Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: A randomised, double-blind, placebo-controlled phase 2 trial

Background: Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. Methods: This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT01302600. Findings: The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0\ub718 for olesoxime and -1\ub782 for placebo (treatment difference 2\ub700 points, 96% CI -0\ub725 to 4\ub725, p=0\ub70676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Interpretation: Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. Funding: AFM T\ue9l\ue9thon and Trophos SA

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity

Background: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. Methods: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. Results: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p Pathophysiology and treatment of rheumatic disease

Measurements of the ϒ(1S), ϒ(2S), and ϒ(3S) differential cross sections in pp collisions at s=7TeV

Differential cross sections as a function of transverse momentum pTpT are presented for the production of ϒ(nS)ϒ(nS) (n = 1, 2, 3) states decaying into a pair of muons. Data corresponding to an integrated luminosity of 4.9View the MathML sourcefb−1 in pp collisions at View the MathML sources=7TeV were collected with the CMS detector at the LHC. The analysis selects events with dimuon rapidity |y|<1.2|y|<1.2 and dimuon transverse momentum in the range View the MathML source10<pT<100GeV. The measurements show a transition from an exponential to a power-law behavior at View the MathML sourcepT≈20GeV for the three ϒ states. Above that transition, the ϒ(3S)ϒ(3S) spectrum is significantly harder than that of the ϒ(1S)ϒ(1S). The ratios of the ϒ(3S)ϒ(3S) and ϒ(2S)ϒ(2S) differential cross sections to the ϒ(1S)ϒ(1S) cross section show a rise as pTpT increases at low pTpT, then become flatter at higher pTpT

Search for vectorlike charge 2/3 T quarks in proton-proton collisions at root(s)=8 TeV

Peer reviewe

Non-AIDS defining cancers in the D:A:D Study-time trends and predictors of survival : a cohort study

BACKGROUND:Non-AIDS defining cancers (NADC) are an important cause of morbidity and mortality in HIV-positive individuals. Using data from a large international cohort of HIV-positive individuals, we described the incidence of NADC from 2004-2010, and described subsequent mortality and predictors of these.METHODS:Individuals were followed from 1st January 2004/enrolment in study, until the earliest of a new NADC, 1st February 2010, death or six months after the patient's last visit. Incidence rates were estimated for each year of follow-up, overall and stratified by gender, age and mode of HIV acquisition. Cumulative risk of mortality following NADC diagnosis was summarised using Kaplan-Meier methods, with follow-up for these analyses from the date of NADC diagnosis until the patient's death, 1st February 2010 or 6 months after the patient's last visit. Factors associated with mortality following NADC diagnosis were identified using multivariable Cox proportional hazards regression.RESULTS:Over 176,775 person-years (PY), 880 (2.1%) patients developed a new NADC (incidence: 4.98/1000PY [95% confidence interval 4.65, 5.31]). Over a third of these patients (327, 37.2%) had died by 1st February 2010. Time trends for lung cancer, anal cancer and Hodgkin's lymphoma were broadly consistent. Kaplan-Meier cumulative mortality estimates at 1, 3 and 5 years after NADC diagnosis were 28.2% [95% CI 25.1-31.2], 42.0% [38.2-45.8] and 47.3% [42.4-52.2], respectively. Significant predictors of poorer survival after diagnosis of NADC were lung cancer (compared to other cancer types), male gender, non-white ethnicity, and smoking status. Later year of diagnosis and higher CD4 count at NADC diagnosis were associated with improved survival. The incidence of NADC remained stable over the period 2004-2010 in this large observational cohort.CONCLUSIONS:The prognosis after diagnosis of NADC, in particular lung cancer and disseminated cancer, is poor but has improved somewhat over time. Modifiable risk factors, such as smoking and low CD4 counts, were associated with mortality following a diagnosis of NADC

Mutations in the TRPV4 gene are not associated with sporadic progressive muscular atrophy.

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Impaired Mandibular Function in Spinal Muscular Atrophy Type II: Need for Early Recognition

Item does not contain fulltextThe aim of the study is to assess mandibular function in young patients with spinal muscular atrophy type II. A total of 12 children and young adults with spinal muscular atrophy type II and 12 healthy matched controls participated. The mandibular function impairment was moderate to severe in 50% of patients. A limited mouth opening (</=30 mm) was observed in 75% of the patients. In patients with a severe reduction of the mandibular range of motion the temporomandibular joint mainly rotated during mouth opening instead of the usual combination of rotation and sliding. The severity of the limited active mouth opening correlated with the severity of the disease (motor function measure scores). This study shows that mandibular dysfunction is common among young patients with spinal muscular atrophy type II. Early recognition of mandibular dysfunction may help to prevent complications such as aspiration as a result of chewing problems

Physiological and phylogenetic study of an ammonium-oxidizing culture at high nitrite concentrations

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