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Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. 77 patients were randomly assigned to study groups (15–16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Sanofi US and Regeneron Pharmaceuticals Incorporated.

Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). Whether suffering from \"true\" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted. This study is registered in clinicaltrials.gov (NCT01493648).

The potential of data assimilation for hydrologic predictions has been demonstrated in many research studies. Watersheds over which multiple observation types are available can potentially further benefit from data assimilation by having multiple updated states from which hydrologic predictions can be generated. However, the magnitude and time span of the impact of the assimilation of an observation varies according not only to its type, but also to the variables included in the state vector. This study examines the impact of multivariate synthetic data assimilation using the ensemble Kalman filter (EnKF) into the spatially distributed hydrologic model CEQUEAU for the mountainous Nechako River located in British Columbia, Canada. Synthetic data include daily snow cover area (SCA), daily measurements of snow water equivalent (SWE) at three different locations and daily streamflow data at the watershed outlet. Results show a large variability of the continuous rank probability skill score over a wide range of prediction horizons (days to weeks) depending on the state vector configuration and the type of observations assimilated. Overall, the variables most closely linearly linked to the observations are the ones worth considering adding to the state vector due to the limitations imposed by the EnKF. The performance of the assimilation of basin-wide SCA, which does not have a decent proxy among potential state variables, does not surpass the open loop for any of the simulated variables. However, the assimilation of streamflow offers major improvements steadily throughout the year, but mainly over the short-term (up to 5 days) forecast horizons, while the impact of the assimilation of SWE gains more importance during the snowmelt period over the mid-term (up to 50 days) forecast horizon compared with open loop. The combined assimilation of streamflow and SWE performs better than their individual counterparts, offering improvements over all forecast horizons considered and throughout the whole year, including the critical period of snowmelt. This highlights the potential benefit of using multivariate data assimilation for streamflow predictions in snow-dominated regions.

By taking a historical perspective on the higher education and the housing sectors in Quebec, we demonstrate how the political cleavage around the national question has had long-term effects on the dynamic of contention in these two sectors. At a general level, the presence of this cleavage has favoured the adoption of institutional arrangements related to funding that have allowed the reproduction of social protest over time. Nevertheless, the institutional arrangements vary from one sector to another: in the case of higher education, Bill 32, adopted in 1983, facilitated the division of the student movement into two branches and, to some extent, its dynamism; in the case of housing, the AccèsLogis program and the contribution au secteur, implemented in 1997, ensured the selection of claims for social housing and favoured the grouping that leads this issue. In both cases, the national question is at the heart of the process that led to the adoption of these policies.

Present guidelines emphasise the importance of low concentrations of LDL cholesterol (LDL-C) in patients with familial hypercholesterolaemia. In most patients with the disease, however, these concentrations are not achieved with present treatments, so additional treatment is therefore warranted. Inhibition of cholesteryl ester transfer protein has been shown to reduce LDL-C concentrations in addition to regular statin treatment in patients with hypercholesterolaemia or at high risk of cardiovascular disease. We aimed to investigate the safety and efficacy of anacetrapib, a cholesteryl ester transfer protein inhibitor, in patients with heterozygous familial hypercholesterolaemia. In this multicentre, randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18–80 years with a genotype-confirmed or clinical diagnosis of heterozygous familial hypercholesterolaemia, on optimum lipid-lowering treatment for at least 6 weeks, and with an LDL-C concentration of 2·59 mmol/L or higher without cardiovascular disease or 1·81 mmol/L or higher with cardiovascular disease from 26 lipid clinics across nine countries were eligible. We randomly allocated participants with a computer-generated allocation schedule (2:1; block size of six; no stratification) to oral anacetrapib 100 mg or placebo for 52 weeks, with a 12 week post-treatment follow-up afterwards. We masked patients, care providers, and those assessing outcomes to treatment groups throughout the study. The primary outcome was percentage change from baseline in LDL-C concentration. We did analysis using a constrained longitudinal repeated measures model. This trial is registered with ClinicalTrials.gov, number NCT01524289. Between Feb 10, 2012, and Feb 12, 2014, we randomly allocated 204 patients to anacetrapib and 102 to placebo. One patient in the anacetrapib group did not receive the drug. At week 52, anacetrapib reduced mean LDL-C concentration from 3·3 mmol/L (SD 0·8) to 2·1 mmol/L (0·8; percentage change 36·0% [95% CI −39·5 to −32·5] compared with an increase with placebo from 3·4 mmol/L (1·2) to 3·5 mmol/L (1·6; percentage change 3·7% [–1·2 to 8·6], with a difference in percentage change between anacetrapib and placebo of −39·7% (95% CI −45·7 to −33·7; p<0·0001). The number of cardiovascular events was increased in patients given anacetrapib compared with those given placebo (4 [2%] of 203 vs none [0%] of 102; p=0·1544), but the proportion with adverse events leading to discontinuation was similar (12 [6%] of 203 vs five [5%] of 102). In patients with heterozygous familial hypercholesterolaemia, treatment with anacetrapib for 1 year was well tolerated and resulted in substantial reductions in LDL-C concentration. Whether this change leads to a reduction of cardiovascular events will be answered in an outcome study. Merck & Co, Inc

The 2022 adoption of a new policy framework on community support in social housing in Québec speaks to a convergence of a multitude of community, government, and municipal actors around this practice. This qualitative study delves into the process by which this approach was institutionalized to demonstrate how community support became a central norm of the social housing field in the province. Drawing from literature on the welfare mix, we situate this phenomenon in the broader context of the transformation of the welfare state, in which nonprofit organizations played an increasing role in providing social housing to vulnerable populations (e.g., people at risk of homelessness). This article demonstrates how power dynamics and negotiations between the state and the third sector were, in this case, a major source of institutional change over time. L’adoption en 2022 d’un nouveau cadre de référence sur le soutien communautaire en logement social au Québec témoigne de la convergence d’une multitude d’acteurs communautaires, gouvernementaux et municipaux autour de cette pratique. Cet article retrace le processus d’institutionnalisation de cette approche pour montrer comment l’offre de soutien communautaire est devenue une norme centrale dans le champ du logement social. En reprenant les écrits sur le welfare mix, nous situons ce phénomène dans le contexte plus large de la transformation de l’État-providence où les organismes sans but lucratif ont joué un rôle grandissant dans la provision de logements sociaux pour des populations vulnérables (ex. personnes à risque d’itinérance). Nous faisons ressortir que les relations de pouvoir et les négociations entre l’État et le tiers secteur ont été dans ce cas une source importante de changement institutionnel au fil du temps.

An important step when using some data assimilation methods, such as the ensemble Kalman filter and its variants, is to calibrate its parameters. Also called hyper-parameters, these include the model and observation errors, which have previously been shown to have a strong impact on the performance of the data assimilation method. Many metrics can be used to calibrate these hyper-parameters but may not all yield the same optimal set of values. The current study investigated the importance of the choice of metric used during the hyper-parameter calibration phase and its impact on discharge forecasts. The types of metrics used each focused on discharge accuracy, ensemble spread or observation-minus-background statistics. The calibration was performed for the ensemble square root Kalman filter over two catchments in Canada using two different hydrologic models per catchment. Results show that the optimal set of hyper-parameters depended heavily on the choice of metric used during the calibration phase, where data assimilation was applied. These sets of hyper-parameters in turn produced different hydrologic forecasts. This influence was reduced as the forecast lead time increased, because of not applying data assimilation in the forecast mode, and accordingly, convergence of model state ensembles produced in the calibration phase. However, the influence could remain considerable for a few days up to multiple weeks depending on the catchment and the model. As such, a preliminary analysis would be recommended for future studies to better understand the impact that metrics can have within and outside the bounds of hyper-parameter calibration.

The fall of the Berlin Wall on November 9th, 1989, inevitably altered the landscape of modern geopolitical history. Watch never before seen footage taken from both sides of the wall, providing a glimpse at the everyday lives of the Berliners living within its confines.

A case of eruptive xanthomas with exceptionally high levels of blood triglycerides without any complication during pregnancy is reported. Eruptive xanthomas may develop in the setting of severe hypertriglyceridemia. Clinically, patients present with small and smooth papules with a characteristic yellow hue. The condition can also be associated with morbid systemic complications. Estrogen replacement therapy is a known cause of secondary hypertriglyceridemia. Estrogen increase in pregnancy is associated with a physiologic elevation of blood triglycerides in order to provide sufficient nutrition for the fetus. However, in the setting of primary dyslipidemia, severe hypertriglyceridemia can occur. The case presented here was explained by a partial primary lipoprotein lipase deficiency with a heterozygous G188E mutation of the LPL gene. The delivery by induced labor and the introduction of fenofibrate led to a rapid decrease of triglycerides and a resolution of cutaneous lesions without any complication for the patient or her baby.

Background Previous studies have reported high plasma concentrations of both intestinal apolipoprotein (apo) B-48-containing lipoproteins and PCSK9 in subjects with familial hypercholesterolemia (FH). However, the extent to which LDL receptor deficiency and PCSK9 levels influence plasma apoB-48 concentrations in humans remains to be fully characterized. The objective of the study was to assess the independent association between FH, PCSK9 concentrations and plasma apoB-48 levels in a large cohort of genetically defined FH heterozygotes (HeFH) and homozygotes (HoFH). Methods A total of 118 HeFH, 6 HoFH, and 117 controls were included in the study. Plasma PCSK9 and apoB-48 concentrations were measured in the fasting state. Results Plasma PCSK9 and apoB-48 levels were higher in FH subjects compared with controls (PCSK9: HoFH: 642.6 ± 246.9 vs. HeFH: 324.9 ± 119.8 vs. controls: 194.5 ± 65.9 ng/mL, P  < 0.0001; apoB-48: HoFH: 14.71 ± 4.36 vs. HeFH: 6.55 ± 4.24 vs. controls: 3.03 ± 2.07 μg/mL; P  < 0.0001). There were no correlations between apoB-48 and PCSK9 plasma levels in both controls (ρ = 0.06, P  = 0.5) and HeFH subjects (ρ = 0.07, P  = 0.4). Multiple linear regression analysis showed that the FH status was the only independent factor associated with apoB-48 levels, contributing to 28.7% of the variance ( P  < 0.0001). Conclusions These data indicate that the elevation in plasma apoB-48 levels associated with FH is independent of PCSK9 levels. Trial registration NCT02225340 .