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The role of Helicobacter pylori (H. pylori) screening and eradication on reducing upper gastrointestinal bleeding (UGIB) complications after acute myocardial infarction (MI) is uncertain. The HELicobacter pylori screening to prevent gastrointestinal bleeding in patients with acute MI (HELP-MI SWEDEHEART) trial aims to determine whether systematic H. pylori screening compared to usual care reduces UGIB, mortality, and cardiovascular outcomes after MI. A cluster randomized, crossover, registry-based clinical trial using SWEDEHEART as trial platform for study population definition and source for data collection in combination with nationwide Swedish health data registries. Thirty-five Swedish hospitals, organized into 18 clusters based on percutaneous coronary intervention networks, were randomized to either routine H. pylori screening for adults with acute type-1 MI or usual care. After 1 year, a 2-month blanking period was followed by a crossover to the alternate allocation for 1 year. The trial enrolment was concluded after one additional year of registry-based follow-up. The primary endpoint is UGIB. Secondary endpoints include all-cause death, cardiovascular death, readmission for MI, stroke, or heart failure. Endpoints will be reported combined (Net Adverse Clinical Events; Major Adverse Cardiac or Cerebrovascular Events) and separately. The primary analysis will include all available follow-up time corresponding to a maximum follow-up time of 3 years and 2 months. HELP-MI SWEDEHEART aims to determine the utility of routine H. pylori screening to reduce UGIB and improve cardiovascular outcomes after MI. By integrating national registry follow-up data with a pragmatic trial design, it has the potential to provide evidence for the effect of the implementation of routine H. pylori screening as part of acute MI care. ClinicalTrials.gov, NCT05024864.

Background The positive impact of fundamental movement skills on physical activity in young children has been shown in previous studies, but little is known about the association between fundamental movement skills and cognitive development in young children. This study protocol describes a 10-month, four-arm cluster randomized crossover trial evaluating the effectiveness of the “Advancing Movement and Physical Literacy Earlier” (AMPLE) program in promoting physical literacy and executive function among 3-5-year-old children in 18 Hong Kong kindergartens. Methods This program integrates fundamental movement skills training with cognitively challenging activities. Four classes per kindergarten will be randomly assigned to one of four conditions: (1) combined fundamental movement skills and cognitive challenge, (2) sedentary with cognitive challenge, (3) fundamental movement skills alone, or (4) sedentary without cognitive challenges. Each condition involves 30-minute sessions, three times per week, with a six-week washout period between the three-week intervention phases. The research team will use multiple objective measures and self-report measures, covering the elements and domains of the assessment of physical literacy and executive function. Three follow-up tests will be conducted within six months after the end of the intervention to evaluate the long-term impact of the program. Intervention implementation and fidelity will be assessed through focus group interviews with teachers and principals. Discussion The “AMPLE” program aims to strengthen the theoretical understanding of motor‒cognitive connections, inform early childhood education practices, and contribute to public health strategies promoting lifelong physical activity. Ultimately, the program seeks to provide evidence-based interventions for fostering holistic child development and establishing healthy lifestyle habits. Trial registration The protocol has been registered at Chinese Clinical Trial Registry on August 27, 2025, under identifier ChiCTR2500108295.

To assess the design and statistical methods used in cluster-randomized crossover (CRXO) trials. We undertook a systematic review of CRXO trials. Searches of MEDLINE, EMBASE, and CINAHL Plus; and citation searches of CRXO methodological articles were conducted to December 2014. We extracted data on design characteristics and statistical methods for sample size, data analysis, and handling of missing data. Ninety-one trials including 139 end point analyses met the inclusion criteria. Trials had a median of nine clusters [interquartile range (IQR), 4–21] and median cluster-period size of 30 individuals (IQR, 14–77); 58 (69%) trials had two periods, and 27 trials (30%) included the same individuals in all periods. A rationale for the design was reported in only 25 trials (27%). A sample size justification was provided in 53 (58%) trials. Only nine (10%) trials accounted appropriately for the design in their sample size calculation. Ten of the 12 cluster-level analyses used a method that accounted for the clustering and multiple-period aspects of the design. In contrast, only 4 of the 127 individual-level analyses used a potentially appropriate method. There is a need for improved application of appropriate analysis and sample size methods, and reporting, in CRXO trials.

Background Femoral shaft fractures are common severe injuries that carry an elevated risk of operative complications, including femoral malrotation, neurologic, and vascular injuries. There is no definitive research comparing two commonly used surgical tables and patient positions in aiding with both reduction and fixation of femoral shaft fractures. The objective of this pilot trial was to test the feasibility of a cluster randomized crossover trial that assesses the comparative effectiveness of supine positioning on a fracture table versus lateral positioning on a radiolucent table for antegrade intramedullary fixation of femoral shaft fractures. Methods Three orthopaedic trauma centres participated in this pilot trial. Each clinical site was randomized to a starting position, crossed over to the other treatment after 2 months, and alternated treatments in this fashion for the length of the trial. During the enrolment phase, we assessed compliance, enrolment rates, participant follow-up, and accurate documentation of the primary clinical outcome. The feasibility success criteria were: (1) 90% enrolment of eligible participants during enrolment phases; (2) 90% compliance with the trial interventions as per the cluster randomization crossover scheme; (3) timely collection of primary outcome data (i.e., within 6 weeks of fracture) in 95% of participants, (4) 90% completion of participant follow-up data; and (5) definition of the primary outcome as a categorical variable with an appropriate threshold value. Feasibility outcomes were summarized using descriptive statistics reported as means (standard deviation) or medians (first quartile, third quartile) for continuous variables depending on their distribution and counts (percentage) for categorical variables. Results All five of the criteria for feasibility were met. Of the 110 eligible patients identified at the three clinical sites, 101 (91.8%) were enroled over a 2.5-year period and 95/101 (94.1%) received the correct cluster-assigned treatment. The primary outcome (malrotation measured on the CT) was accurately documented within 6 weeks of fracture for 98% of participants (99/101) with 93 participants completing the final follow-up (92.0%). Lastly, the trial data informed an appropriate threshold, a malrotation cut off of 15°, for the primary outcome in the definitive trial. Conclusions These results confirm the feasibility of a definitive trial comparing patient positioning during intramedullary fixation of femoral shaft fractures using a cluster randomized crossover trial design. However, due to funding limitations, a slower than anticipated enrolment, and concerns with surgical equipoise, this trial did not proceed to the definitive phase. Trial registration ClincialTrials.gov NCT03868280.

Background: Chlamydia trachomatis , Neisseria gonorrhoeae , Trichomonas vaginalis and bacterial vaginosis have been associated with preterm birth and low birth weight, and are highly prevalent among pregnant women in many low- and middle-income settings. There is conflicting evidence on the potential benefits of screening and treating these infections in pregnancy. Newly available diagnostic technologies make it possible, for the first time, to conduct definitive field trials to fill this knowledge gap. The primary aim of this study is to evaluate whether antenatal point-of-care testing and immediate treatment of these curable sexually transmitted and genital infections (STIs) leads to reduction in preterm birth and low birth weight. Methods : The Women and Newborn Trial of Antenatal Interventions and Management (WANTAIM) is a cluster-randomised crossover trial in Papua New Guinea to compare point-of-care STI testing and immediate treatment with standard antenatal care (which includes the WHO-endorsed STI ‘syndromic’ management strategy based on clinical features alone without laboratory confirmation). The unit of randomisation is a primary health care facility and its catchment communities. The primary outcome is a composite measure of two events: the proportion of women and their newborns in each trial arm, who experience either preterm birth (delivery <37 completed weeks of gestation as determined by ultrasound) and/or low birth weight (<2500 g measured within 72 hours of birth). The trial will also evaluate neonatal outcomes, as well as the cost-effectiveness, acceptability and health system requirements of this strategy, compared with standard care. Conclusions: WANTAIM is the first randomised trial to evaluate the effectiveness, cost-effectiveness, acceptability and health system requirements of point-of-care STI testing and treatment to improve birth outcomes in high-burden settings. If the intervention is proven to have an impact, the trial will hasten access to these technologies and could improve maternal and neonatal health in high-burden settings worldwide. Registration: ISRCTN37134032 .

Background The cluster randomised crossover (CRXO) design is gaining popularity in trial settings where individual randomisation or parallel group cluster randomisation is not feasible or practical. Our aim is to stimulate discussion on the content of a reporting guideline for CRXO trials and to assess the reporting quality of published CRXO trials. Methods We undertook a systematic review of CRXO trials. Searches of MEDLINE, EMBASE, and CINAHL Plus as well as citation searches of CRXO methodological articles were conducted to December 2014. Reporting quality was assessed against both modified items from 2010 CONSORT and 2012 cluster trials extension and other proposed quality measures. Results Of the 3425 records identified through database searching, 83 trials met the inclusion criteria. Trials were infrequently identified as “cluster randomis(z)ed crossover” in title ( n  = 7, 8%) or abstract ( n  = 21, 25%), and a rationale for the design was infrequently provided ( n  = 20, 24%). Design parameters such as the number of clusters and number of periods were well reported. Discussion of carryover took place in only 17 trials (20%). Sample size methods were only reported in 58% ( n  = 48) of trials. A range of approaches were used to report baseline characteristics. The analysis method was not adequately reported in 23% ( n  = 19) of trials. The observed within-cluster within-period intracluster correlation and within-cluster between-period intracluster correlation for the primary outcome data were not reported in any trial. The potential for selection, performance, and detection bias could be evaluated in 30%, 81%, and 70% of trials, respectively. Conclusions There is a clear need to improve the quality of reporting in CRXO trials. Given the unique features of a CRXO trial, it is important to develop a CONSORT extension. Consensus amongst trialists on the content of such a guideline is essential.

A challenge in achieving the malaria-elimination target in the Greater Mekong Subregion, including Thailand, is the predominance of Plasmodium vivax malaria, which has shown extreme resilience to control measures. This proof-of-concept study aimed to provide evidence for implementing primaquine mass drug administration (pMDA) as a strategy for P. vivax elimination in low-endemicity settings. The study employed a mixed-methods trial to thoroughly evaluate the effectiveness, safety, acceptability, and community engagement of pMDA. The quantitative part was designed as a 2-period cluster-crossover randomized controlled trial. The intervention was pMDA augmented to the national prevention and control standards with directly observed treatment (DOT) by village health volunteers. The qualitative part employed in-depth interviews and brainstorming discussions. The study involved 7 clusters in 2 districts of 2 southern provinces in Thailand with persistently low P. vivax transmission. In the quantitative part, 5 cross-sectional blood surveys were conducted in both the pMDA and control groups before and 3 months after pMDA. The effectiveness of pMDA was determined by comparing the proportions of P. vivax infections per 1000 population between the 2 groups, with a multilevel zero-inflated negative binomial model adjusted for cluster and time as covariates and the interaction. The safety data comprised adverse events after drug administration. Thematic content analysis was used to assess the acceptability and engagement of stakeholders. In the pre-pMDA period, the proportions of P. vivax infections in the pMDA (n=1536) and control (n=1577) groups were 13.0 (95% CI 8.2-20.4) and 12.0 (95% CI 7.5-19.1), respectively. At month 3 post-pMDA, these proportions in the pMDA (n=1430) and control (n=1420) groups were 8.4 (95% CI 4.6-15.1) and 5.6 (95% CI 2.6-11.5), respectively. No statistically significant differences were found between the groups. The number of malaria cases reduced in all clusters in both groups, and thus, the impact of pMDA was inconclusive. There were no major safety concerns. Acceptance among the study participants and public health care providers at local and national levels was high, and they believed that pMDA had boosted awareness in the community. pMDA was associated with high adherence, safety, and tolerability, but it may not significantly impact P. vivax transmission. As this was a proof-of-concept study, we decided not to scale up the intervention with larger clusters and samples. An alternative approach involving a targeted primaquine treatment strategy with primaquine and DOT is currently being implemented. We experienced success regarding effective health care workforces at point-of-care centers, effective collaborations in the community, and commitment from authorities at local and national levels. Our efforts boosted the acceptability of the malaria-elimination initiative. Community engagement is recommended to achieve elimination targets. Thai Clinical Trials Registry TCTR20190806004; https://www.thaiclinicaltrials.org/show/TCTR20190806004.

Background Patients are at risk of drug-related problems (DRPs) at transition points during hospitalization. The community pharmacist (CP) is often the first healthcare professional patients visit after discharge. CPs lack sufficient information about the patient and so they may be unable to identify problems in medications, which may lead to dispensing the wrong drugs or dosage, and/or giving wrong information. We aim to assess the impact of a complex intervention comprising of medication reconciliation performed at discharge by a hospital pharmacist (HP) with communication between the HP and CP on DRPs during the seven days following discharge. Methods/Design The study is a cluster randomized crossover trial involving 46 care units (each unit corresponding to a cluster) in 22 French hospitals during two consecutive 14-day periods, randomly assigned as ‘experimental’ or ‘control’ (usual care) periods. We will recruit patients older than 18 years of age and visiting the same CP for at least three months. We will exclude patients with a hospital length of stay of more than 21 days, who do not return home or those in palliative care. During the experimental period, the HP will perform a medications reconciliation that will be communicated to the patient. The HP will inform the patient’s CP about the patient’s drug therapy (modification in home medication, acute drugs prescribed, nonprescription treatments, and/or lab results). The primary outcome will be a composite outcome of any kind of drug misuse during the seven days following discharge assessed at day seven (±2) post-discharge by a pharmacist in charge of the study who will contact both patients and CPs by phone. The secondary outcome will be unplanned hospitalizations assessed by phone contact at day 35 (±5) after discharge. We plan to recruit 1,176 patients. Discussion This study will assess the impact of a reconciliation of medications performed at patient discharge followed by communication between the HP and the patient’s CP. It will allow for identifying the type of patients in France for which the intervention is most relevant. Trial registration This study was registered with ClinicalTrials.gov (number: NCT02006797 ) on 5 December 2013.

Background Patient participation is an important indicator of quality care. Currently, there is little evidence to support the belief that participation in care is possible for patients during the acute postoperative period. Previous work indicates that there is very little opportunity for patients to participate in care in the acute context. Patients require both capability, in terms of having the required knowledge and understanding of how they can be involved in their care, and the opportunity, facilitated by clinicians, to engage in their acute postoperative care. This cluster randomised crossover trial aims to test whether a multimedia intervention improves patient participation in the acute postoperative context, as determined by pain intensity and recovery outcomes. Methods/design A total of 240 patients admitted for primary total knee replacement surgery will be invited to participate in a cluster randomised, crossover trial and concurrent process evaluation in at least two wards at a major non-profit private hospital in Melbourne, Australia. Patients admitted to the intervention ward will receive the multimedia intervention daily from Day 1 to Day 5 (or day of discharge, if prior). The intervention will be delivered by nurses via an iPad™, comprising information on the goals of care for each day following surgery. Patients admitted to the control ward will receive usual care as determined by care pathways currently in use across the organization. The primary endpoint is the “worst pain experienced in the past 24 h” on Day 3 following TKR surgery. Pain intensity will be measured using the numerical rating scale. Secondary outcomes are interference of pain on activities of daily living, length of stay in hospital, function and pain following TKR surgery, overall satisfaction with hospitalisation, postoperative complications and hospital readmission. Discussion The results of this study will contribute to our understanding of the effectiveness of interventions that provide knowledge and opportunity for patient participation during postoperative in-hospital care in actually increasing participation, and the impact of participation on patient outcomes. The results of this study will also provide data about the barriers and enablers to participation in the acute care context. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12614000340639 Trial Registration date 31/03/2014.

In the cluster randomized crossover trial, a sequence of treatment conditions, rather than just one treatment condition, is assigned to each cluster. This contribution studies the optimal number of time periods in studies with a treatment switch at the end of each time period, and the optimal number of treatment switches in a trial with a fixed number of time periods. This is done for trials with a fixed number of clusters, and for trials in which the costs per cluster, subject, and treatment switch are taken into account using a budgetary constraint. The focus is on trials with a cross-sectional design where a continuous outcome variable is measured at the end of each time period. An exponential decay correlation structure is used to model dependencies among subjects within the same cluster. A linear multilevel mixed model is used to estimate the treatment effect and its associated variance. The optimal design minimizes this variance. Matrix algebra is used to identify the optimal design and other highly efficient designs. For a fixed number of clusters, a design with the maximum number of time periods is optimal and treatment switches should occur at each time period. However, when a budgetary constraint is taken into account, the optimal design may have fewer time periods and fewer treatment switches. The Shiny app was developed to facilitate the use of the methodology in this contribution.