Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene ...abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.
STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30–60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).
From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36–100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79–100) survived free from permanent ventilation at age 14 months (vs 6 26%, 8–44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).
Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit–risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.
Novartis Gene Therapies.
Objective To examine the personal financial impact of atopic dermatitis (AD) and attempt to correlate cost of AD with emotional impact. Study design Between March 2011 and December 2013, 82 ...caretakers of children 6 months to 12 years of age with moderate-to-severe AD were recruited at the time of dermatology clinic visits in Cleveland, Ohio, to complete surveys. The response rate was >95%. Participants were asked questions about direct expenses (medical visits, medications, and other products) and indirect expenses (time missed from work, childcare costs) related to AD in the past 4 weeks. Emotional impact was measured by the Childhood Atopic Dermatitis Impact Scale. Results The mean monthly personal cost of AD in the month before the office visit was $274 (median $114; IQR $29, $276), with $75 from direct costs (median $45; IQR $20, $110) and $199 from indirect costs (median $0; IQR $0, $208). An average of 34.8% of available monthly money was spent on AD care in the month before the office visit. For patients with Medicaid, there was a significant correlation between monthly adjusted personal cost and Childhood Atopic Dermatitis Impact Scale score (r = 0.548; P < .001); however, this correlation did not exist for patients who had commercial insurance (r = 0.269; P = .166). Conclusions Our results illustrate the high emotional and financial burden of childhood AD and provide insight into spending patterns. In addition, our study correlate costs with emotional burden of AD for lower-income patients.
The erm(41) gene confers inducible macrolide resistance in Mycobacterium abscessus subsp. abscessus, calling into question the usefulness of macrolides for treating M. abscessus subsp. abscessus ...infections. With an extended incubation (14 days), isolates with MICs of ≥8 μg/ml are considered macrolide resistant by current CLSI guidelines. Our goals were to determine the incidence of macrolide susceptibility in U.S. isolates, the validity of currently accepted MIC breakpoints, and the erm(41) sequences associated with susceptibility. Of 349 isolates (excluding those with 23S rRNA gene mutations), 85 (24%) had clarithromycin MICs of ≤8 μg/ml. Sequencing of the erm(41) genes from these isolates, as well as from isolates with MICs of ≥16 μg/ml, including ATCC 19977T, revealed 10 sequevars. The sequence in ATCC 19977T was designated sequevar (type) 1; most macrolide-resistant isolates were of this type. Seven sequevars contained isolates with MICs of >16 μg/ml. The T28C substitution in erm(41), previously associated with macrolide susceptibility, was identified in 62 isolates (18%) comprising three sequevars, with MICs of ≤2 (80%), 4 (10%), and 8 (10%) μg/ml. No other nucleotide substitution was associated with macrolide susceptibility. We recommend that clarithromycin susceptibility breakpoints for M. abscessus subsp. abscessus be changed from ≤2 to ≤4 μg/ml and that isolates with an MIC of 8 μg/ml have repeat MIC testing or erm sequencing performed. Our studies suggest that macrolides are useful for treating approximately 20% of U.S. isolates of M. abscessus subsp. abscessus. Sequencing of the erm gene of M. abscessus subsp. abscessus will predict inducible macrolide susceptibility.
The stereotype content model (SCM) proposes potentially universal principles of societal stereotypes and their relation to social structure. Here, the SCM reveals theoretically grounded, ...cross‐cultural, cross‐groups similarities and one difference across 10 non‐US nations. Seven European (individualist) and three East Asian (collectivist) nations (N=1,028) support three hypothesized cross‐cultural similarities: (a) perceived warmth and competence reliably differentiate societal group stereotypes; (b) many out‐groups receive ambivalent stereotypes (high on one dimension; low on the other); and (c) high status groups stereotypically are competent, whereas competitive groups stereotypically lack warmth. Data uncover one consequential cross‐cultural difference: (d) the more collectivist cultures do not locate reference groups (in‐groups and societal prototype groups) in the most positive cluster (high‐competence/high‐warmth), unlike individualist cultures. This demonstrates out‐group derogation without obvious reference‐group favouritism. The SCM can serve as a pancultural tool for predicting group stereotypes from structural relations with other groups in society, and comparing across societies.
Benthic foraminifera are valuable indicators in environmental studies, including those on marine pollution monitoring. While a great deal of foraminiferal biomonitoring research utilizes abundance ...and distributional data, further value resides in better understanding the incorporation of heavy metal pollutants in foraminiferal calcite. By experimentally growing assemblages of foraminifera from propagules (small juveniles) gathered from Sapelo Island, Georgia and Little Duck Key, Florida, this study examines foraminiferal incorporation of the heavy metals arsenic, cadmium, nickel, and zinc over a range of concentrations.
Surface sediment was collected and sieved to concentrate the propagules. The propagules were then used to experimentally grow assemblages with each exposed to a different heavy metal. After one month, the experimentally grown foraminifera were harvested and samples of the two most common species from each location, Ammonia tepida (Cushman) and Haynesina germanica (Ehrenberg) from Sapelo Island and Quinqueloculina sabulosa (Cushman) and Triloculina oblonga (Montagu) from Little Duck Key, were selected for trace element analysis. Calcite of the tests was analyzed using LA-ICP-MS to quantify the heavy metal incorporation.
Rotalid species A. tepida and H. germanica incorporated more cadmium as its concentration in the surrounding water increased, whereas miliolid species Q. sabulosa and T. oblonga incorporated more of the metals zinc and nickel. This study shows that while foraminiferal incorporation of heavy metals has great potential as a biomonitoring tool, multiple factors (especially inter-clade variation) must be considered carefully. In future marine environmental research, these factors may help to create a more targeted assessment of environmental pollution.
•Foraminifera grown experimentally from propagules while exposed to heavy metals.•Heavy metals (arsenic, cadmium, nickel, zinc) represent a range of essentiality.•LA-ICP-MS showed clear differences in incorporation between rotalids and miliolids.•Rotalids incorporated more arsenic and cadmium as content in water increased.•Miliolids incorporated more zinc and nickel as content in water increased.
•Provider interpretation of ambiguous genetic results influenced patients’ decisions.•Patients with a variant of uncertain significance result were not worried.•Patients made decisions about ...ambiguity and risk management and sharing the result.•Ambiguity motivated uptake and adherence to health promotion behaviors.•Patients could use support managing ambiguity of their result.
We know little about how patients make decisions when they receive a variant of uncertain significance result (VUS) from genetic testing. The purpose of this study was to elucidate a model of patient-informed decision-making after receiving a VUS result.
Using an adapted Mental Models Approach, we conducted semi-structured interviews with women who received a VUS result from genetic testing for hereditary breast cancer (N = 20) to explore factors they believed were relevant to their decision-making. Two coders used a coding scheme informed by experts in hereditary breast cancer to conduct analysis. Inter-coder reliability was α = .86.
Three overarching decision themes emerged from the interviews: managing ambiguity, medical risk management, and sharing results with others. While participants noted some difficulty understanding their result, genetic counselors’ interpretations, psychosocial factors (e.g., risk perceptions), and competing extrinsic demands influenced their decisions.
Complex influences affect patient decision-making after a VUS result from genetic testing and may encourage health protective behavior.
Even patients who understand their test result could use support managing the ambiguity of their test result and sharing it with others.
Objective: To investigate, among women with breast cancer, how postdiagnosis diet quality and the combination of diet quality and recreational physical activity are associated with prognosis. ...Methods: This multiethnic, prospective observational cohort included 670 women diagnosed with local or regional breast cancer. Thirty months after diagnosis, women completed self-report assessments on diet and physical activity and were followed for 6 years. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals for death from any cause and breast cancer death. Results: Women consuming better-quality diets, as defined by higher Healthy Eating Index-2005 scores, had a 60% reduced risk of death from any cause (HR Q4:Q1 : 0.40,95% CI: 0.17, 0.94) and an 88% reduced risk of death from breast cancer (HR Q4:Q1 : 0.12, 95% CI: 0.02, 0.99). Compared with inactive survivors consuming poor-quality diets, survivors engaging in any recreational physical activity and consuming better-quality diets had an 89% reduced risk of death from any cause (HR: 0.11,95% CI: 0.04, 0.36) and a 91% reduced risk of death from breast cancer (HR: 0.09, 95% CI: 0.01, 0.89). Associations observed were independent of obesity status. Conclusion: Women diagnosed with localized or regional breast cancer may improve prognosis by adopting betterquality dietary patterns and regular recreational physical activity. Lifestyle interventions emphasizing postdiagnosis behavior changes are advisable in breast cancer survivors.
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