Osteoporosis case finding in the general practice: phalangeal radiographic absorptiometry with and without risk factors for osteoporosis to select postmenopausal women eligible for lumbar spine and hip densitometry

Mass screening for osteoporosis using DXA measurements at the spine and hip is presently not recommended by health authorities. Instead, risk factor questionnaires and peripheral bone measurements may facilitate the selection of women eligible for axial bone densitometry. The aim of this study was to validate a case finding strategy for postmenopausal women who would benefit most from subsequent DXA measurement by using phalangeal radiographic absorptiometry (RA) alone or in combination with risk factors in a general practice setting. The sensitivity and specificity of this strategy in detecting osteoporosis (T-score ≤2.5SD at the spine and/or the hip) were compared with those of the current reimbursement criteria for DXA measurements in Switzerland. Four hundred and twenty-three postmenopausal women with one or more risk factors for osteoporosis were recruited by 90 primary care physicians who also performed the phalangeal RA measurements. All women underwent subsequent DXA measurement of the spine and the hip at the Osteoporosis Policlinic of the University Hospital of Berne. They were allocated to one of two groups depending on whether they matched with the Swiss reimbursement conditions for DXA measurement or not. Logistic regression models were used to predict the likelihood of osteoporosis versus "no osteoporosis” and to derive ROC curves for the various strategies. Differences in the areas under the ROC curves (AUC) were tested for significance. In women lacking reimbursement criteria, RA achieved a significantly larger AUC (0.81; 95% CI 0.72-0.89) than the risk factors associated with patients' age, height and weight (0.71; 95% C.I. 0.62-0.80). Furthermore, in this study, RA provided a better sensitivity and specificity in identifying women with underlying osteoporosis than the currently accepted criteria for reimbursement of DXA measurement. In the Swiss environment, RA is a valid case finding tool for patients with risk factors for osteoporosis, especially for those who do not qualify for DXA reimbursemen

Genetic diversity of the highly variable V1 region interferes with Human Immunodeficiency Virus type 1 envelope functionality.

BACKGROUND: The HIV envelope (Env) promotes viral entry in the host cell. During this process, Env undergoes several conformational changes to ensure its function. At the same time, the gp120 component of Env is the protein of the virus presenting the largest genetic diversity. Understanding how the virus maintains the balance between the competing requirements for maintenance of functionality and antigenic variation of this protein is central for the comprehension of its strategies of evolution and can highlight vulnerable aspects of its replication cycle. We focused on the variable domains V1 and V2 of the HIV-1 gp120 that are involved in conformational changes and are critical for viral escape from antibody neutralization. RESULTS: Despite the extensive sequence diversity found in the epidemic for these regions and their location on the external face of the protein, we observed that replacing V1V2 of one primary isolate with that of another severely interferes with Env functionality in more than half of the cases studied. Similar results were obtained for intra- and intersubtype chimeras. These observations are indicative of an interference of genetic diversity in these regions with Env functionality. Therefore, despite the extensive sequence diversity that characterizes these regions in the epidemic, our results show that functional constraints seem to limit their genetic variation. Defects in the V1V2 chimeras were not relieved by the insertion of the V3 region from the same isolate, suggesting that the decrease in functionality is not due to perturbation of potential coevolution networks between V1V2 and V3. Within the V1V2 domain, the sequence of the hypervariable loop of the V1 domain seems to be crucial for the functionality of the protein. CONCLUSIONS: Besides the well-documented role of V1V2 in the interplay with the immune response, this work shows that V1 is also involved in the selection of functional envelopes. By documenting a compromise between the opposing forces of sequence diversification and retention of functionality, these observations improve our understanding of the evolutionary trajectories of the HIV-1 envelope gene

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

peer reviewedDespite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain–specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA’s predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies

Age at onset as stratifier in idiopathic Parkinson’s disease – effect of ageing and polygenic risk score on clinical phenotypes

Several phenotypic differences observed in Parkinson’s disease (PD) patients have been linked to age at onset (AAO). We endeavoured to find out whether these differences are due to the ageing process itself by using a combined dataset of idiopathic PD (n = 430) and healthy controls (HC; n = 556) excluding carriers of known PD-linked genetic mutations in both groups. We found several significant effects of AAO on motor and non-motor symptoms in PD, but when comparing the effects of age on these symptoms with HC (using age at assessment, AAA), only positive associations of AAA with burden of motor symptoms and cognitive impairment were significantly different between PD vs HC. Furthermore, we explored a potential effect of polygenic risk score (PRS) on clinical phenotype and identified a significant inverse correlation of AAO and PRS in PD. No significant association between PRS and severity of clinical symptoms was found. We conclude that the observed non-motor phenotypic differences in PD based on AAO are largely driven by the ageing process itself and not by a specific profile of neurodegeneration linked to AAO in the idiopathic PD patients

Understanding the genetic flexibility of the HIV-1 envelope protein through the study of the network of its coevolving amino acids

Une des caractéristiques du Virus de l’Immunodéficience Humaine de type 1 (VIH-1) est sa diversification génétique extensive, qui lui permet d’échapper au système immunitaire. Néanmoins, il est nécessaire que le taux de mutation requis pour à cette évolution rapide ne compromette pas la fonctionnalité de ses protéines. Les travaux présentés ici ont eu pour objectif l’étude des réseaux de coévolution qui composent les glycoprotéines d’enveloppe (Env) afin de comprendre les règles qui sous-tendent leur évolution. Il a été mis en évidence que les régions variables de ces protéines, grâce à leur flexibilité structurelle, peuvent aussi servir à faciliter l’incorporation de mutations touchant les régions plus constantes. De plus, un réseau de coévolution impliqué dans les changements de conformations nécessaires à l’activité de Env a été identifié, soutenant le fait que ces régions variables ont un rôle central dans ces changements. Ces études démontrent le rôle crucial joué par les régions variables en dévoilant un nouvel aspect de leur contribution à l’évolution du VIH-1.The Human Immunodeficiency Virus type 1 (HIV-1) is characterized by an extensive genetic diversification of its strains that allows the virus to escape the immune system. However, the mutation rate needed for this rapid evolution must not compromise the functionality of the viral proteins. The aim of the work presented here has been to study the coevolution networks that constitute the envelope glycoproteins (Env) in order to understand the rules driving their evolution. The results have highlighted that variable regions, thanks to their structural freedom, can facilitate the incorporation of mutations in more constant regions. Moreover, a coevolution network involved in the conformational changes required for the activity of Env has been identified, underlining the central role played by variable regions in these processes. Besides underscoring the crucial role played by variable regions in the functionality of Env, these studies unveil a new aspect of their contribution to HIV-1 evolution

Understanding the genetic flexibility of the HIV-1 envelope protein through the study of the network of its coevolving amino acids

Une des caractéristiques du Virus de l’Immunodéficience Humaine de type 1 (VIH-1) est sa diversification génétique extensive, qui lui permet d’échapper au système immunitaire. Néanmoins, il est nécessaire que le taux de mutation requis pour à cette évolution rapide ne compromette pas la fonctionnalité de ses protéines. Les travaux présentés ici ont eu pour objectif l’étude des réseaux de coévolution qui composent les glycoprotéines d’enveloppe (Env) afin de comprendre les règles qui sous-tendent leur évolution. Il a été mis en évidence que les régions variables de ces protéines, grâce à leur flexibilité structurelle, peuvent aussi servir à faciliter l’incorporation de mutations touchant les régions plus constantes. De plus, un réseau de coévolution impliqué dans les changements de conformations nécessaires à l’activité de Env a été identifié, soutenant le fait que ces régions variables ont un rôle central dans ces changements. Ces études démontrent le rôle crucial joué par les régions variables en dévoilant un nouvel aspect de leur contribution à l’évolution du VIH-1.The Human Immunodeficiency Virus type 1 (HIV-1) is characterized by an extensive genetic diversification of its strains that allows the virus to escape the immune system. However, the mutation rate needed for this rapid evolution must not compromise the functionality of the viral proteins. The aim of the work presented here has been to study the coevolution networks that constitute the envelope glycoproteins (Env) in order to understand the rules driving their evolution. The results have highlighted that variable regions, thanks to their structural freedom, can facilitate the incorporation of mutations in more constant regions. Moreover, a coevolution network involved in the conformational changes required for the activity of Env has been identified, underlining the central role played by variable regions in these processes. Besides underscoring the crucial role played by variable regions in the functionality of Env, these studies unveil a new aspect of their contribution to HIV-1 evolution

Comprendre la flexibilité génétique de la protéine d’enveloppe de VIH-1 à travers l’étude du réseau de coévolution de ses acides aminés

The Human Immunodeficiency Virus type 1 (HIV-1) is characterized by an extensive genetic diversification of its strains that allows the virus to escape the immune system. However, the mutation rate needed for this rapid evolution must not compromise the functionality of the viral proteins. The aim of the work presented here has been to study the coevolution networks that constitute the envelope glycoproteins (Env) in order to understand the rules driving their evolution. The results have highlighted that variable regions, thanks to their structural freedom, can facilitate the incorporation of mutations in more constant regions. Moreover, a coevolution network involved in the conformational changes required for the activity of Env has been identified, underlining the central role played by variable regions in these processes. Besides underscoring the crucial role played by variable regions in the functionality of Env, these studies unveil a new aspect of their contribution to HIV-1 evolution.Une des caractéristiques du Virus de l’Immunodéficience Humaine de type 1 (VIH-1) est sa diversification génétique extensive, qui lui permet d’échapper au système immunitaire. Néanmoins, il est nécessaire que le taux de mutation requis pour à cette évolution rapide ne compromette pas la fonctionnalité de ses protéines. Les travaux présentés ici ont eu pour objectif l’étude des réseaux de coévolution qui composent les glycoprotéines d’enveloppe (Env) afin de comprendre les règles qui sous-tendent leur évolution. Il a été mis en évidence que les régions variables de ces protéines, grâce à leur flexibilité structurelle, peuvent aussi servir à faciliter l’incorporation de mutations touchant les régions plus constantes. De plus, un réseau de coévolution impliqué dans les changements de conformations nécessaires à l’activité de Env a été identifié, soutenant le fait que ces régions variables ont un rôle central dans ces changements. Ces études démontrent le rôle crucial joué par les régions variables en dévoilant un nouvel aspect de leur contribution à l’évolution du VIH-1

TheReSE: SysML extension for thermal modeling

International audienceDuring the conceptual design phase, System Architects perform fast pre-validation of alternative architectures of the system to be designed. In order to provide them with a means to achieve this task, a SysML extension called TheReSE is proposed. It aims at modeling thermal effects on components with simplified geometry, by covering radiation, conduction, and convection heat transfers. It also ensures traceability between requirements and simulation results. In order to assess the relevance of this extension, this approach has been applied to an aircraft air conditioning case study

Automatic runtime customization for variability awareness on multicore platforms

Driven by increasingly aggressive CMOS technology scaling, sub-wavelength lithography is incurring more evident variability in the technology parameters of the semiconductors fabrication process. That variability results in otherwise identical designs displaying very different performances, power consumption levels and lifespans once fabricated. Hence, process variability may lead to execution uncertainties, impacting the expected quality of service and energy efficiency of the running software. As such uncertainties are intolerable in certain application domains such as automotive and avionic infotainment systems, it has become a persistent necessity to customize runtime engines to introduce measures for variability awareness in task allocation decisions. The purpose of compensating process variability is to avoid performance degradation and energy inefficiency. And customization is meant to take place automatically through exporting the variability-impacted platform characteristics - such as per-core manufactured clock frequency - for the runtime library to perform variability-aware workload sharing on the target cores of the hardware platform. Hence, we can eventually achieve noticeable optimization results, not only on the system performance and energy consumption levels, but also in increasing productivity in systems development, testing, integration, and marketing. This paper presents a holistic approach starting from a system model of the target multicore platform, to building and integrating the runtime library, and finally highlighting the optimization results achieved through the proposed runtime customization paradig