ESHO 1-85. Hyperthermia as an adjuvant to radiation therapy in the treatment of locally advanced breast carcinoma. A randomized multicenter study by the European Society for Hyperthermic Oncology.

BACKGROUND: The ESHO protocol 1-85 is a multicenter randomized trial initiated by the European Society for Hyperthermic Oncology with the aim to investigate the value of hyperthermia (HT) as an adjuvant to radiotherapy (RT) in treatment of locally advanced breast carcinoma. The trial is one of the largest studies of hyperthermia in radiotherapy but has not been previously published. PATIENTS AND METHODS: Between February 1987 and November 1993, 155 tumors in 151 patients were included. Tumors were stratified according to institution and size (T2-3/T4) and randomly assigned to receive radiotherapy alone (2 Gy/fx, 5 fx/wk) to a total dose of 65-70 Gy, incl. boost, or the same radiotherapy followed once weekly by hyperthermia (aimed for 43 °C for 60 min). Radiation was given with high voltage photons or electrons. The primary endpoint was persistent complete response (local control) in the treated area. RESULTS: A total of 146 tumors in 142 patients were evaluable, with a median observation time of 19 (range 1-134) months. Seventy tumors were randomized to RT alone and 76 to RT + HT. Size was T4 in 92, and T2-3 in 54 tumors, respectively. The compliance to RT was good with all but 4 patients fulfilling the planned RT treatment. The tolerance to HT was fair, but associated with moderate to severe pain and discomfort in 15 % of the treatments. In 84 % of the heated patients a least one heat treatment achieved the target temperature, but the temperature variation was large. Addition of heat did not significantly increase the acute nor late radiation reactions. Overall, the 5-year actuarial local failure rate was 57 %. Univariate analysis showed a significant influence of hyperthermia (RT alone 68 % versus RT + HT 50 %, p = 0.04, and T-size (T4 75 % versus T2-3 36 %, p < 0.01). A Cox multivariate analysis showed the same factors to be the only significant prognostic parameters: hyperthermia (HR: 0.61 [0.38-0.98], and small tumor strata (HR: 0.46 [0.26-0.92]. Consequentially, more patients given RT + HT (36 %) survived without disease (DFS), than after RT alone (19 %), p = 0.021) CONCLUSION: A randomized multicenter trial investigating the addition of a weekly hyperthermia treatment to radiotherapy of patients with locally advanced breast cancer significantly enhanced the 5-year tumor control and yielded more patients surviving free from cancer. The results substantiate the potential clinical benefit of hyperthermic oncology.

Association of mandibular canine impaction and anatomical factors: A multicentre retrospective panoramic study in Latin America.

INTRODUCTION: Mandibular canine impaction is infrequent in dental eruption anomalies and treatment is very challenging. The aim of this multicenter retrospective panoramic study in Latin America was to evaluate panoramic radiographic imaging characteristics of mandibular canine impaction (impaction area, mandibular base contact, transmigration, impaction height and sex) and their associations. MATERIAL AND METHODS: This cross-sectional study evaluated 212 digital panoramic radiographs from three radiological centres in Tingo Maria (Peru), Bogota and Tunja (Colombia). The study included children of both sexes with impacted mandibular canines. Mandibular alpha angle, contact with mandibular basal bone (MBB), impacted sector according to 10 sectors with an adaptation of the Ericson and Kurol method, presence of transmigration and the impacted height were measured and the relationship among these measures was analyzed. Fisher's exact test, Chi-square and binary logistic regression were used. (P<0.05). RESULTS: The mandibular canine impaction showed contact with the MBB (32.08%), dental transmigration (36.79%), mainly located at an apical (40.09%) and sub-apical (36.79%) level. Transmigration mainly occurred in sectors 6 (33.30%) and 10 (25.60%) (P<0.001). It was found that for each year of increase in age, the possibility of contact with the MBB decreased (ß=0.89, P=0.010), and as the alpha angle increased by one degree the probability of contact with the MBB decreased (ß=0.97, P=0.001) and the probability of transmigration increased (ß=1.05, P<0.001). CONCLUSIONS: One third of the impacted canines were in contact with the MBB, while another third presented dental transmigration and were mainly located apically and subapically of the incisor roots. These imaging features should be taken into account when planning orthodontic treatment.

Designing multicenter individually randomized group treatment trials.

In an individually randomized group treatment (IRGT) trial, participant outcomes can be positively correlated due to, for example, shared therapists in treatment delivery. Oftentimes, because of limited treatment resources or participants at one location, an IRGT trial can be carried out across multiple centers. This design can be subject to potential correlations in the participant outcomes between arms within the same center. While the design of a single-center IRGT trial has been studied, little is known about the planning of a multicenter IRGT trial. To address this gap, this paper provides analytical sample size formulas for designing multicenter IRGT trials with a continuous endpoint under the linear mixed model framework. We found that accounting for the additional center-level correlation at the design stage can lead to sample size reduction, and the magnitude of reduction depends on the amount of between-therapist correlation. However, if the variance components of therapist-level random effects are considered as input parameters in the design stage, accounting for the additional center-level variance component has no impact on the sample size estimation. We presented our findings through numeric illustrations and performed simulation studies to validate our sample size procedures under different scenarios. Optimal design configurations under the multicenter IRGT trials have also been discussed, and two real-world trial examples are drawn to illustrate the use of our method.

Historia de la hipertensión arterial: revisión narrativa / History of high blood pressure: narrative review

Introducción: La medición de la presión arterial es uno de los procedimientos más realizados en la práctica clínica. La presente revisión narrativa pretende sintetizar los aspectos relevantes que rodearon la definición de la hipertensión arterial, el recorrido histórico del tratamiento de esta y el aporte de los estudios a la disminución de la mortalidad por enfermedad cardiovascular en el tiempo. Metodología: Revisión narrativa de la historia de la hipertensión arterial, desde el reconocimiento de la presión arterial alta como un factor asociado al riesgo cardiovascular y la evolución histórica del tratamiento hasta los hallazgos significativos del estudio SPRINT, publicado en 2015. Resultados: Hasta hace aproximadamente 50 años la hipertensión arterial era conocida como una patología esencial, es decir, esta condición no siempre fue considerada como una enfermedad. El descubrimiento de la presión sanguínea ha sido atribuido a Stephen Hales, poeta, orador y sacerdote nacido en Inglaterra. La primera medición de la presión sanguínea e incidentalmente de la presión del pulso la realizó en 1733 en animales. Se describe el origen de la presión arterial, la hipertensión arterial, el camino recorrido para el reconocimiento de esta condición como enfermedad y posteriormente su tratamiento, hasta llegar al estudio SPRINT en 2015, el cual fue contundente en demostrar el beneficio de reducir la cifra de presión arterial sistólica objetivo en una población no diabética. Conclusión: Los resultados de esta revisión narrativa exponen cómo el reconocimiento de la presión arterial alta como un factor de riesgo cardiovascular permitió el avance en la investigación científica para determinar el tratamiento y las cifras de presión arterial que favorecen la reducción de la mortalidad y morbilidad por esta causa.

Background: Blood pressure measurement is one of the most performed procedures in clinical practice. This narrative review aims to expose the relevant aspects surrounding the definition of arterial hypertension, the historical path of its treatment, and the contribution of studies to the decrease in mortality due to cardiovascular disease over time. Methodology: Narrative review of the history of arterial hypertension from recognizing high blood pressure as a factor associated with cardiovascular risk to the historical evolution of treatment up to the SPRINT study published in 2015. Results: Until about 50 years ago, arterial hypertension was known as an essential pathology; this condition was not always considered a disease. The discovery of blood pressure has been attributed to Stephen Hales, a poet, orator and priest born in England. The first measurement of blood pressure and incidentally pulse pressure was made in 1733 in animals. The origin of blood pressure, arterial hypertension, and the path travelled for recognizing this condition as a disease and later its treatment until reaching the SPRINT study in 2015, which demonstrated the benefit of reducing the target systolic blood pressure figure in a non-diabetic population. Conclusion: This narrative review demonstrates that the recognition of high blood pressure as a cardiovascular risk factor allowed progress in scientific research to determine the treatment and blood pressure figures that favor the reduction of mortality and morbidity from this cause.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Best (but oft forgotten) practices: Efficient sample sizes for commonly used trial designs.

Designing studies such that they have a high level of power to detect an effect or association of interest is an important tool to improve the quality and reproducibility of findings from such studies. Since resources (research subjects, time, and money) are scarce, it is important to obtain sufficient power with minimum use of such resources. For commonly used randomized trials of the treatment effect on a continuous outcome, designs are presented that minimize the number of subjects or the amount of research budget when aiming for a desired power level. This concerns the optimal allocation of subjects to treatments and, in case of nested designs such as cluster-randomized trials and multicenter trials, also the optimal number of centers versus the number of persons per center. Since such optimal designs require knowledge of parameters of the analysis model that are not known in the design stage, in particular outcome variances, maximin designs are presented. These designs guarantee a prespecified power level for plausible ranges of the unknown parameters and minimize research costs for the worst-case values of these parameters. The focus is on a 2-group parallel design, the AB/BA crossover design, and cluster-randomized and multicenter trials with a continuous outcome. How to calculate sample sizes for maximin designs is illustrated for examples from nutrition. Several computer programs that are helpful in calculating sample sizes for optimal and maximin designs are discussed as well as some results on optimal designs for other types of outcomes.

Comparing high-dose dual therapy with bismuth-containing quadruple therapy for the initial eradication of Helicobacter pylori infection on Hainan Island: A randomized, multicenter clinical trial.

BACKGROUND: Traditional bismuth-containing quadruple therapy, as a first-line eradication treatment for Helicobacter pylori (H. pylori), has several disadvantages, including drug side effects, low medication adherence, and high costs. Trials of high-dose dual treatment have demonstrated its advantages, which include good safety and adherence profiles. In this study, we investigated the efficacy, safety, and compliance of a high-dose dual therapy when compared with bismuth-based quadruple treatment for the initial eradication of H. pylori infection on Hainan Island, China. METHODS: We randomized 846 H. pylori-infected patients into two groups. A bismuth-containing quadruple therapy group was administered the following: esomeprazole 20 mg, amoxicillin 1000 mg, and clarithromycin 500 mg twice daily, and colloidal bismuth pectin in suspension 150 mg three times/day for 2 weeks. A high-dose dual therapy group was administered the following: esomeprazole 20 mg four times/day and amoxicillin 1000 mg three times/day for 2 weeks. Patients were given a 13C urea breath test at 4 weeks at treatment end. Adverse effects and compliance were evaluated at follow-up visits. RESULTS: Eradication rates in the high-dose dual therapy group were: 90.3% (381/422, 95% confidence interval [CI]: 87.1%-92.9%) in intention-to-treat (ITT) and 93.6% (381/407, 95% CI: 90.8%-95.8%) in per-protocol (PP) analyses. Eradication rates were 87.3% in ITT (370/424, 95% CI: 83.7%-90.3%) and 91.8% in PP analyses (370/403, 95% CI: 88.7%-94.3%) for quadruple therapy, with no statistical differences (P = 0.164 in ITT and P = 0.324 in PP analyses). Adverse effects were 13.5% (55/407) in the dual group and 17.4% (70/403) in the quadruple group (P = 0.129). Compliance was 92.4% (376/407) in the dual group and 86.6% (349/403) in the quadruple group (P = 0.007). CONCLUSIONS: High-dose dual therapy had high eradication rates comparable with bismuth-based quadruple treatment, with no differences in adverse effects, however higher adherence rates were recorded.

Agreement of Clinician-Administered and Modified Parent-Administered House-Brackmann Scales in Children with Bell's Palsy.

Objective: Currently there is no parent administered scale for facial nerve function in children. We set out to assess the agreement between a newly developed parent-administered modified version of the House-Brackmann (HB) scale and the standard clinician-administered HB scale in children with Bell's palsy. Study Design: Secondary analysis of a triple-blind, randomized, placebo-controlled trial of corticosteroids to treat idiopathic facial paralysis (Bell's palsy) in children (6 months to <18 years). Setting: Multicenter study at pediatric hospitals with recruitment in emergency departments. Methods: Children were recruited within 72 hours of symptom onset and assessed using the clinician-administered and the parent-administered modified HB scales at baseline, and at 1, 3, and 6 months until recovered. Agreement between the 2 scales was assessed using intraclass coefficient (ICC) and a Bland-Altman plot. Results: Data were available for 174 of the 187 children randomized from at least 1 study time point. The mean ICC between clinician and parent HB scores across all time points was 0.88 (95% confidence interval, CI: 0.86, 0.90). The ICC for the data collected at baseline was 0.53 (95% CI: 0.43, 0.64), at 1 month was 0.88 (95% CI: 0.84, 0.91), at 3 months was 0.80 (95% CI: 0.71, 0.87) and at 6 months was 0.73 (95% CI: 0.47, 0.89). A Bland-Altman plot indicated a mean difference between the 2 scores (clinician-reported minus parent-reported) of only -0.07 (95% limits of agreement -1.37 to 1.23). Conclusion: There was good agreement between the modified parent-administered and the clinician-administered HB scales.

Contemporary Management and Outcomes of Injuries to the Inferior Vena Cava: A Prospective Multicenter Trial From PROspective Observational Vascular Injury Treatment.

INTRODUCTION: Injuries to the inferior vena cava (IVC), while uncommon, have a high mortality despite modern advances. The goal of this study is to describe the diagnosis and management in the largest available prospective data set of vascular injuries across anatomic levels of IVC injury. METHODS: The American Association for the Surgery of Trauma PROspective Observational Vascular Injury Treatment (PROOVIT) registry was queried from November 2013 to January 2019. Demographics, diagnostic modalities, injury patterns, and management strategies were recorded and analyzed. Comparisons between anatomic levels were made using non-parametric Wilcoxon rank-sum statistics. RESULTS: 140 patients from 19 institutions were identified; median age was 30 years old (IQR 23-41), 75% were male, and 62% had penetrating mechanism. The suprarenal IVC group was associated with blunt mechanism (53% vs 32%, P = .02), had lower admission systolic blood pressure, pH, Glasgow Coma Scale (GCS), and higher ISS and thorax and abdomen AIS than the infrarenal injury group. Injuries were managed with open repair (70%) and ligation (30% overall; infrarenal 37% vs suprarenal 13%, P = .01). Endovascular therapy was used in 2% of cases. Overall mortality was 42% (infrarenal 33% vs suprarenal 66%, P<.001). Among survivors, there was no difference in first 24-hour PRBC transfusion requirement, or hospital or ICU length of stay. CONCLUSIONS: Current PROOVIT registry data demonstrate continued use of ligation extending to the suprarenal IVC, limited adoption of endovascular management, and no dramatic increase in overall survival compared to previously published studies. Survival is likely related to IVC injury location and total injury burden.

Wound drain in lumbar arthrodesis for degenerative disease: an experimental, multicenter, randomized controlled trial.

INTRODUCTION: Drains for surgical wound management are frequently used in spine surgery. They are often used to decrease the incidence of postoperative hematoma and decrease wound tension. No conclusive evidence in the literature supports using drains to avoid complications in degenerative lumbar spine surgery. PURPOSE: We aimed to evaluate wound drains in patients with lumbar arthrodesis for degenerative disorders based on clinical outcomes, complications, hematocrit, and length of stay. STUDY DESIGN: A multicenter randomized prospective controlled clinical trial. PATIENT SAMPLE: We enrolled surgical candidates for posterior lumbar decompression and fusion surgery for degenerative disorders from October 2019 to August 2021. Patients were randomized into the drain or nondrain group at nine hospitals. The inclusion criteria were as follows: patients aged 40 to 80 years with lumbar and radicular pain, lumbar degenerative disorder, and primary surgery up to three levels. The exclusion criteria were bleeding abnormalities, bleeding >2,500 mL and dural tears. OUTCOME MEASURES: Preoperative data including Oswestry disability index (ODI), SF-36, lumbar and lower extremity visual analog scale (VAS), body mass index (BMI), hematocrit, and temperature were recorded. Surgical parameters, including surgical time, complications, estimated blood loss (EBL), postoperative temperature and hematocrit (days 1 and 4), dressing saturation, and length of hospital stay (LOS), were registered. METHODS: The two groups were assessed preoperatively, perioperatively and at the 1-month follow-up. A REDCap database was used for registration. Data analysis was performed using classical statistics. RESULTS: One hundred one patients were enrolled using the Redcap database, and 93 patients were evaluated at the final follow-up. Forty-five patients were randomized to the drain group, and 48 were randomized to the nondrain group. The preoperative characteristics were equivalent in both groups: demographic aspects, pain, ODI, SF-36, BMI, hematocrit, and spine pathology. Surgical time, EBL and complications were similar, with no difference between the groups. No difference was found between BMI and complications. No difference was observed in dressing saturation or postoperative temperature between the groups. The postoperative day 4 hematocrit was higher in the nondrain group [36.4% (32-39)] than in the drain group [34% (29.7-37.6)] without statistically differences (p=.054). The LOS was higher in the drain group [4 (3-5) days] than in the nondrain group [3 (2-4) days] (p=.007). The quality-of-life score, SF-36, was higher in the nondrain group [67.9 (53.6-79.2)] than in the drain group [56.7 (49.1-66)] (p=.043). CONCLUSIONS: Nondrain patients presented shorter LOS and better outcomes, with similar complication rates. No difference was found between BMI and complications. Based on this study, in patients undergoing primary posterior spinal decompression and fusion up to three levels for degenerative lumbar disorders, we do not recommend the use of postoperative drains.

Effectiveness of a phone-based nurse monitoring assessment and intervention for chemotherapy-related toxicity: A randomized multicenter trial.

Purpose: Anticancer treatment-related toxicities can impact morbidity and mortality, hamper the administration of treatment, worsen the quality of life and increase the burden on the healthcare system. Therefore, their prompt identification is crucial. NICSO (Italian Network for Supportive Care in Cancer) conducted a nationwide randomized trial to evaluate the role of a planned, weekly phone-based nurse monitoring intervention to prevent and treat chemotherapy, targeted therapy- and immunotherapy-related toxicities. Here, we report the results from the chemotherapy arm. Methods: This was a nationwide, randomized, open-label trial conducted among 29 Italian centers (NCT04726020) involving adult patients with breast, colon, or lung cancer and a life expectancy ≥6 months receiving adjuvant chemotherapy. Patients received either a weekly nurse monitoring phone call and an educational leaflet reporting practical advice about prevention and treatment of toxicities (experimental group) or the educational leaflet only (control group). Results: The addition of a nurse monitoring intervention may help reduce time spent with severe toxicities (grade ≥3), particularly those less frequently reported in clinical practice, such as fatigue. When considering grade 1-2 AEs, times with mild/moderate diarrhea, mucositis, fatigue and pain were shorter in the experimental arm. Time spent without AEs was significantly longer in the experimental arms for all the toxicities. The requirement for special medical attention was comparable between groups. Conclusion: This study suggests the need for implementing a better system of toxicity assessment and management for patients treated with adjuvant chemotherapy to promote effective preventive and/or therapeutic intervention against these events.

Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC-MSC-NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial.

Background: Neuromyelitis Optica spectrum disorder (NMOSD) is severe relapsing and disabling autoimmune disease of the central nervous system. Its optimal first-line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. We will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of human umbilical cord mesenchymal stem cells (hUC-MSCs) in treating NMOSD. Methods: The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. It consists of three consecutive stages. The first stage will be carried out in the leading center only and aims to evaluate the safety of hUC-MSCs. Patients will be treated with three different doses of hUC-MSCs: 1, 2, or 5 × 106 MSC/kg·weight for the low-, medium-, and high-dose group, respectively. The second and third stages will be carried out in six centers. The second stage aims to find the optimal dosage. Patients will be 1:1:1:1 randomized into the low-, medium-, high-dose group and the controlled group. The third stage aims to evaluate the effectiveness. Patients will be 1:1 randomized into the optimal dose and the controlled group. The primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index, and SF-36 scores. Endpoint events and side effects will be evaluated every 3 months for 2 years. Discussion: Although hUC-MSC has shown promising treatment effects of NMOSD in preclinical studies, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC-MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC-MSC in treating NMOSD and might be able to determine the optimal dose of hUC-MSC for NMOSD patients. Trial registration: The study was registered with the Chinese Clinical Trial Registry (CHICTR.org.cn) on 2 March 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on 16 March 2020.

Clinical Implementation and Evaluation of Three Implementation Interventions for a Family-Oriented Care for Children of Mentally Ill Parents (ci-chimps): Study Protocol for a Randomized Controlled Multicenter Trial.

Background: In Germany, approximately three million children under the age of eighteen have a mentally ill parent. These children are at an increased risk of developing a mental illness themselves (1) as well as a physical illness (2). While research has identified numerous evidence-based family-oriented interventions, little is known about how to implement such interventions effectively and efficiently in clinical practice in Germany. This implementation study (ci-chimps) evaluates three clinical implementation projects with three different implementation interventions for the optimal implementation of the tailored family-oriented preventive and therapeutic interventions in the CHIMPS-NET (children of mentally ill parents-research network) with an implementation model for children of mentally ill parents. Methods: A two-group randomized controlled multicenter trial will examine changes in family-oriented practice and aspects of implementation at baseline as well as at 12- and 24-months follow-up. The CHIMPS-Network consists of 20 clinical centers. The centers in the intervention group receive the support of all of the three implementation interventions: (1) optimal pathways to care, (2) education and a training program for professionals, and (3) systematic screening for children. The centers in the control group do not receive this specific implementation support. Discussion: While we know that children of mentally ill parents are an important target group to be addressed by preventive and therapeutic interventions, there is often a lack of structured implementation of family-oriented interventions in clinical practice in Germany. Using a randomized controlled multicenter trial design with a large and wide-ranging sample (clinics for adult psychiatry and clinics for child and adolescent psychiatry, university clinics and clinics at the real health care) will provide a robust understanding of implementing family-oriented changes in German clinical practice. Trial Registration: The CHIMPS-NET-study was registered with the German Clinical Trials Register on 2019-12-19 (DRKS00020380) and with Clinical Trials on 2020-4-30 (NCT04369625), the ci-chimps-study was registered with the German Clinical Trials Register (DRKS00026217) on 2021-08-27, the Clinical Trials registration is in review process.

Efficacy of combined orthokeratology and 0.01% atropine for myopia control: the study protocol for a randomized, controlled, double-blind, and multicenter trial.

BACKGROUND: The prevalence of myopia is increasing worldwide and is presently recognized as a major public health issue. Researchers and clinicians have been devoted in exploring appropriate clinical interventions to slow its progression in children. Mounting publications have proven that both orthokeratology (OK lens) and 0.01% atropine eyedrop can retard eye growth and myopia progression. However, it remains unclear whether the combination of OK lens and 0.01% atropine has the potential to magnify the effectiveness of myopia control. The present study aims to compare the myopia control efficiency of the combination of OK lens and 0.01% atropine with the monotherapy of OK lens in children. METHODS: The present study is a randomized, controlled, double-blind and multicenter clinical trial. A total of 96 children within 8-12 years old were recruited. These participants are treated with the combination of OK lens and 0.01% atropine eyedrop or the combination of OK lens and placebo eyedrop. Each group includes 48 participants. The inclusion criteria are as follows: myopia between - 1.00 and - 4.00 D in either eye and astigmatism of no more than 1.50 D. The follow-up time points will be 1, 6, 12, 18, and 24 months from randomization. The primary outcome is determined by the difference in axial length of the two groups, between the baseline and 24 months from randomization. DISCUSSION: The present randomized, controlled clinical trial would indicate the additive effects of the combination of OK lens and 0.01% atropine, and the extent of these effects, in retarding myopia progression and axial elongation in children. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), ChiCTR1800018419 . Registered on 17 September 2018. http://www.chictr.org.cn/showproj.aspx?proj=29216.

Joining Forces: How to Coordinate Large, Multicenter Randomized Trials.

This article details the pros, cons, challenges/pitfalls, and elements required for the successful conduct of multicenter randomized trials, with specific focus on trials related to pleural diseases. Several networks dedicated to the multicenter study of important pleural conditions have developed, yielding practice-changing studies in pleural disease. This review describes the importance of multicenter trials, major elements required for the conduct of such trials, and lessons learned from the ongoing development of the Interventional Pulmonary Outcomes Group, a consortium of interventional pulmonologists dedicated to advancing diagnostic and management strategies in pleural, pulmonary parenchymal, and airway disease by generating high-quality multicenter evidence.

Clinical effectiveness of patient-oriented depression feedback in primary care: The empirical method of the GET.FEEDBACK.GP multicenter randomized controlled trial.

GET.FEEDBACK.GP1 is a multicenter randomized controlled trial testing the efficacy of patient-oriented depression feedback in primary care. This paper describes the complex methods and procedures of the trial. The primary outcome is depression severity six months after feedback, and we vary who is the target of the feedback as follows: no one receives feedback, only general practitioners receive feedback, and both patients and general practitioners receive feedback. The procedure includes a baseline assessment in primary care practices and three telephone follow-up interviews after one, six, and twelve months. The patients completed a baseline assessment, which determined their depression severity. Those with at least a moderate depression severity (PHQ-95 ≥ 10) were randomly allocated to three groups stratified by depression severity. A standardized mean difference of d = 0.25 with power 1 - ß = 0.80 required a total sample size of N = 699. The patients provided responses regarding the primary and secondary outcomes at follow-up. The extensive planning for GET.FEEDBACK.GP involved experts from diverse medical specialties and external corporations. Of particular importance were (a) blinding in the study inclusion and random assignment with data capture software, (b) representative and unbiased patient selection in practice waiting rooms, (c) a data management and safety plan supplied by a specialized trial center, and (d) the use of participant pseudonyms supplied by a specialized service (Mainzelliste). The data collection started in July 2019 and will continue until June 2022. Five university study centers in Germany are participating in the trial.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Factors Affecting Image Quality and Lesion Evaluability in Breast Diffusion-weighted MRI: Observations from the ECOG-ACRIN Cancer Research Group Multisite Trial (A6702).

OBJECTIVE: The A6702 multisite trial confirmed that apparent diffusion coefficient (ADC) measures can improve breast MRI accuracy and reduce unnecessary biopsies, but also found that technical issues rendered many lesions non-evaluable on diffusion-weighted imaging (DWI). This secondary analysis investigated factors affecting lesion evaluability and impact on diagnostic performance. METHODS: The A6702 protocol was IRB-approved at 10 institutions; participants provided informed consent. In total, 103 women with 142 MRI-detected breast lesions (BI-RADS assessment category 3, 4, or 5) completed the study. DWI was acquired at 1.5T and 3T using a four b-value, echo-planar imaging sequence. Scans were reviewed for multiple quality factors (artifacts, signal-to-noise, misregistration, and fat suppression); lesions were considered non-evaluable if there was low confidence in ADC measurement. Associations of lesion evaluability with imaging and lesion characteristics were determined. Areas under the receiver operating characteristic curves (AUCs) were compared using bootstrapping. RESULTS: Thirty percent (42/142) of lesions were non-evaluable on DWI; 23% (32/142) with image quality issues, 7% (10/142) with conspicuity and/or localization issues. Misregistration was the only factor associated with non-evaluability (P = 0.001). Smaller (≤10 mm) lesions were more commonly non-evaluable than larger lesions (p <0.03), though not significant after multiplicity correction. The AUC for differentiating benign and malignant lesions increased after excluding non-evaluable lesions, from 0.61 (95% CI: 0.50-0.71) to 0.75 (95% CI: 0.65-0.84). CONCLUSION: Image quality remains a technical challenge in breast DWI, particularly for smaller lesions. Protocol optimization and advanced acquisition and post-processing techniques would help to improve clinical utility.

Actual versus ideal body weight dosing of sugammadex in morbidly obese patients offers faster reversal of rocuronium- or vecuronium-induced deep or moderate neuromuscular block: a randomized clinical trial.

BACKGROUND: This randomized, double-blind trial evaluated sugammadex-mediated recovery time from rocuronium- or vecuronium-induced moderate (M-) or deep (D-) neuromuscular block in morbidly obese adults dosed by actual (ABW) or ideal body weight (IBW). METHODS: Adults with BMI ≥40 kg/m2 were randomized to 1 of 5 groups: M-neuromuscular block, sugammadex 2 mg/kg ABW; M-neuromuscular block, sugammadex 2 mg/kg IBW; M-neuromuscular block, neostigmine 5 mg, and glycopyrrolate 1 mg; D-neuromuscular block, sugammadex 4 mg/kg ABW; or D-neuromuscular block, sugammadex 4 mg/kg IBW. Supramaximal train of four (TOF) stimulation of the ulnar nerve (TOF-watch SX®) monitored recovery. Primary endpoint was time to TOF ratio ≥ 0.9 for ABW and IBW groups pooled across neuromuscular blocking agent (NMBA)/blocking depth, analyzed by log-rank test stratified for agent and depth. Prespecified safety outcomes included treatment-emergent bradycardia, tachycardia, and other arrhythmias, and adjudicated hypersensitivity and anaphylaxis. RESULTS: Of 207 patients randomized, 188 received treatment (28% male, BMI 47 ± 5.1 kg/m2, age 48 ± 13 years). Recovery was 1.5 min faster with ABW vs IBW dosing. The sugammadex 2 mg/kg groups recovered 9-fold faster [time 0.11-fold, 95% CI 0.08 to 0.14] than the neostigmine group. ABW (5.3%) and IBW (2.7%) groups had similar incidences of recovery time > 10 min (95% CI of difference: - 4.8 to 11.0%); 84% for neostigmine group. Re-curarization occurred in one patient each in the 2 mg/kg IBW and neostigmine groups. Prespecified safety outcomes occurred with similar incidences. CONCLUSIONS: ABW-based sugammadex dosing yields faster reversal without re-curarization, supporting ABW-based sugammadex dosing in the morbidly obese, irrespective of the depth of neuromuscular block or NMBA used. TRIAL REGISTRATION: Registered on November 17, 2017, at ClinicalTrials.gov under number NCT03346070 .

Treatment of HBV Cirrhosis with Fuzheng Huayu Tablet () and Entecavir: Design of a Randomized, Double-Blind, Parallel and Multicenter Clinical Trial / 中国结合医学杂志

BACKGROUND@#Antiviral therapy can lead to regression of fibrosis in chronic hepatitis B (CHB), but it has a limited effect on cirrhosis. Chinese medicines (CMs), particularly Fuzheng Huayu Tablet (, FZHY), have an antifibrotic effect in patients with CHB.@*OBJECTIVE@#To observe the safety and efficacy of adjunctive FZHY in patients with hepatitis B virus (HBV) cirrhosis, this study was designed as a randomized, placebo-controlled, double-blind, parallel assignment, multicenter trial at 20 centers in China. The total 700 naive patients will be enrolled with compensate cirrhosis due to HBV, and randomly assigned into 2 groups, receiving entecavir (0.5 mg, daily) and FZHY placebo (1.6 g, 3 times a day), or entecavir (0.5 mg, daily) and FZHY (1.6 g, 3 times a day), respectively. The primary endpoint was histological improvement at week 48. The secondary outcome is the decline values of liver fibrosis using the noninvasive methods from baseline to week 48 in each arm of the study. Adverse events such as stomach upset, headache, fatigue, dizziness, nausea will be strictly recorded.@*DISCUSSION@#Through this study, we hope to generate a solid evidence for the therapeutic strategy of HBV cirrhosis with a combination of anti-viral such as ETV and anti-fibrotic herbal product such as FZHY. Protocol version: Version 1.3, Date: 2014.12.4.@*TRIAL REGISTRATION NUMBER@#NCT02241590.