EClinicalMedicine最新文献

Background: Brain tumor in children can induce hemianopia, a loss of conscious vision, profoundly impacting their development and quality of life, yet no effective intervention exists for this pediatric population. This study aimed to explore the feasibility, safety, and potential effectiveness of a home-based audiovisual stimulation in immersive virtual-reality (3D-MOT-IVR) to improve visual function and functional vision.

Methods: In a phase 2a, open-labeled, nonrandomized, single-arm study, conducted from July 2022 to October 2023 (NCT05065268), 10 children and adolescents with stable hemianopia were enrolled to perform 20-min sessions of 3D-MOT-IVR every other day for six weeks from home. We assessed feasibility by monitoring adoption, adherence and completion rates, remote data transfer and qualitative feedback. Safety was evaluated using validated cybersickness questionnaires. Comprehensive vision assessments following standardized low-vision evaluation procedures were conducted pre- and post-intervention, with follow-ups at 1- and 6 months.

Findings: The home-based 3D-MOT-IVR intervention proved both feasible and safe, with no reported adverse events. All participants completed the prescribed stimulations and the pre- and post-intervention assessment points, 90% completed the follow-ups. Nine out of ten participants showed clinically meaningful enhancement in visual function and/or functional vision, namely binocular visual field restoration and increased reading speed, but two showed concomitant deterioration in monocular visual field. These positive effects were sustained at the 6-month follow-up. Exploratory outcomes revealed a significant positive correlation between the performance at the 3D-MOT-IVR intervention and the visual perception at the binocular visual field test.

Interpretation: Our findings underscore the feasibility and safety of home-based audiovisual stimulation in immersive virtual-reality as a potential intervention for improving visual perception in children/adolescents with hemianopia consecutive to a pediatric brain tumor. These promising results lay a strong foundation for a larger randomized controlled trial, offering hope for a meaningful breakthrough in visual rehabilitation for this vulnerable population.

Funding: Meagan Bebenek Foundation and University Health Network Foundation.

Background: Rhabdomyosarcoma and other soft tissue sarcomas (STS) with high-risk features are still associated with an unsatisfactory outcome. We evaluated the efficacy of oral maintenance therapy added at the end of standard therapy in patients with high-risk rhabdomyosarcoma and STS.

Methods: CWS-2007-HR was a multicentre, open-label, randomised controlled, phase 3 trial done at 87 centers in 5 countries. Eligible patients were those aged 6 months to 21 years with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring in unfavourable sites with unfavourable age (≥10 years) and/or tumour size (>5 cm); all non-metastatic alveolar rhabdomyosarcoma and those with any non-metastatic rhabdomyosarcoma with nodal involvement. A further group was also eligible: patients with non-metastatic undifferentiated sarcoma, extraskeletal Ewing sarcoma and primary unresected synovial sarcoma. Patients in complete remission at the end of standard therapy (nine cycles of ifosfamide, vincristine with doxorubicine or dactinomycin, and surgery or radiotherapy, or both) were randomised to either stop treatment (S-arm) or to receive oral maintenance therapy (M-arm) with eight 10-day courses (25 weeks) of trofosfamide (2 × 75 mg/m²/day) and idarubicin (1 × 5 mg/m²/day 1,4,7,10) alternating with trofosfamide and etoposide (2 × 25 mg/m²/day). The primary outcome was event-free survival (EFS) and the secondary outcome was overall survival (OS) in the intent-to treat population. This trial is registered at ClinicalTrials.gov, NCT00876031, and, EudraCT 2007-0001478-10.

Findings: Between July 1st, 2009 and June 30th, 2019, 195 patients were randomly assigned to the M-arm (n = 96) or S-arm (n = 99). In the intent-to-treat population, with a median follow-up of 5.2 years (IQR 3.9-6.1) for surviving patients, the 3-year EFS in the M-arm was 66.9% (95% CI 58.1-77.2) versus 75.6% (67.6-84.6) in the S-arm (hazard ratio, (HR) 1.62, 95% CI 0.98-2.69, p = 0.06). 3-year OS was 82.8% (95% CI 75.4-90.8) in the M-arm versus 84.7% (95% CI 77.8-92.1) in the S-arm (HR 1.55, 95% CI 0.84-2.89, p = 0.17). Grade 3-4 adverse events were haematological in 66% of patients, febrile infections in 6%, gastrointestinal in 10%, and sensory neuropathy in 1%.

Interpretation: The addition of 25 weeks of oral maintenance therapy with trofosfamide, etoposide and idarubicin after standard therapy does not improve EFS and OS in patients with high-risk rhabdomyosarcoma and other STS.

Funding: Deutsche Kinderkrebsstiftung Grant No.DKS 2009.09, DKS 2012.06, DKS 2015.13, DKS 2018.10 and DKS 2021.04.

[This corrects the article DOI: 10.1016/j.eclinm.2024.102621.].

There has been tremendous progress in building and promoting evidence-based practice around parenting programming in low- and middle-income countries. However, there remains a dearth of evidence specifically examining gender transformative programming designed to address gender-based violence in humanitarian settings. To inform this gap, we examine how existing gender transformative programmatic material addresses the unique circumstances of parenting in humanitarian settings. Incorporating lessons from the field, we inform considerations of how to adapt future content to address gender-based violence in humanitarian settings. We reviewed two gender transformative programs in humanitarian settings: Safe at Home and Sibling Support for Adolescent Girls in Emergencies. Four thematic recommendations emerged for gender-transformative parenting programming in humanitarian settings to address gender-based violence, specifically intimate partner violence and violence against children. These recommendations include: 1) Recognize the diversity of families in humanitarian settings, 2) Prioritize participatory approaches from the start, 3) Set realistic parameters and goals for the specific humanitarian context, and 4) Ensure pathways to scale and sustainability within the initial program design. We advocate for broader application of these principals to support gender-transformative parenting programming that is tailored to address gender-based violence in humanitarian settings and that will continue to build the respective evidence base.

Background: There is a significant association between low vitamin D levels at diagnosis of indolent B-cell lymphomas and inferior overall survival (OS). To determine whether supplemental vitamin D improves event-free survival (EFS) in these patients, we conducted a comparative double-blind study of vitamin D₃ vs. placebo.

Methods: In this phase 3, randomized, double-blind, placebo-controlled trial, patients with low tumor burden follicular, marginal zone or small lymphocytic lymphoma, age 18 or older, with stage two or greater disease and no prior systemic treatment were enrolled at 7 academic cancer centers. Patients were stratified by histology and FLIPI (Follicular Lymphoma International Prognostic Index) score and randomized 2:1 to receive 2000 IU vitamin D₃ or placebo daily beginning on day one with rituximab 375 mg/m² administered weekly times four. 257 patients were assessed for participation: 24 were not eligible and 22 refused. Patients with stable disease or disease progression at week 13 counted as events; responding patients continued treatment with vitamin D or placebo until progression for up to three years. The primary endpoint was EFS, defined as the time from randomization to lack of response at week 13, initiation of a new treatment, disease progression or death. Secondary endpoints included week 13 response and OS. This trial is registered at clinicaltrials.gov, NCT03078855.

Findings: 206 evaluable patients (135 on vitamin D and 71 on placebo) were enrolled between September 2017 and March 2022 with a median EFS follow-up of 19.6 months (IQR, 9.3-33.5). The median age was 62 years (IQR, 54-70); 118 (57%) female; 182 (89%) white. At week 13 the mean vitamin D level increased to 41.6 ng/mL (SD 10.1) in the vitamin D arm vs. remaining stable (31.3 ng/mL, SD 11.2) in the placebo arm. There was insufficient evidence of a difference in EFS between the two arms (P = 0.26): three-year EFS in the vitamin D arm was 47.7% (95% CI, 39.0-58.4) compared to 49.5% (95% CI, 37.6-65.0) in the placebo arm. There was no difference in week 13 response between the arms (both 84%). Adverse events associated with vitamin D supplementation were rare. The median OS follow-up was 35.1 months (IQR, 22.9-45.1), overall survival was 96.6% (95% CI, 93.1-98.6) and there was no significant difference between the vitamin D and placebo arms (P = 0.47).

Interpretation: As tested in this study, there is no benefit to routine vitamin D supplementation in patients with indolent lymphoma treated with rituximab. These results have implications for ongoing and planned studies of vitamin D supplementation in other malignancies.

Funding: This study was funded by the National Institutes of Health, National Cancer Institute grant R01CA214890.

Background: Between 1% and 4% of febrile infants, aged from birth to 90 days of age, presenting to hospital will be diagnosed with an invasive bacterial infection (IBI). Traditional teaching has advocated a treat all approach but more recently a number of clinical decision aids (CDA) have been developed to classify febrile infants into lower and higher risk cohorts, with lower risk infants suitable for management without immediate parenteral antibiotics and lumbar puncture. The aim of this study was to apply these CDA to a UK and Irish cohort.

Methods: This was a prospective multicentre cohort study of febrile infants presenting to 35 Paediatric Emergency Research in the UK and Ireland (PERUKI) sites between the 6th July 2022 and the 31st August 2023. All infants received standard care as per local policy. IBI was defined as growth of bacterial pathogen in blood or cerebrospinal fluid. The performance of the following CDAs were assessed, National Institute for Health and Care Excellence (NICE) guidelines NG143 (Fever under 5 years), British Society Antimicrobial Chemotherapy (BSAC), Aronson rule and American Academy of Pediatrics (AAP) CDA. A cost comparison of each CDA against a treat all approach was conducted. Trial registration: NCT05259683.

Findings: 1821 were included in the final analysis. The median age was 46 days (IQR: 30-64 days), with 1108 (61%) being male. Of the 1821 infants, 67 (3.7%) had IBI. The AAP and BSAC CDAs were the most sensitive at 0.99 (95% CI 0.92-1.0) for both with specificities of 0.23 (95% CI 0.21-0.25) and 0.20 (95% CI 0.18-0.22) respectively. The NICE NG143 and Aronson CDA were the most specific CDAs with values of 0.27 (95% CI 0.25-0.30) and 0.30 (95% CI 0.28-0.32) respectively, but their sensitivity was lower. The AAP CDA performed equally well with either procalcitonin (PCT) or C-reactive protein (CRP) as the biomarker of choice. Of the 1821 infants, 77% were admitted, 14% were discharged and 9% were ambulated. All CDAs were cost saving for hospital services when compared to a treat all approach, with the lowest mean cost per patient estimated for Aronson (£1171; bootstrap 95% CI £1129-£1214) and NICE NG143 CDA (£1218; bootstrap 95% CI £1174-£1263).

Interpretation: The AAP and BSAC CDAs are highly sensitive at excluding IBI, with a cost saving to hospital services when compared to a treat all approach. The substitution of CRP for PCT made no difference to the performance of the AAP CDA in this cohort and was more costly.

Funding: The Febrile Infant Diagnostic Assessment and Outcome (FIDO) study is funded by Royal College of Emergency Medicine Doctoral Fellowship (RCEM 02/03/2021). Procalcitonin analysis was supported by the Public Health Agency Northen Ireland Grant (HSC R&D-COM/5745/22). The funders played no part in the conception or design of this study.

Background: Rapid diagnosis of tuberculosis (TB) is important for improving outcomes and reducing transmission. Previous studies assessing the impact of Xpert MTB/RIF (Xpert), a molecular assay that provides results within 2 h, on mortality have been inconclusive. In this planned analysis of a pragmatic cluster-randomized trial in Uganda, we assessed whether a multicomponent strategy, including decentralized Xpert testing, decreased mortality among adults evaluated for TB.

Methods: Ten community health centers were randomized, using a computer-generated randomization sequence, to the XPEL-TB intervention (on-site Xpert testing plus implementation supports) and ten to routine TB care without any modifications (on-site smear microscopy and referral-based Xpert testing for selected patients). The trial included all adults ( $\ge$ 18 years of age) undergoing evaluation for presumptive TB at each trial health center. All-cause mortality was a secondary outcome of the trial. For this analysis, the primary outcome was the mortality rate (censored at 18 months), and the secondary outcome was the six-month mortality risk. We compared the outcomes between trial arms using cluster-level analyses to account for stratified randomization and patient-level covariates. The trial was registered with the US National Institutes of Health (identifier: NCT03044158) and the Pan African Clinical Trials Registry (identifier: PACTR201610001763265).

Findings: Vital status was ascertained for 8413 of 9563 (88%) XPEL-TB trial participants who presented at the health centers from October 22, 2018 through February 29, 2020. The adjusted rate ratio (aRR) was 0.77 (95% CI: 0.47-1.28), comparing the intervention (145 deaths/3655 person-years) to routine care (154 deaths/3015 person-years). In sub-group analyses, point estimates for mortality were lower in the intervention arm among people without HIV (aRR = 0.50, 95% CI: 0.26-0.96) and among females (aRR = 0.64, 95% CI: 0.33-1.23). The mortality risk analysis yielded similar results.

Interpretation: Consistent point estimates favoring the intervention in our trial and previous ones suggest that Xpert testing may have an impact on mortality at community health centers. However, the magnitude of effect is small, and statistically significant results are unlikely to be attained within a single trial. Future trials of novel TB diagnostics at community health centers should focus on more proximal outcomes including TB detection and treatment initiation.

Funding: This work was supported by the National Heart, Lung, and Blood Institute of the US National Institutes of Health under award number R01HL130192.

Background: Previous spontaneous preterm birth (sPTB) is a strong risk indicator for recurrent preterm birth (PTB). Cervical cerclage is an accepted intervention to prevent recurrent PTB in high risk patients. Cervical pessary might be a less invasive alternative. The objective of this study is to determine whether a cervical pessary is non-inferior to cerclage in the prevention of recurrent PTB.

Methods: We performed an international, open-label, non-inferiority, randomised controlled trial in 21 hospitals between March 2014 and December 2022. We included singleton pregnancies with an indication for cerclage based on either multiple previous sPTBs <34 weeks or with a previous sPTB <34 weeks and an asymptomatic mid-trimester short cervix (≤25 mm). Randomisation was 1:1, stratified by centre and indication, to cervical pessary or vaginal cerclage. Primary outcome was PTB <32 weeks. Secondary outcomes included (s)PTB rates, obstetric, and maternal outcomes and a composite of adverse perinatal outcomes including perinatal mortality and severe neonatal morbidity. Analysis was by intention-to-treat. Treatment effect was expressed as relative risk (RR), absolute risk difference (aRD) and 95% confidence intervals (CI). Sample size was calculated at 400 participants with a non-inferiority margin for pessary of 10%, meaning that non-inferiority is proven if the upper limit of the CI of the risk difference is <10%. Trial registration at ICTRP: NL-OMON26958.

Findings: We randomised 261 participants to pessary (n = 133) or cerclage (n = 128). After the third interim analysis (n = 228 participants), recruitment was halted due to safety concerns and the apparent challenge in establishing non-inferiority of pessary treatment. PTB <32 weeks occurred in 44/130 cases after pessary vs 30/125 cases after cerclage (33.8% vs 24.0% aRR 1.4, 95% CI 0.95-2.1, p = 0.09, aRD 9.8% 95% CI -1.2 to 20.9). The composite of adverse perinatal outcomes occurred in 42 cases after pessary compared to 29 cases in cerclage (32.2% vs 23.2%; RR 1.4 95% CI 0.93-2.1 p = 0.1) and consisted mainly of perinatal death (22.3% vs 14.4% RR 1.5 95% CI 0.9-2.6 p = 0.1).

Interpretation: Non-inferiority of cervical pessary compared to cerclage in preventing recurrent PTB <32 weeks was not proven. Cerclage is the recommended treatment.

Funding: ZonMw (#837002406), a Dutch Organisation for Health Research and Development.