Development and validation of an improved algorithm for overlaying flexible molecules

A program for overlaying multiple flexible molecules has been developed. Candidate overlays are generated by a novel fingerprint algorithm, scored on three objective functions (union volume, hydrogen-bond match, and hydrophobic match), and ranked by constrained Pareto ranking. A diverse subset of the best ranked solutions is chosen using an overlay-dissimilarity metric. If necessary, the solutions can be optimised. A multi-objective genetic algorithm can be used to find additional overlays with a given mapping of chemical features but different ligand conformations. The fingerprint algorithm may also be used to produce constrained overlays, in which user-specified chemical groups are forced to be superimposed. The program has been tested on several sets of ligands, for each of which the true overlay is known from protein–ligand crystal structures. Both objective and subjective success criteria indicate that good results are obtained on the majority of these sets

Factors affecting the measurement variability of SV95C in ambulant patients with Duchenne muscular dystrophy

peer reviewedStride Velocity at the 95th Centile (SV95C) is a novel clinical outcome measure that is captured during normal daily living using wearable technology and represents the maximum ambulatory ability of a patient. SV95C is qualified by the European Medicines agency (EMA) for use as a secondary endpoint in pivotal studies in DMD, and is an important real-world functional endpoint complementary to the traditional in-clinic assessments such as the North Star Ambulatory Assessment scale and the Six Meter Walk Test. The Context of Use of SV95C as defined by EMA states that SV95C should be measured for at least 50h during normal daily living to yield an outcome variability that would render SV95C suitable for regulatory decision-making. Considering the increasing use of SV95C in drug development for DMD, it is critical to understand the most common drivers of endpoint variability. Using data from ActiLiège-NEXT, a prospective natural history study in ambulant patients with DMD designed to longitudinally characterise functional disease progression using multiple outcome measures, we evaluated the impact of the time of day, the day of the week as well as seasonal changes on the measurement variability of SV95C in ambulant patients with DMD. Specifically, SV95C will be computed for morning only (8am-12pm) and afternoon recording periods (2pm-6pm) and compared. A similar sensitivity analysis will be done for SV95C computed on weekdays (Monday-Friday) and weekend (Saturday-Sunday). The seasonal impact on the compliance and SV95C will be conducted on longitudinal data and adjusted by the geographical location of the patients, restricting to countries where the maximal temperature difference over the year exceeds 15° and maximal temperature does not exceed 30°C. This data provides important context to the factors that impact the measurement variability of SV95C and will be useful to inform clinical trial design in DMD, when using SV95C as an outcome measure of efficacy

Longitudinal multi-centric study to assess the digital outcomes issued from wearable magneto-inertial devices in ambulant DMD

peer reviewedDuchenne muscular dystrophy is a muscle disease characterized by severe and rapidly progressive muscle weakness. One of the key challenges in treating this condition is identifying objective, reliable, and sensitive outcome measures to measure the effects of drug. For this purpose, the ActiMyo® (Sysnav, France), a magneto-inertial wearable device, was developed. Among the assessments with performed by this wearable device, the 95th centile stride velocity (SV95C) was qualified as the 2nd endpoint in 2019 by the European Medical Agency, representing the most rapid 5% of strides during real-life activities. The ActiLiège study is a multicentre clinical study with the aim of gathering data issued from a magneto-inertial wearable. Ambulant patients with DMD and healthy controls were included and will be followed up for three years. The patients wore the ActiMyo® on their ankle and wrist during the first 3 months after the inclusion and afterwards for one month every 3 months. Controls wear the device for a period of one month every 12 months. Digital outputs from the wearable sensors are compared to gold standard assessments. We enrolled seventy-six ambulant DMD patients aged between 4 and 20 years in 7 centres (Belgium, Poland, Hungary, Romania, Czech Republic, Slovenia, and Egypt). Thirty-five of them completed at least 1 year of follow-up. All ambulant patients were either on a 6-month stable course of steroids or started steroids at baseline. The baseline data of the patients and controls will be presented, along with longitudinal data that may provide an indication of sensitivity to change in comparison with other commonly performed outcomes

Analysis of the natural evolution of SV95C in ambulant patients with Duchenne muscular dystrophy

peer reviewedThe progressive nature of functional loss in Duchenne Muscular Dystrophy (DMD) is well established and routinely characterised in clinic using assessments such as the North Star Ambulatory Assessment and the Six Meter Walk Test. The trajectory of functional loss depends on the patient's age and baseline functional ability. There is a need to better characterise the trajectory of disease progression in order to try to predict disease evolution and optimise patient care. Stride Velocity at the 95th Centile (SV95C) is a novel clinical outcome measure that is captured during normal daily living using wearable technology and represents the maximum ambulatory ability of a patient. SV95C is qualified by the European Medicines agency (EMA) for use as a secondary endpoint in pivotal studies in DMD and is an important real-world functional endpoint complementing the traditional in-clinic assessments. SV95C declines by approximately 7% per year in ambulant patients with DMD who are on a stable dose of steroids. In other functional endpoints such as the NSAA and 6MWT the decline is dependent on the patient's age and baseline ambulatory abilities. This study aims to investigate how yearly change of SV95C is also dependent upon age and baseline function. We will analyse how the evolution of SV95C can be predicted by the baseline value of SV95C and age, using non-linear and linear multiparametric regression models. This analysis will be conducted on data from ActiLiège-NEXT, a prospective natural history study in ambulant patients with DMD. This study was designed to characterise longitudinal functional disease progression using multiple outcome measures, including SV95C. It includes patients with DMD between 4 and 20 years old studied over 1 year. SV95C was measured daily using ActiMyo®, a class I CE medical device with two sensors worn on the ankles. These data will advance our understanding of the importance of SV95C as an outcome measure for functional disease progression in DMD

Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder

Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22–5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment

Ethnic inequalities in positive SARS-CoV-2 tests, infection prognosis, COVID-19 hospitalisations and deaths: Analysis of 2 years of a record linked national cohort study in Scotland

Background This study aims to estimate ethnic inequalities in risk for positive SARS-CoV-2 tests, COVID-19 hospitalisations and deaths over time in Scotland. Methods We conducted a population-based cohort study where the 2011 Scottish Census was linked to health records. We included all individuals ≥ 16 years living in Scotland on 1 March 2020. The study period was from 1 March 2020 to 17 April 2022. Self-reported ethnic group was taken from the census and Cox proportional hazard models estimated HRs for positive SARS-CoV-2 tests, hospitalisations and deaths, adjusted for age, sex and health board. We also conducted separate analyses for each of the four waves of COVID-19 to assess changes in risk over time. Findings Of the 4 358 339 individuals analysed, 1 093 234 positive SARS-CoV-2 tests, 37 437 hospitalisations and 14 158 deaths occurred. The risk of COVID-19 hospitalisation or death among ethnic minority groups was often higher for White Gypsy/Traveller (HR 2.21, 95% CI (1.61 to 3.06)) and Pakistani 2.09 (1.90 to 2.29) groups compared with the white Scottish group. The risk of COVID-19 hospitalisation or death following confirmed positive SARS-CoV-2 test was particularly higher for White Gypsy/Traveller 2.55 (1.81-3.58), Pakistani 1.75 (1.59-1.73) and African 1.61 (1.28-2.03) individuals relative to white Scottish individuals. However, the risk of COVID-19-related death following hospitalisation did not differ. The risk of COVID-19 outcomes for ethnic minority groups was higher in the first three waves compared with the fourth wave. Interpretation Most ethnic minority groups were at increased risk of adverse COVID-19 outcomes in Scotland, especially White Gypsy/Traveller and Pakistani groups. Ethnic inequalities persisted following community infection but not following hospitalisation, suggesting differences in hospital treatment did not substantially contribute to ethnic inequalities

Reducing pain in children with cancer: Methodology for the development of a clinical practice guideline

Abstract Although pain is one of the most prevalent and bothersome symptoms children with cancer experience, evidence-based guidance regarding assessment and management is lacking. With 44 international, multidisciplinary healthcare professionals and nine patient representatives, we aimed to develop a clinical practice guideline (following GRADE methodology), addressing assessment and pharmacological, psychological, and physical management of tumor-, treatment-, and procedure-related pain in children with cancer. In this paper, we present our thorough methodology for this development, including the challenges we faced and how we approached these. This lays the foundation for our clinical practice guideline, for which there is a high clinical demand

Reducing pain in children with cancer: Methodology for the development of a clinical practice guideline

Abstract Although pain is one of the most prevalent and bothersome symptoms children with cancer experience, evidence-based guidance regarding assessment and management is lacking. With 44 international, multidisciplinary healthcare professionals and nine patient representatives, we aimed to develop a clinical practice guideline (following GRADE methodology), addressing assessment and pharmacological, psychological, and physical management of tumor-, treatment-, and procedure-related pain in children with cancer. In this paper, we present our thorough methodology for this development, including the challenges we faced and how we approached these. This lays the foundation for our clinical practice guideline, for which there is a high clinical demand