Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

BACKGROUND: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. FINDINGS: Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. INTERPRETATION: Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. FUNDING: Marinus Pharmaceuticals

Techniques and tools for measuring energy efficiency of scientific software applications

Volume: 608The scale of scientific High Performance Computing (HPC) and High Throughput Computing (HTC) has increased significantly in recent years, and is becoming sensitive to total energy use and cost. Energy-efficiency has thus become an important concern in scientific fields such as High Energy Physics (HEP). There has been a growing interest in utilizing alternate architectures, such as low power ARM processors, to replace traditional Intel x86 architectures. Nevertheless, even though such solutions have been successfully used in mobile applications with low I/O and memory demands, it is unclear if they are suitable and more energy-efficient in the scientific computing environment. Furthermore, there is a lack of tools and experience to derive and compare power consumption between the architectures for various workloads, and eventually to support software optimizations for energy efficiency. To that end, we have performed several physical and software-based measurements of workloads from HEP applications running on ARM and Intel architectures, and compare their power consumption and performance. We leverage several profiling tools (both in hardware and software) to extract different characteristics of the power use. We report the results of these measurements and the experience gained in developing a set of measurement techniques and profiling tools to accurately assess the power consumption for scientific workloads.Peer reviewe

Trophic complexity enhances ecosystem functioning in an aquatic detritus-based model system

1. Understanding the functional significance of species interactions in ecosystems has become a major challenge as biodiversity declines rapidly worldwide. Ecosystem consequences arising from the loss of diversity either within trophic levels (horizontal diversity) or across trophic levels (vertical diversity) are well documented. However, simultaneous losses of species at dif- ferent trophic levels may also result in interactive effects, with potentially complex outcomes for ecosystem functioning. 2. Because of logistical constraints, the outcomes of such interactions have been difficult to assess in experiments involving large metazoan species. Here, we take advantage of a detri- tus–based model system to experimentally assess the consequences of biodiversity change within both horizontal and vertical food-web components on leaf-litter decomposition, a fun- damental process in a wide range of ecosystems. 3. Our concurrent manipulation of fungal decomposer diversity (0, 1 or 5 species), detritivore diversity (0, 1 or 3 species), and the presence of predatory fish scent showed that trophic com- plexity is key to eliciting diversity effects on ecosystem functioning. Specifically, although fungi and detritivores tended to promote decomposition individually, rates were highest in the most complete community where all trophic levels were represented at the highest possible species richness. In part, the effects were trait-mediated, reflected in the contrasting foraging responses of the detritivore species to predator scent. 4. Our results thus highlight the importance of interactive effects of simultaneous species loss within multiple trophic levels on ecosystem functioning. If a common phenomenon, this out- come suggests that functional ecosystem impairment resulting from widespread biodiversity loss could be more severe than inferred from previous experiments confined to varying diver- sity within single trophic levels

Kidney transplant in diabetic patients: modalities, indications and results

<p>Abstract</p> <p>Background</p> <p>Diabetes is a disease of increasing worldwide prevalence and is the main cause of chronic renal failure. Type 1 diabetic patients with chronic renal failure have the following therapy options: kidney transplant from a living donor, pancreas after kidney transplant, simultaneous pancreas-kidney transplant, or awaiting a deceased donor kidney transplant. For type 2 diabetic patients, only kidney transplant from deceased or living donors are recommended. Patient survival after kidney transplant has been improving for all age ranges in comparison to the dialysis therapy. The main causes of mortality after transplant are cardiovascular and cerebrovascular events, infections and neoplasias. Five-year patient survival for type 2 diabetic patients is lower than the non-diabetics' because they are older and have higher body mass index on the occasion of the transplant and both pre- and posttransplant cardiovascular diseases prevalences. The increased postransplant cardiovascular mortality in these patients is attributed to the presence of well-known risk factors, such as insulin resistance, higher triglycerides values, lower HDL-cholesterol values, abnormalities in fibrinolysis and coagulation and endothelial dysfunction. In type 1 diabetic patients, simultaneous pancreas-kidney transplant is associated with lower prevalence of vascular diseases, including acute myocardial infarction, stroke and amputation in comparison to isolated kidney transplant and dialysis therapy.</p> <p>Conclusion</p> <p>Type 1 and 2 diabetic patients present higher survival rates after transplant in comparison to the dialysis therapy, although the prevalence of cardiovascular events and infectious complications remain higher than in the general population.</p

Atención primaria de salud en la Enfermedad Cerebrovascular

Se realiza un estudio retrospectivo-descriptivo para evaluar las acciones de salud que el Médico de la Familia realizó sobre los pacientes con enfermedad cerebrovascular y que fallecieron por ese motivo en el Área de Salud "Carlos Verdugo", Matanzas, durante los años 1994 y 1995. Se estudiaron 50 fallecidos en entrevista médico-familiar; se obtuvieron los datos de, edad, sexo y antecedentes patológicos personales que recogieron: enfermedades crónicas y factores de riesgo; dispensarización, que recogió número de controles realizados en los últimos 12 meses que precedieron a la defunción ya fueran en consultas, visitas de terreno y visitas integrales, así como el cumplimiento del tratamiento indicado. Se encontró que se dispensarizaron en el 100 % de los fallecidos la hipertensión arterial, la cardiopatía isquémica, la obesidad y la hiperlipidemia. El 72,4 % (12 fallecidos) recibió entre 1 y 3 controles en consultas. El 79,3 % (16 fallecidos) recibió entre 1 y 3 controles en visitas de terreno y el 100 % se controló entre 1 y 3 ocasiones en visitas integrales a la familia. Se concluyó que el cumplimiento del tratamiento indicado para la enfermedad cerebrovascular, los factores de riesgo y enfermedades crónicas no fue satisfactorio en el grupo estudiado. Se recomienda realizar un mayor número de controles en la atención primaria a los pacientes con enfermedad cerebrovascular sobre todo cuando en la dispensarización se encuentra la asociación hipertensión arterial, hábito de fumar y mayores de 65 años.<br>A retrospective descriptive study was conducted to evaluate the health actions taken by the family physician in connection with those patients that suffered from cerebrovascular disease and died due to this cause in the "Carlos Verdugo" health area, Matanzas, during 1994 and 1995. 50 dead patients were studied through doctor relative interviews. The following data were obtained: age, sex, personal pathological history; including chronic diseases and risk factors, classification; which made possible to know the number of controls made during the last 12 months before death at the physician office or through field visits and comprehensive visits, and the fulfilment of treatment. 100 % of the dead patients were classified into arterial hypertension, ischaemic heart disease, obesity and hyperlipidaemia. 72.4 % (12 deceased patients) received between I and 3 controls at the physician's office. 79.3 % (16 dead patients) were controlled between 1 and 3 times by field visits, whereas 100 % were controlled from 1 to 3 occassions in comprehensive visits to the family. It was concluted that the fulfilment of the treatment indicated for the cerebrovascular disease, the risk factors and the chronic diseases was not satisfactory in the studied group. It is recommended to increase the number of controls at the primary care level among those patients with cerebrovascular disease, mainly when within the classification there is an association between hypertension and smoking habit in patients over 65