A meta-analysis of randomized double-blind clinical trials in CMT1A to assess the change from baseline in CMTNS and ONLS scales after one year of treatment

International audienceCMT1A is the most common inherited peripheral neuropathy. There is currently no approved treatment. We performed a meta-analysis including four randomized, double-blind, Placebo-controlled clinical trials to assess the disease progression after one year under Placebo, Ascorbic Acid (AA) or PXT3003, a combination of three repurposed drugs. We observed a weak deterioration in patients under Placebo, well below the reported natural disease progression. Patients treated with AA were stable after one year but not significantly different from Placebo. Patients undergoing PXT3003 treatment showed an improvement in CMTNS and ONLS, statistically significant versus Placebo and potentially precursory of a meaningful change in the disease course

Subjects with mild alopecia benefit from aminexil clinical 5: results of a large international observational study

Introduction and objectives: Androgenetic alopecia in men (AGA) and female pattern hair loss (FPHL) are common hair loss causes which may heavily influence self-esteem and self-image. AGA and FPHL are caused by the heightened sensitivity of scalp follicles to dihydro-testosterone leading to dysregulation of downstream signaling cascades of inflammation. As a consequence a process of hair miniaturization develops over the time usually paralleled with a characteristic pattern distribution that varies between men and women. Histological observations showed perifollicular cells infiltrates and micro-inflammation. As this is a chronic condition, efficacy of products but also tolerability, cosmetic acceptance and patient satisfaction are key to ensure a good compliance. The aim of this study was to assess the benefit and tolerability of Aminexil clinical 5 (AC5, containing Aminexil, Arginine, SP94, piroctone olamine and Vichy mineralizing water as active ingredients) in subjects with mild alopecia. Materials and methods: This was an open-label, observational, international study conducted in real life settings in 527 adult female and male subjects with mild alopecia. At baseline subjects underwent a clinical examination including Ludwig for female and Hamilton Norwood scoring for male subjects and received AC5 to be applied once daily for a minimum of 45 days. At the end of treatment, subjects assessed their hair growth and quality, satisfaction and local tolerance; investigators evaluated the impact of AC5 on the subjects’ hair. Results: Data from 421 subjects were evaluable for the efficacy analysis. Tolerability data were available for 509 subjects. 58.7% of subjects were females; the mean age was 34.1±9.1 years. Duration of hair loss was 1.3±1.8 years in women and 2.3±2.6 years, overall mean duration was 1.7±2.2 years. AC5 was used in combination with prescription treatments in 14.8% of cases (mainly topical) at inclusion with non-medical products (topicals and/or orals) in 42.2% of cases; 71.3% of women had a Ludwig score of 1 and 40.8% of males had a Hamilton Norwood score of 2. After a mean of 82.9±17.5 days of use dermatologist evaluation rated an improvement in hair loss in 87.1% of subjects compared to baseline; it was somewhat better in women (91.8%) than in men (80.3%). Subject satisfaction on a scale from 0 (not satisfied at all) to 10 (completely satisfied) was 7.9±1.7. Tolerance was good to very good in 98.6% of subjects. The texture was considered pleasant by 95% of subjects. Conclusion: In subjects with mild alopecia, AC5 reduces hair loss in both men and women with a pleasant texture. AC5 was well tolerated and highly appreciated by subjects and investigators

Whole brain radiotherapy (WBRT) after local treatment of brain metastases in melanoma patients: Statistical Analysis Plan

Background: The WBRTMel trial is a multinational, open-label, phase III randomised controlled trial comparing whole brain radiotherapy (WBRT) to observation following local treatment of one to three melanoma brain metastases with surgery and/or stereotactic irradiation. The primary trial endpoint was to determine the effect of adding WBRT to local treatment on distant intracranial control, and the secondary endpoints were neurocognitive function, quality of life (QoL), performance status, overall survival, death from intracranial causes, death from melanoma and cost-effectiveness. Objective: The objective of this update is to outline and publish the pre-determined statistical analysis plan (SAP) before the database lock and the start of analysis. Methods: The SAP describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues and the specific statistical procedures for analysing efficacy and safety outcomes. The SAP was approved after closure of recruitment and before completion of patient follow-up. It outlines the planned primary analyses and a range of subgroup and sensitivity analyses regarding the clinical and QoL outcomes. Health economic outcomes are not included in this plan but will be analysed separately. The SAP will be adhered to for the final data analysis of this trial to avoid analysis bias arising from knowledge of the data. Results: The resulting SAP is consistent with best practice and will allow open and transparent reporting. Conclusion: We have developed a SAP for the WBRTMel trial which will be followed to ensure high-quality standards of internal validity to minimise analysis bias

Whole brain radiotherapy after local treatment of brain metastases in melanoma patients - a randomised phase III trial

<p>Abstract</p> <p>Background</p> <p>Cerebral metastases are a common cause of death in patients with melanoma. Systemic drug treatment of these metastases is rarely effective, and where possible surgical resection and/or stereotactic radiosurgery (SRS) are the preferred treatment options. Treatment with adjuvant whole brain radiotherapy (WBRT) following neurosurgery and/or SRS is controversial. Proponents of WBRT report prolongation of intracranial control with reduced neurological events and better palliation. Opponents state melanoma is radioresistant; that WBRT yields no survival benefit and may impair neurocognitive function. These opinions are based largely on studies in other tumour types in which assessment of neurocognitive function has been incomplete.</p> <p>Methods/Design</p> <p>This trial is an international, prospective multi-centre, open-label, phase III randomised controlled trial comparing WBRT to observation following local treatment of intracranial melanoma metastases with surgery and/or SRS. Patients aged 18 years or older with 1-3 brain metastases excised and/or stereotactically irradiated and an ECOG status of 0-2 are eligible. Patients with leptomeningeal disease, or who have had previous WBRT or localised treatment for brain metastases are ineligible. WBRT prescription is at least 30 Gy in 10 fractions commenced within 8 weeks of surgery and/or SRS. Randomisation is stratified by the number of cerebral metastases, presence or absence of extracranial disease, treatment centre, sex, radiotherapy dose and patient age. The primary endpoint is the proportion of patients with distant intracranial failure as determined by MRI assessment at 12 months. Secondary end points include: survival, quality of life, performance status and neurocognitive function.</p> <p>Discussion</p> <p>Accrual to previous trials for patients with brain metastases has been difficult, mainly due to referral bias for or against WBRT. This trial should provide the evidence that is currently lacking in treatment decision-making for patients with melanoma brain metastases. The trial is conducted by the Australia and New Zealand Melanoma Trials Group (ANZMTG-study 01-07), and the Trans Tasman Radiation Oncology Group (TROG) but international participation is encouraged. Twelve sites are open to date with 43 patients randomised as of the 31st March 2011. The target accrual is 200 patients.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12607000512426.aspx">ACTRN12607000512426</a></p

Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease:analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies

Background Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). Methods In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. Results This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. Conclusions Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated

Flight of the Bumblebee: the Early Excess Flux of Type Ia Supernova 2023bee revealed by TESSTESS, SwiftSwift and Young Supernova Experiment Observations

We present high-cadence ultraviolet through near-infrared observations of the Type Ia supernova (SN Ia) 2023bee in NGC~2708 ($D = 32 \pm 3$ Mpc), finding excess flux in the first days after explosion relative to the expected power-law rise from an expanding fireball. This deviation from typical behavior for SNe Ia is particularly obvious in our 10-minute cadence $TESS$ light curve and $Swift$ UV data. Compared to a few other normal SNe Ia with detected early excess flux, the excess flux in SN 2023bee is redder in the UV and less luminous. We present optical spectra of SN 2023bee, including two spectra during the period where the flux excess is dominant. At this time, the spectra are similar to those of other SNe Ia but with weaker Si II, C II and Ca II absorption lines, perhaps because the excess flux creates a stronger continuum. We compare the data to several theoretical models that have been proposed to explain the early flux excess in SNe Ia. Interaction with either a nearby companion star or close-in circumstellar material is expected to produce a faster evolution than seen in the data. Radioactive material in the outer layers of the ejecta, either from a double detonation explosion or simply an explosion with a $^{56}$Ni clump near the surface, can not fully reproduce the evolution either, likely due to the sensitivity of early UV observable to the treatment of the outer part of ejecta in simulation. We conclude that no current model can adequately explain the full set of observations. We find that a relatively large fraction of nearby, bright SNe Ia with high-cadence observations have some amount of excess flux within a few days of explosion. Considering potential asymmetric emission, the physical cause of this excess flux may be ubiquitous in normal SNe Ia.Comment: 21 pages, 12 figures. Accepted by the astrophysical journa

Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs

MicroRNA (miRNA) play a major role in the post-transcriptional regulation of gene expression. Mammalian miRNA biogenesis begins with co-transcriptional cleavage of RNA polymerase II (Pol II) transcripts by the Microprocessor complex. While most miRNA are located within introns of protein coding genes, a substantial minority of miRNA originate from long non coding (lnc) RNA where transcript processing is largely uncharacterized. Here, by detailed characterization of liver-specific lnc-pri-miR-122 and genome-wide analysis, we show that most lnc-pri-miRNA do not use the canonical cleavage and polyadenylation (CPA) pathway but instead use Microprocessor cleavage to terminate transcription. Microprocessor inactivation leads to extensive transcriptional readthrough of lnc-pri-miRNA and transcriptional interference with downstream genes. Consequently we define a novel RNase III-mediated, polyadenylation-independent mechanism of Pol II transcription termination in mammalian cells

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms

Background: Hyperekplexia mutations have provided much information about glycine receptor structure and function. Results: Weidentified and characterized nine new mutations. Dominant mutations resulted in spontaneous activation, whereas recessive mutations precluded surface expression. Conclusion: These data provide insight into glycine receptor activation mechanisms and surface expression determinants. Significance: The results enhance our understanding of hyperekplexia pathology and glycine receptor structure-function. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Published in the U.S.A

A continuum from clear to cloudy hot-Jupiter exoplanets without primordial water depletion

Thousands of transiting exoplanets have been discovered, but spectral analysis of their atmospheres has so far been dominated by a small number of exoplanets and data spanning relatively narrow wavelength ranges (such as 1.1–1.7 micrometres). Recent studies show that some hot-Jupiter exoplanets have much weaker water absorption features in their near-infrared spectra than predicted. The low amplitude of water signatures could be explained by very low water abundances, which may be a sign that water was depleted in the protoplanetary disk at the planet’s formation location, but it is unclear whether this level of depletion can actually occur. Alternatively, these weak signals could be the result of obscuration by clouds or hazes, as found in some optical spectra. Here we report results from a comparative study of ten hot Jupiters covering the wavelength range 0.3–5 micrometres, which allows us to resolve both the optical scattering and infrared molecular absorption spectroscopically. Our results reveal a diverse group of hot Jupiters that exhibit a continuum from clear to cloudy atmospheres. We find that the difference between the planetary radius measured at optical and infrared wavelengths is an effective metric for distinguishing different atmosphere types. The difference correlates with the spectral strength of water, so that strong water absorption lines are seen in clear-atmosphere planets and the weakest features are associated with clouds and hazes. This result strongly suggests that primordial water depletion during formation is unlikely and that clouds and hazes are the cause of weaker spectral signatures

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual