Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 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 vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
Objective
To continue evaluation of the long‐term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy ...(DMD). Three‐year progression of eteplirsen‐treated patients was compared to matched historical controls (HC).
Methods
Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open‐label basis. The primary functional assessment in this study was the 6‐Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.
Results
At 36 months, eteplirsen‐treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen‐treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.
Interpretation
Over 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271
Abstract The motor skills of patients with spinal muscular atrophy, type I (SMA-I) are very limited. It is difficult to quantify the motor abilities of these patients and as a result there is ...currently no validated measure of motor function that can be utilized as an outcome measure in clinical trials of SMA-I. We have developed the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (“CHOP INTEND”) to evaluate the motor skills of patients with SMA-I. The test was developed following the evaluation of 26 infants with SMA-I mean age 11.5 months (1.4–37.9 months) with the Test of Infant Motor Performance and The Children’s Hospital of Philadelphia Test of Strength in SMA, a newly devised motor assessment for SMA. Items for the CHOP INTEND were selected by an expert panel based on item mean and standard deviation, item frequency distribution, and Chronbach’s alpha. Intra-rater reliability of the resulting test was established by test–retest of 9 infants with SMA-I over a 2 month period; Intraclass correlation coefficient (ICC) (3,1) = 0.96. Interrater reliability was by video analysis of a mixed group of infants with neuromuscular disease by 4 evaluators; ICC (3,4) = 0.98 and in a group of 8 typically developing infants by 5 evaluators ICC (3,5) = 0.93. The face validity of the CHOP INTEND is supported by the use of an expert panel in item selection; however, further validation is needed. The CHOP INTEND is a reliable measure of motor skills in patients with SMA-I and neuromuscular disorders presenting in infancy.
Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on ...the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions.
As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps.
This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.
The aim of the study was to assess different outcome measures in a cohort of ambulant boys with Duchenne muscular dystrophy (DMD) over 12 months in order to establish the spectrum of possible changes ...in relation to age and steroid treatment.
The study is a longitudinal multicentric cohort study. A total of 106 ambulant patients with DMD were assessed using the 6-minute walk test (6MWT) and North Star Ambulatory Assessment (NSAA) at baseline and 12 months. Clinical data including age and steroid treatment were collected.
During the 12 months of the study, we observed a mean decline of 25.8 meters in the 6MWT with a SD of 74.3 meters. On NSAA, the mean decline was 2.2 points with a SD of 3.7. Not all the boys with DMD in our cohort showed a decline over the 12 months, with young boys showing some improvement in their 6MWT and NSAA scores up to the age of 7. NSAA and the 6MWT had the highest correlation (r = 0.52, p < 0.001).
This study provides longitudinal data of NSAA and 6MWT over a 12-month period. These data can be useful when designing a clinical trial.
•48-week phase 3 RCT evaluating efficacy and safety of drisapersen 6 mg/kg/week.•The pre-specified analyses did not meet statistical significance.•Due to increased data variation, statistical power ...for 6MWD was reduced to 53%.•Evidence for a greater treatment benefit was seen in a selected population post-hoc.•Most common adverse events were injection-site reactions and subclinical proteinuria.
This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300–400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.
Counselling has been shown to improve adherence to medication in people living with HIV (PLHIV). The aim of this study was to investigate factors associated with regular counselling attendance of ...patients taking antiretroviral therapy (ART).
We conducted a cross-sectional, paper-based survey among 880 PLHIV patients on ART attending outpatient clinics of a referral hospital in Jakarta. Patients on ART, above 18 years old, providing written consent were included. The primary outcome was regular counselling attendance (i.e., having attended at least 3 sessions in the previous 3 months) using records from counsellors. Factors associated with regular counselling attendance were assessed using logistic regression analysis.
The majority of patients were male (71.1%) and had regular counselling (78.4%). Being 31 to 40 years old (odds ratio (OR) = 0.55, 95% confidence interval (CI) = 0.32-0.93, > 40 years (OR = 0.30, 95% CI = 0.16-0.55) vs < 30 years, hepatitis B/C co-infection (OR = 0.42, 95% CI = 0.24-0.75), living > 20 km from the hospital (OR = 0.55, 95% CI = 0.33-0.93), transmission male-to-male (OR = 0.13, 95% CI = 0.04-0.44), unemployment (OR = 1.88, 95% CI = 1.02-3.44), part-time employment (OR = 10.71, 95% CI = 4.09-28.02), household member with HIV (OR = 3.31, 95% CI = 1.70-6.44), and Christianity (OR = 1.82, 95% CI = 1.12-2.94) were associated with regular counselling attendance.
This study suggests that counselling services should be reviewed to ensure that they are near home and fit the needs of older patients or patients with co-morbidities and minorities. Tailoring counselling may improve attendance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fungi are among the most biodiverse organisms in the world. Accurate species identification is imperative for studies on fungal ecology and evolution. The internal transcribed spacer (ITS) rDNA ...region has been widely accepted as the universal barcode for fungi. However, several recent studies have uncovered intragenomic sequence variation within the ITS in multiple fungal species. Here, we mined the genome of 2414 fungal species to determine the prevalence of intragenomic variation and found that the genomes of 641 species, about one-quarter of the 2414 species examined, contained multiple ITS copies. Of those 641 species, 419 (∼65%) contained variation among copies revealing that intragenomic variation is common in fungi. We proceeded to show how these copies could result in the erroneous description of hundreds of fungal species and skew studies evaluating environmental DNA (eDNA) especially when making diversity estimates. Additionally, many genomes were found to be contaminated, especially those of unculturable fungi.
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•The ITS region is the most prevalent barcode used in studies of kingdom Fungi•There are multiple copies of the ITS region within the fungal genome•ITS intragenomic variation and contaminated genomes are common in fungi•Intragenomic variation can affect taxonomy, eDNA studies, and diversity estimates
Molecular biology; Microbiology; Evolutionary biology
Abstract The aim of this study was to investigate the suitability of the North Star Ambulatory Assessment as a possible outcome measure in multicentric clinical trials. More specifically we wished to ...investigate the level of training needed for achieving a good interobserver reliability in a multicentric setting. The scale was specifically designed for ambulant children with Duchenne Muscular Dystrophy and includes 17 items that are relevant for this cohort. Thirteen Italian centers participated in the study. In the first phase of the study we provided two training videos and an example of the scale performed on a child. After the first session of training, all the 13 examiners were asked to send a video with an assessment performed in their centre and to score all the videos collected. There were no difficulties in performing the items and in obtaining adequate videos with a hand held camera but the results showed a poor interobserver reliability (<.5). After a second training session with review and discussion of the videos previously scored, the same examiners were asked to score three new videos. The results of this session had an excellent interobserver reliability (.995). The level of agreement was maintained even when the same videos were rescored after a month, showing a significant intra-observer reliability (.95). Our results suggest that the NSAA is a test that can be easily performed, completed in 10 min and can be used in a multicentric setting, providing that adequate training is administered.
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