenous propofol were administered in the control group. ICP and cerebral oxygen extraction fraction (OEF) were monitored in all patients. Hemodynamic and respiratory support parameters, transcranial Doppler ultrasound scan, brain bioelectrical activity, brain CT scan, laboratory parameters, markers of inflammation, patients' need for sedation and mechanical ventilation, and length of ICU stay were also evaluated.Results. The use of inhalation sedation contributed to the reduction of ICP on day 2 (9.5 mmHg in the sevoflurane group and 17.3 mmHg in the propofol group, P=0.003) and day 3 (10 mmHg and 14.2 mmHg, respectively, P=0.005). BIS monitoring showed no significant difference in depth of sedation between groups on day 2 (60 vs. 48.5, P=0.070) and day 3 (61 vs. 46, P=0.095). Inhalation sedation reduced cerebral OEF on the injury side compared to propofol on day 2 (23.3 vs. 30.2%, P=0.006) and day 3 (22.7 vs. 31.2%, P&lt;0.001). After 24 hours of sedation therapy, there was a significant difference in P/F (PaO₂/FiO₂) ratios between the groups. On days 1, 3, and 7, the sevoflurane group had P/F ratios of 340, 324, and 323 mmHg, while the propofol group had significantly lower ratios of 271, 278, and 275 mmHg (P&lt;0.001). Pneumonia was documented in 9 cases in the sevoflurane group vs. 18 cases in the propofol group (P=0.028), and a similar trend was observed in the total number of infectious complications: 13 vs. 21 cases, respectively (P=0.046).Conclusion. Sevoflurane in the acute phase of severe TBI was not only safe, but also improved several vital functions, including ICP, blood pressure, P/F ratio, and also slowed brain metabolism via reduced oxygen consumption without affecting the depth of sedation according to BIS monitoring data. All of the above suggests that inhalation sedation may improve the prognosis for patient recovery. However, multicenter randomized clinical trials are needed to identify and verify all positive and negative effects of inhalation sedation in this patient population.

601TiP A multicenter randomized clinical trial evaluating the negative hyperselection of patients with RAS/BRAF wild-type metastatic colorectal cancer who are eligible for anti-EGFR therapy

601TiP A multicenter randomized clinical trial evaluating the negative hyperselection of patients with RAS/BRAF wild-type metastatic colorectal cancer who are eligible for anti-EGFR therapy

Sacubitril/valsartan reduces incident anaemia and iron therapy utilization in heart failure: The PARAGON-HF trial.

Renin-angiotensin system inhibitors (RASi) have been shown to lower haemoglobin levels, potentially related to reductions in erythropoietin levels and haematopoiesis. We examined whether sacubitril/valsartan might attenuate this effect of RASi alone on incident anaemia in patients with heart failure (HF) with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). PARAGON-HF was a global, multicentre randomized clinical trial of sacubitril/valsartan versus the RASi valsartan in patients with HF and left ventricular ejection fraction ≥45%. We evaluated haemoglobin trajectory and risks of incident anaemia and new iron therapy initiation during follow-up. Among 4795 participants, 1111 (23.2%) had anaemia at randomization and 5.6% were treated with iron at baseline. Over a median follow-up of 2.9 years, patients with anaemia were at significantly higher risk for total HF hospitalizations and cardiovascular death, compared with those without anaemia (21.6 vs. 11.5 per 100 patient-years; adjusted rate ratio 1.31; 95% confidence interval [CI] 1.12-1.54; p = 0.001). Sacubitril/valsartan slightly slowed the decline in haemoglobin levels by 0.1 g/dl (95% CI 0.0-0.2 g/dl; p = 0.005). Participants treated with sacubitril/valsartan were at significantly lower risk of developing anaemia (30.3% vs. 37.6%; hazard ratio [HR] 0.76; 95% CI 0.68-0.85; p < 0.001) and starting iron therapy (8.1% vs. 10.0%; HR 0.81; 95% CI 0.67-0.97; p = 0.026). Treatment effects of sacubitril/valsartan versus valsartan on total HF hospitalizations and cardiovascular death were consistent among patients across the haemoglobin spectrum (pinteraction = 0.60). Among patients with HFmrEF/HFpEF, treatment with sacubitril/valsartan resulted in modestly smaller declines in haemoglobin, lower rates of incident anaemia, and fewer new initiations of iron therapy compared with RASi. ClinicalTrials.gov ID NCT01920711.

552. COMPARING ROBOTIC ESOPHAGECTOMY TO VIDEO-ASSISTED THORACOSCOPIC ESOPHAGECTOMY FOR ESOPHAGEAL SQUAMOUS CELL CARCINOMA: RESULTS FROM THE REVATE RANDOMIZED CLINICAL TRIAL

Abstract Background The treatment of esophageal squamous cell carcinoma (ESCC) includes dissecting lymph nodes along the recurrent laryngeal nerve (RLN), which is oncologically important but is technical demanding. Vocal cord palsy as a result from RLN injury, carries significant morbidities. This randomized clinical trial (RCT) compared the efficacy and safety of robotic esophagectomy (RE) and video-assisted thoracoscopic esophagectomy (VATE) for performing RLN lymph node dissection (LND) Methods We conducted a multicenter RCT(NCT03713749) from November 2018 to March 2022, enrolling patients with ESCC who required McKeown esophagectomy. The primary endpoint was to determine the success rate of left RLN LND. Success was defined as the removal of lymph nodes confirmed by pathology, without causing permanent nerve palsy (duration &amp;gt; 6 months). Secondary endpoints encompassed perioperative and oncological outcomes. Results The per-protocol analysis included data from 203 patients (RE group: n=103; VATE group: n=100). The primary endpoint was achieved in 88.3% of the RE group and 69% of the VATE group (p&amp;lt;0.001). Additionally, the RE group had a higher mediastinal lymph node harvest (16 [12−22] versus 14 [10−20], p=0.04), shorter thoracic operating time (110 [89−137] min versus 124[103.5−154] min, p=0.004), and earlier drainage removal (4 [3−7] days versus 6 [4−9] days, p=0.007) compared to the VATE group. The two study arms exhibited comparable complication rates with no recorded in-hospital deaths in either group. Conclusion This multicenter trial demonstrates the effectiveness of RE in enhancing the feasibility and safety of RLN LND in ESCC. Additionally, RE leads to an improved mediastinal lymphadenectomy, shorter operating times, and earlier removal of drainage.

Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

Big data analysis of endovascular treatment for acute ischemic stroke: a study based on bibliometric analysis.

While bibliometric analyses are prevalent in the medical field, few have focused on ther endovascular treatment for acute ischemic stroke (AIS). To employ big data analysis to examine the research status, trends, and hotspots in endovascular treatment for AIS. We conducted a comprehensive search using the Web of Science (WOS) database to identify relevant articles on the endovascular treatment for AIS from 1980 to the present. We used various tools for data analysis, including an online platform (https://bibliometric.com/app), the Citespace software, the Vosviewer software, and the ArcMap software, version 10.8. A number of bibliometric indicators were collected and analyzed, such as publication date, country where the studies were conducted, institutions to which the authors were affiliated, authors, high-frequency keywords, cooperative relationship etc. RESULTS: A total of 5,576 articles were retrieved. A substantial increase in the number of articles occurred after 2010. High-frequency keywords included terms such as large vessel occlusion, reperfusion, outcome, and basilar artery occlusion. Among the top 10 most productive authors, Raul G. Nogueira ranked first, with 136 published articles. Among the journals, The New England Journal of Medicine ranked first, with 5,631 citations. The United States has the closest collaborative ties with other nations. In the present study, we found that the reports of endovascular treatment for AIS gradually increased after 2010. Among them, Raul G. Nogueira was the most productive author in this field. The New England Journal of Medicine was the most cited, and it had the greatest impact. The Multicenter Randomized Clinical Trial of Endovascular Treatment of Acute Ischemic Stroke in the Netherlands (MR CLEAN) trial study was the most cited, and it was a landmark study. There are many interesting studies on endovascular treatment for AIS, such as ischemic penumbra, collateral circulation, bridging therapy etc.

Histological and immunohistochemical soft-tissue response to cylindrical and concave abutments: Multicenter randomized clinical trial.

This study aimed to analyze the influence of concave and cylindrical abutments on peri-implant soft tissue. Dimensions, collagen fiber orientation, and immunohistochemical data were assessed. A multicenter, split-mouth, double-blind randomized clinical trial was conducted. Two groups were analyzed: cylindrical abutments and concave abutments. After a 12-week healing period, peri-implant soft tissue samples were collected, processed, and evaluated for dimensions, collagen fiber orientation, and immunohistochemical data. Inflammatory infiltration and vascularization were assessed, and the abutment surfaces were analyzed using scanning electron microscopy. The statistical analysis was performed using the SPSS version 20.0 statistical package. A total of 74 samples in 37 patients were evaluated. Histological evaluation of peri-implant soft tissue dimensions revealed significant differences between concave and cylindrical abutments. Concave abutments exhibited greater total height (concave: 3.57±0.28 - cylindrical: 2.95±0.27) and barrier epithelium extension (concave: 2.46±0.17 - cylindrical: 1.89±0.21) (p<0.05), while the supracrestal connective tissue extension (concave: 1.11±0.17 - cylindrical: 1.03±0.16) was slightly greater (p>0.05). Collagen fiber orientation favored concave abutments (23.76±5.86), with significantly more transverse/perpendicular fibers than for cylindrical abutments (15.68±4.57). The immunohistochemical analysis evidenced greater inflammatory and vascular intensity in the lower portion for both abutments, though concave abutments showed lower overall intensity (concave: 1.05±0.78 - cylindrical: 1.97±0.68) (p<0.05). The abutment surface analysis demonstrated a higher percentage of tissue remnants on concave abutments (42.47±1.32; 45.12±3.03) (p<0.05). Within the limitations of this study, concave abutments presented significantly greater peri-implant tissue height, linked to an extended barrier epithelium, versus cylindrical abutments in thick tissue phenotype. This enhanced soft tissue sealing, favoring a greater percentage of transversely oriented collagen fibers. The concave design reduced chronic inflammatory exudation with T and B cells, thus minimizing the risk of chronic inflammation. This study looked at how 2 different shapes of dental implant abutments (the parts that connect the implant to the crown), specifically concave and cylindrical, affect the soft tissue around the implants. We wanted to see how these shapes influenced the tissue's size, structure, and health. We conducted a clinical trial with 37 patients, comparing the 2 types of abutments in the same mouth over 12weeks. Our findings showed that the concave abutments led to a taller and more extensive layer of protective tissue around the implant compared to the cylindrical ones. This protective tissue had more favorable collagen fiber orientation, which is important for the strength and health of the tissue. Additionally, the concave abutments resulted in less inflammation and better tissue integration. In conclusion, concave abutments may provide better support and health for the soft tissue around dental implants, reducing the risk of chronic inflammation and potentially leading to better long-term outcomes for patients with dental implants.

Non- or minimally displaced distal radius fractures in adult patients < 50 years of age

BackgroundCurrently, non- or minimally displaced distal radius fractures are treated by 3 to 5 weeks of cast immobilisation. Many patients with a distal radius fracture suffer from long-term functional restrictions, which might be related to stiffness due to cast immobilisation. Current literature indicates that 1 week of immobilisation might be safe; however, no level 1 evidence is available. This trial aims to compare 1 week of brace immobilisation with 3 weeks of cast immobilisation in patients with distal radius fractures that do not need reduction.MethodsThe aim of this trial is to evaluate the non-inferiority of 1 week of brace immobilisation in patients with non- or minimally displaced distal radius fractures. A two-armed single blinded multicentre randomised clinical trial will be conducted in three hospitals. Adult patients, between 18 and 50 years old, independent for activities of daily living, with a non- or minimally displaced distal radius fracture can be included in this study. The intervention group is treated with 1 week of brace immobilisation, and the control group with 3 weeks of cast immobilisation. Primary outcome is the patient-reported outcome measured by the Patient-Related Wrist Evaluation score (PRWE) at 6 months. Secondary outcomes are patient-reported outcome measured by the Quick Disabilities of the Arm, Shoulder and Hand score at 6 weeks and 6 months, PRWE at 6 weeks, range of motion, patient-reported pain score measured by VAS score, radiological outcome (dorsal/volar tilt, radial height, ulnar variance, presence of intra-articular step off), complications and cost-effectiveness measured by the EuroQol 5 Dimension questionnaire, Medical Consumption Questionnaire and Productivity Cost Questionnaire.DiscussionThis study will provide evidence on the optimal period of immobilisation in non-operatively treated displaced and reduced distal radius fractures. Both treatment options are accepted treatment protocols and both treatment options have a low risk of complications. Follow-up will be according to the current treatment protocol. This study will provide level 1 evidence on the optimal period and way of immobilisation for non- or minimally displaced distal radius fractures in adult patients.Trial registrationABR 81638 | NL81638.029.22 | www.toetsingonline.nl. 18th of October 2023

Once-Weekly Insulin Icodec in Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Clinical Trials (ONWARDS Clinical Program).

One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D). PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks. The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of -0.14% [95%CI -0.25; -0.03], p = 0.01, and I2 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I2 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I2 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of -0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (-5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93]). Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients' education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680.

Stenting versus medical treatment alone for symptomatic intracranial artery stenosis: a preplanned pooled individual patient data analysis

BackgroundWhether the safety and efficacy of percutaneous transluminal angioplasty and stenting (PTAS) is significantly different from that of medical treatment alone for symptomatic intracranial arterial stenosis (ICAS) is debatable. A...

Advances in understanding and managing pediatric heart failure and transplant.

This article highlights the most recent advances in a review of the current literature in the field of pediatric heart failure and transplantation. Diagnostically, the identification of new genetic factors has contributed to a deeper understanding of cardiomyopathy in children. Novel medications like sacubitril/valsartan and Sodium-Glucose cotransporter-2 (SGLT2) inhibitors, which are now standard in the adult population are being studied in pediatric population and offer new promise of pediatric heart failure treatment. Ventricular assist devices are more commonly used in cardiomyopathy patients and single ventricle patients as a bridge to transplant. Recent pediatric heart transplant society (PHTS) data demonstrated that waitlist survival improved significantly over the past decades (i) and new treatments such as daratumumab and eculizumab have been used in high-risk populations and demonstrate promising results. TEAMMATE trial is the first multicenter randomized clinical trial (RCT) in pediatric heart transplant (HT) to evaluate the safety and efficacy of everolimus (EVL) and low-dose tacrolimus (TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). It will provide valuable information about the safety and efficacy of EVL, TAC, and MMF (ii).Donor cell-free DNA has been used more in pediatric transplant recipients and has significantly decreased invasive EMB (iii). This past 5 years have witness dramatic progress in the field of pediatric heart failure and transplantation including more use of mechanical support in heart failure patients with various underlying etiology, especially use of mechanical support in single ventricle patients and the use of sacubitril/valsartan and SGLT2 inhibitors in the pediatric population. The problem of the highly sensitized transplant recipient remains, although novel therapeutics have been added to our toolbox of options to maintain healthy allograft function. Ongoing research aims to further enhance our understanding and management of pediatric heart failure, emphasizing the need for continued innovation in this complex field.

Vitrectomy as an Adjunct to Treat-and-Extend Anti-VEGF Injections for Diabetic Macular Edema

There are reported benefits from vitrectomy for diabetic macular edema (DME); however, data precede anti-vascular endothelial growth therapy (VEGF) therapy, supporting a need to assess the current role of vitrectomy. To determine rates of recruitment and efficacy outcomes of vitrectomy plus internal limiting membrane (ILM) peeling adjunctive to treat-and-extend (T&E) anti-VEGF injections for diabetic macular edema (DME). This was a single-masked, multicenter randomized clinical trial at 21 sites in the United Kingdom from June 2018 to January 2021, evaluating single eyes of treatment-naive patients with symptomatic vision loss from DME for less than 1 year. Inclusion criteria were best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score greater than 35 (approximate Snellen equivalent, 20/200 or better) and central subfield thickness (CST) greater than 350 μm after 3 monthly intravitreal injections of ranibizumab or aflibercept. Data analysis was performed in July 2023. Patients were randomized 1:1 into vitrectomy plus standard care or standard care alone and further stratified into groups with vs without vitreomacular interface abnormality. Both groups received a T&E anti-VEGF injection regimen with aflibercept, 2 mg, or ranibizumab, 0.5 mg. The vitrectomy group additionally underwent pars plana vitrectomy with epiretinal membrane or ILM peel within 1 month of randomization. Rate of recruitment and distance BCVA. Secondary outcome measures were CST, change in BCVA and CST, number of injections, rate of completed follow-up, and withdrawal rate. Over 32 months, 47 of a planned 100 patients were enrolled; 42 (89%; mean [SD] age, 63 [11] years; 26 [62%] male) completed 12-month follow-up visits. Baseline characteristics appeared comparable between the control (n = 23; mean [SD] age, 66 [10] years) and vitrectomy (n = 24; mean [SD] age, 62 [12] years) groups. No difference in 12-month BCVA was noted between groups, with a 12-month median (IQR) BCVA letter score of 73 (65-77) letters (Snellen equivalent, 20/40) in the control group vs 77 (67-81) letters (Snellen equivalent, 20/32) in the vitrectomy group (difference, 4 letters; 95% CI, -8 to 2; P = .24). There was no difference in BCVA change from baseline (median [IQR], -1 [-3 to 2] letters for the control group vs -2 [-8 to 2] letters for the vitrectomy group; difference, 1 letter; 95% CI, -5 to 7; P = .85). No difference was found in CST changes (median [IQR], -94 [-122 to 9] μm for the control group vs -32 [-48 to 25] μm for the vitrectomy group; difference, 62 μm; 95% CI, -110 to 11; P = .11). Enrollment goals could not be attained. However, with 47 participants, evidence did not support a clinical benefit of vitrectomy plus ILM peeling as an adjunct to a T&E regimen of anti-VEGF therapy for DME. isrctn.org Identifier: ISRCTN59902040.