Prognostic factors and treatment-effect modifiers in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with Type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years. Individuals with Types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of Types 1, 2 and 3 SMA. In untreated infants with Type 1 SMA, absence of symptoms at birth, a later symptom onset and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in Type 1 SMA. In patients with Types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching or summarizing results from different studies on the treatments for SMA

Solar Drinking Water Disinfection (SODIS) to Reduce Childhood Diarrhoea in Rural Bolivia: A Cluster-Randomized, Controlled Trial

Daniel Maeusezahl and colleagues conducted a cluster-randomized controlled trial in rural Bolivia of solar drinking water disinfection, and find only moderate compliance with the intervention and no evidence of reduction in diarrhea among children

Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study.

A family of dual Src/Abl inhibitors characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold was previously reported and proved to be active against several tumor cell lines. Among these compds., a promising antileukemia lead (I) has been recently identified, but, unfortunately, it suffers from substandard pharmaceutical properties. Accordingly, an approach for the optimization of the lead I is described in the present work. A series of more sol. pyrazolo[3,4-d]pyrimidine derivs. were rationally designed and proved to maintain the dual Src/Abl activity of the lead. Selected compds. showed an interesting activity profile against three different leukemic cells also in hypoxic conditions, which are usually characterized by imatinib-resistance. Finally, in vitro ADME properties (PAMPA permeation, water soly., microsomal stability) for the most promising inhibitors were also evaluated, thus allowing the identification of a few optimized analogs of lead I as promising antileukemia agents

Comparative efficacy of atezolizumab plus bevacizumab and other treatment options for patients with unresectable hepatocellular carcinoma: A network meta-analysis

Background: Most phase 3 clinical trials of systemic therapy for first-line unresectable hepatocellular carcinoma (HCC) have failed, with the exception of SHARP, REFLECT, and IMbrave150. We conducted indirect comparisons of therapies evaluated for first-line HCC treatment. Summary: We conducted a systematic review and meta-analysis of treatments for adults with locally advanced or metastatic unresectable HCC and no prior systemic treatment, including atezolizu-mab plus bevacizumab, sorafenib, lenvatinib, nivolumab, selective internal radiotherapy (SIRT), transarterial chemoembolization, and placebo or best supportive care. Randomized controlled trials published from January 1, 2007, to March 12, 2020, were retrieved from MEDLINE and Embase. Qualitative assessment of heterogeneity evaluated study designs, populations, and outcomes. Indirect comparisons used generalized linear models with random effects within a Bayesian framework and informative priors. We calculated relative efficacy estimates with 95% credible intervals (CrIs) and Bayesian posterior probability estimates of atezolizumab-bevacizumab being superior to other treatments. Nine clinical studies with a total of 3,897 participants were identified from 8,783 records and used to build the all-trials evidence network. Indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus lenvatinib (odds ratio, 0.63 [95% CrI 0.39-1.04]; with 97% Bayesian posterior probability of being superior), nivolumab (0.68 [95% CrI 0.41-1.14]; 94%), sorafenib (0.59 [95% CrI 0.39-0.87]; 99%), SIRT (0.51 [95% CrI 0.32-0.82]; 100%), or placebo/best supportive care (0.40 [95% CrI 0.25-0.64]; 100%). Key Messages: Within the context of indirect comparisons, analyses of OS favored atezolizumab-bevacizumab versus other treatment options for patients with locally advanced or metastatic unresectable HCC

Solar drinking water disinfection (SODIS) to reduce childhood diarrhoea in rural Bolivia: a cluster-randomized, controlled trial.

BackgroundSolar drinking water disinfection (SODIS) is a low-cost, point-of-use water purification method that has been disseminated globally. Laboratory studies suggest that SODIS is highly efficacious in inactivating waterborne pathogens. Previous field studies provided limited evidence for its effectiveness in reducing diarrhoea.Methods and findingsWe conducted a cluster-randomized controlled trial in 22 rural communities in Bolivia to evaluate the effect of SODIS in reducing diarrhoea among children under the age of 5 y. A local nongovernmental organisation conducted a standardised interactive SODIS-promotion campaign in 11 communities targeting households, communities, and primary schools. Mothers completed a daily child health diary for 1 y. Within the intervention arm 225 households (376 children) were trained to expose water-filled polyethyleneteraphtalate bottles to sunlight. Eleven communities (200 households, 349 children) served as a control. We recorded 166,971 person-days of observation during the trial representing 79.9% and 78.9% of the total possible person-days of child observation in intervention and control arms, respectively. Mean compliance with SODIS was 32.1%. The reported incidence rate of gastrointestinal illness in children in the intervention arm was 3.6 compared to 4.3 episodes/year at risk in the control arm. The relative rate of diarrhoea adjusted for intracluster correlation was 0.81 (95% confidence interval 0.59-1.12). The median length of diarrhoea was 3 d in both groups.ConclusionsDespite an extensive SODIS promotion campaign we found only moderate compliance with the intervention and no strong evidence for a substantive reduction in diarrhoea among children. These results suggest that there is a need for better evidence of how the well-established laboratory efficacy of this home-based water treatment method translates into field effectiveness under various cultural settings and intervention intensities. Further global promotion of SODIS for general use should be undertaken with care until such evidence is available.Trial registrationwww.ClinicalTrials.govNCT00731497 Please see later in the article for Editors' Summary