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Bone and bone marrow are not only anatomically, but also functionally interdependent. In a systematic review, we examined bone health in patients with hematopoietic disorders and demonstrated that an increased hematopoietic cell proliferation, such as in patients with hemolytic anemias, was associated with bone loss, while bone marrow hypocellularity, such as in patients with chronic myelofibrosis (CMF), was associated with bone gain [Steer K et al. J Bone Miner Res 2017]. Since bone mass in CMF increases at the expense of bone marrow, it contributes to patients' morbidity as it is associated with bone pain, and mortality as it may lead to bone marrow failure. A mouse model with a global knockout of the megakaryocyte (MK) lineage specific inhibitory receptor G6b-B was shown to develop myelofibrosis secondary to aberrant platelet production and function [Mazharian A et al Sci Signal 2012]. Moreover, a group of patients with primary myelofibrosis was identified to have loss-of-function mutations in the G6b-B gene [Hofmann I et al Blood 2018]. The objective of this study was to characterize temporal changes in the skeleton of the G6b-B knockout mice. We examined age- and sex-related changes in 4, 8, 16, and 32 week-old G6b-B+/+, G6b-B-/- female and male mice. Starting from 8 weeks-of-age, spleen progressively increased in female G6b-B-/- mice compared to corresponding G6b-B+/+ mice, reaching 2.9-fold increase at 32 weeks (p < 0.001) (Fig.1A). Micro-computed tomography analysis of femur demonstrated that starting at 8 weeks of age female G6b-B-/- mice had a significantly higher proportion of cortical bone and a respectively lower proportion of marrow (Fig.1B). Starting at 16 weeks of age, female G6b-B-/- mice developed trabecula in the medullary cavity normally occupied by the bone marrow, which by 32 weeks led to a 38-fold increase (p < 0.001) in the proportion of bone to tissue volume compared to G6b-B+/+ (Fig.1C,D). At 32-weeks of age, female G6b-B-/- mice also demonstrated a 7-fold increase in BV/TV (p < 0.001) in the region of metaphysis. While some abnormalities were found in male G6b-B-/- mice, they were considerably less severe compared to females. To establish whether the observed bone phenotype is due to MK and platelet functional defects, we performed microcomputed tomography analysis on femurs of 22 week-old G6b-Bfl/fl;Gp1ba-Cre-/- mice with a MK/platelet-specific knockout of G6b-B. Changes in trabecular bone of G6b-Bfl/fl;Gp1ba-Cre-/- mice recapitulated changes of G6b-B-/- mice. However, periosteal perimeter in male G6b-Bfl/fl;Gp1ba-Cre-/- mice was significantly larger, and in female G6b-Bfl/fl;Gp1ba-Cre-/- mice - significantly smaller than in corresponding control mice, while in global G6b-B-/- mice periosteal perimeter was not affected. Female G6b-B-/- mice demonstrated severe splenomegaly as well as progressive osteosclerosis, which was confirmed in G6b-Bfl/fl;Gp1ba-Cre-/- mice, indicating that trabecular bone gain in G6b-B-/- mice is consequent to a MK disfunction. Dramatic sexual dimorphism suggests that sex-related factors play an important role in the development of osteosclerosis. The differences in cortical bone phenotype between the global and conditional knockout of G6b-B suggest the potential role of G6b-B signaling in osteoclasts or osteoblasts. This study demonstrates that MK-associated myelofibrosis is sufficient to induce osteosclerosis of bone marrow, and that sex hormones play an important role either in protecting male mice from osteosclerosis or in exacerbating osteosclerosis in female mice. Disclosures No relevant conflicts of interest to declare.

Faldaprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, was evaluated in HCV genotype 1-infected patients who failed peginterferon and ribavirin (PegIFN/RBV) treatment during one of three prior faldaprevir trials. Patients who received placebo plus PegIFN/RBV and had virological failure during a prior trial were enrolled and treated in two cohorts: prior relapsers (n = 43) and prior nonresponders (null responders, partial responders and patients with breakthrough; n = 75). Both cohorts received faldaprevir 240 mg once daily plus PegIFN/RBV for 24 weeks. Prior relapsers with early treatment success (ETS; HCV RNA <25 IU/mL detectable or undetectable at week 4 and <25 IU/mL undetectable at week 8) stopped treatment at week 24. Others received PegIFN/RBV through week 48. The primary efficacy endpoint was sustained virological response (HCV RNA <25 IU/mL undetectable) 12 weeks post treatment (SVR12). More prior nonresponders than prior relapsers had baseline HCV RNA ≥ 800,000 IU/mL (80% vs 58%) and a non-CC IL28B genotype (91% vs 70%). Rates of SVR12 (95% CI) were 95.3% (89.1, 100.0) among prior relapsers and 54.7% (43.4, 65.9) among prior nonresponders; corresponding ETS rates were 97.7% and 65.3%. Adverse events led to faldaprevir discontinuations in 3% of patients. The most common Division of AIDS Grade ≥ 2 adverse events were anaemia (13%), nausea (10%) and hyperbilirubinaemia (9%). In conclusion, faldaprevir plus PegIFN/RBV achieved clinically meaningful SVR12 rates in patients who failed PegIFN/RBV in a prior trial, with response rates higher among prior relapsers than among prior nonresponders. The adverse event profile was consistent with the known safety profile of faldaprevir.

Amino acids play fundamental roles in the cell both as the building blocks of new proteins and as metabolic precursors. To adapt to their limitation during periods of protein starvation, multiple adaptive mechanisms have evolved, including a rapid cessation of new protein synthesis, an increase in amino acid biosynthesis and transport, and autophagy. Here, we discuss what we currently know about how amino acid limitation is sensed, and how this sensing might be transmitted to mTORC1 to regulate protein synthesis and autophagy.

A benzoylthiourea-pyrrolidine catalyst was developed for the asymmetric Michael addition of ketones to chalcones. The corresponding products were obtained in high yields with high level of diastereoselectivities (up to 99:1 dr) and high level of enantioselectivities (up to 94% ee) under mild conditions.

The implications of increased understanding of the genetic contribution to schizophrenia for patients and their families remain unclear. We carried out a study of Chinese patients’ (n = 118) and relatives’ (n = 78) views of illness severity, attribution of cause, concern about developing illness, and effect of schizophrenia on family planning. A comparison sample of English-survey respondents was also obtained, using the same series of questions (n = 42 patients, n = 127 relatives). Fewer Chinese patients and family members rated schizophrenia as very severe (33%) than did the predominantly North American respondents (67%, p < 0.0001). The pattern of attribution of cause differed between samples (p < 0.0001), favouring environmental alone in the Chinese sample (52%), with a low frequency of genetics alone (9%). Although comparatively fewer Chinese respondents were very concerned about developing schizophrenia themselves or about the risk of illness in their families (21%), this high level of concern was more common in family members (28%). Finally, Chinese respondents were somewhat less likley to indicate that schizophrenia impacted on family planning decisions (31%) than were English-survey respondents (45%, p = 0.02). The descriptive findings contribute to understanding schizophrenia in China. The comparative findings must be regarded as preliminary, since differences in demographics could influence results. The present findings suggest that understanding patients’ and families’ attributions of cause of schizophrenia may be important for developing a shared model of illness in order to decrease stigmatization, and improve therapeutic alliances.

Few scientific studies present gender-based analyses on the subject of mistreatment experienced by older women. Nevertheless, women who have lived through such a situation can suffer serious consequences in their daily lives. How do they react when they have been mistreated? How do they express a request for help—or do they ask at all? This chapter presents the findings from research carried out in Quebec (Canada), as part of a doctoral dissertation that uses a phenomenological research design, and that seeks to better understand older women’s experience of mistreatment, the decision-making process that leads them to ask—or not ask—for help in this context, and the significance they attribute to this request for help. The chapter begins with a description of the state of knowledge on mistreatment of older adults and the objectives to, and incentives for, asking for help following an episode of mistreatment. Next, it presents the methodological approach, from data collection through to their analysis using NVivo software, and a sample composed of five women aged between 71 and 77. Semi-directed, qualitative interviews were held with these women. This section is followed by a diagrammatic conceptual framework for the main findings drawn from a review of the literature and an analysis of the data. Finally, avenues are suggested so that more mistreated older women will be encouraged to break the silence about their experiences and share their stories with someone they trust.

A controlled quantum system can alter its environment by feedback, leading to reduced-entropy states of the environment and to improved system coherence. Here, using a quantum-dot electron spin as a control and probe, we prepare the quantum-dot nuclei under the feedback of coherent population trapping and observe their evolution from a thermal to a reduced-entropy state, with the immediate consequence of extended qubit coherence. Via Ramsey interferometry on the electron spin, we directly access the nuclear distribution following its preparation and measure the emergence and decay of correlations within the nuclear ensemble. Under optimal feedback, the inhomogeneous dephasing time of the electron, T_{2}^{*}, is extended by an order of magnitude to 39 ns. Our results can be readily exploited in quantum information protocols utilizing spin-photon entanglement and represent a step towards creating quantum many-body states in a mesoscopic nuclear-spin ensemble. We acknowledge financial support from the European Research Council ERC Consolidator Grant Agreement No. 617985 and the EPSRC National Quantum Technologies Program NQIT EP/M013243/1. G.E-M. acknowledges financial support from NSERC.

This paper analyzes subsidy schemes that are widely used in reducing waiting times for public healthcare service. We assume that public healthcare service has no user fee but an observable delay, while private healthcare service has a fee but no delay. Patients in the public system are given a subsidy s to use private service if their waiting times exceed a pre-determined threshold t. We call these subsidy schemes (s, t) policies. As two extreme cases, the (s, t) policy is called an unconditional subsidy scheme if t = 0, and a full subsidy scheme if s is equal to the private service fee. There is a fixed budget constraint so that a scheme with larger s has a larger t. We assess policies using two criteria: total patient cost and serviceability (i.e. the probability of meeting a waiting time target for public service). We prove analytically that, if patients are equally sensitive to delay, a scheme with a smaller subsidy outperforms one with a larger subsidy on both criteria. Thus, the unconditional scheme dominates all other policies. Using empirically derived parameter values from the Hong Kong Cataract Surgery Program, we then compare policies numerically when patients differ in delay sensitivity. Total patient cost is now unimodal in subsidy amount: the unconditional scheme still yields the lowest total patient cost, but the full subsidy scheme can outperform some intermediate policies. Serviceability is unimodal too, and the full subsidy scheme can outperform the unconditional scheme in serviceability when the waiting time target is long. This article is protected by copyright. All rights reserved.