As climate change research becomes increasingly applied, the need for actionable information is growing rapidly. A key aspect of this requirement is the representation of uncertainties. The ...conventional approach to representing uncertainty in physical aspects of climate change is probabilistic, based on ensembles of climate model simulations. In the face of deep uncertainties, the known limitations of this approach are becoming increasingly apparent. An alternative is thus emerging which may be called a ‘storyline’ approach. We define a storyline as a physically self-consistent unfolding of past events, or of plausible future events or pathways. No a priori probability of the storyline is assessed; emphasis is placed instead on understanding the driving factors involved, and the plausibility of those factors. We introduce a typology of four reasons for using storylines to represent uncertainty in physical aspects of climate change: (i) improving risk awareness by framing risk in an event-oriented rather than a probabilistic manner, which corresponds more directly to how people perceive and respond to risk; (ii) strengthening decision-making by allowing one to work backward from a particular vulnerability or decision point, combining climate change information with other relevant factors to address compound risk and develop appropriate stress tests; (iii) providing a physical basis for partitioning uncertainty, thereby allowing the use of more credible regional models in a conditioned manner and (iv) exploring the boundaries of plausibility, thereby guarding against false precision and surprise. Storylines also offer a powerful way of linking physical with human aspects of climate change.
Osteoporotic fractures present a major health problem with an increasing prevalence in older people. Fractures are associated with premature mortality, reduced quality of life, subsequent fracture, ...and increased costs. Hence, it is crucial to identify those at higher risk of fracture. Fracture risk assessment tools incorporated clinical risk factors to improve fracture predictive power over BMD alone. However, fracture risk prediction using these algorithms remains suboptimal, warranting further improvement.
Muscle strength and physical performance measurements have been associated with fracture risk. In contrast, the contribution of sarcopenia, the composite condition of low muscle mass, muscle strength and/or physical performance, to fracture risk is unclear. It is uncertain whether this is due to the problematic definition of sarcopenia per se or limitations of the diagnostic tools and cut-off points of the muscle mass component. The recent position statement from the Sarcopenia Definition and Outcomes Consortium confirmed the inclusion of muscle strength and performance in the definition of sarcopenia but not DXA-assessed lean mass. Therefore, clinicians should focus on functional assessment (muscle strength and performance) rather than muscle mass, at least as assessed by DXA, as predictors of fractures.
Muscle strength and performance are modifiable risk factors. Resistance exercise improves muscle parameters in the elderly, potentially leading to reduced risk of falls and fractures in the general population and in those who sustained a fracture. Therapists may consider exercise intervention to improve muscle parameters and potentially reduce the risk of fractures.
The aim of this review was to explore 1) the contribution of muscle parameters (i.e., muscle mass, strength, and physical performance) to fracture risk in older adults, and 2) the added predictive accuracy of these parameters beyond the existing fracture assessment tools. These topics provide the rationale for investigating strength and physical performance interventions to reduce fracture risk.
Most of the included publications showed that muscle mass is not a good predictor of fracture risk, while poor muscle strength and performance are associated with an increased risk of fracture, particularly in men, independent of age, BMD, and other risk factors for fractures. Muscle strength and performance can potentially improve the predictive accuracy in men beyond that obtained by the fracture risk assessment tools, Garvan FRC and FRAX.
•Muscle strength and physical performance are associated with fracture risk.•Their rate of decline is associated with fractures independent of baseline values.•Muscle strength and physical performance significantly improve fracture prediction.•DXA-measured muscle mass shows inconsistent association with fracture risk.
Approximately 12,000 glioblastomas are diagnosed annually in the United States. The median survival rate for this disease is 12 months, but individual survival rates can vary with patient-specific ...factors, including extent of surgical resection (EOR). The goal of our investigation is to develop a reliable strategy for personalized survival prediction and for quantifying the relationship between survival, EOR, and adjuvant chemoradiotherapy.
We used accelerated failure time (AFT) modeling using data from 721 newly diagnosed patients with glioblastoma (from 1993 to 2010) to model the factors affecting individualized survival after surgical resection, and we used the model to construct probabilistic, patient-specific tools for survival prediction. We validated this model with independent data from 109 patients from a second institution.
AFT modeling using age, Karnofsky performance score, EOR, and adjuvant chemoradiotherapy produced a continuous, nonlinear, multivariable survival model for glioblastoma. The median personalized predictive error was 4.37 months, representing a more than 20% improvement over current methods. Subsequent model-based calculations yield patient-specific predictions of the incremental effects of EOR and adjuvant therapy on survival.
Nonlinear, multivariable AFT modeling outperforms current methods for estimating individual survival after glioblastoma resection. The model produces personalized survival curves and quantifies the relationship between variables modulating patient-specific survival. This approach provides comprehensive, personalized, probabilistic, and clinically relevant information regarding the anticipated course of disease, the overall prognosis, and the patient-specific influence of EOR and adjuvant chemoradiotherapy. The continuous, nonlinear relationship identified between expected median survival and EOR argues against a surgical management strategy based on rigid EOR thresholds and instead provides the first explicit evidence supporting a maximum safe resection approach to glioblastoma surgery.
Working memory (WM) is a central construct in cognitive neuroscience because it comprises mechanisms of active information maintenance and cognitive control that underpin most complex cognitive ...behavior. Individual variation in WM has been associated with multiple behavioral and health features including demographic characteristics, cognitive and physical traits and lifestyle choices. In this context, we used sparse canonical correlation analyses (sCCAs) to determine the covariation between brain imaging metrics of WM-network activation and connectivity and nonimaging measures relating to sensorimotor processing, affective and nonaffective cognition, mental health and personality, physical health and lifestyle choices derived from 823 healthy participants derived from the Human Connectome Project. We conducted sCCAs at two levels: a global level, testing the overall association between the entire imaging and behavioral-health data sets; and a modular level, testing associations between subsets of the two data sets. The behavioral-health and neuroimaging data sets showed significant interdependency. Variables with positive correlation to the neuroimaging variate represented higher physical endurance and fluid intelligence as well as better function in multiple higher-order cognitive domains. Negatively correlated variables represented indicators of suboptimal cardiovascular and metabolic control and lifestyle choices such as alcohol and nicotine use. These results underscore the importance of accounting for behavioral-health factors in neuroimaging studies of WM and provide a neuroscience-informed framework for personalized and public health interventions to promote and maintain the integrity of the WM network.
•CFA of the 17 items of the HRSD demonstrated sub-optimal psychometric performance.•EFA failed to identify a model of depression for the HRSD-17 at baseline and psychometric performance of the ...outcome model with baseline data was sub-optimal.•Abbreviated outcome models demonstrated adequate fit.•The HRSD-17 was sex non-invariant, while abbreviated models were scalar non-invariant meaning male and female scores should not be compared.•Neither the HRSD-17 nor the found abbreviated model is appropriate for use in antidepressant clinical trials.
The 17-item Hamilton Rating Scale for Depression (HRSD-17) is the most popular depression measure in antidepressant clinical trials. Prior evidence indicates poor replicability and inconsistent factorial structure. This has not been studied in pooled randomised trial data, nor has a psychometrically optimal model been developed.
To examine the psychometric properties of the HRSD-17 for pre-treatment and post-treatment clinical trial data in a large pooled database of antidepressant randomised controlled trial participants, and to determine an optimal abbreviated version.
Data for 6843 participants were obtained from the data repository Vivli.org and randomly split into groups for exploratory (n = 3421) and confirmatory (n = 3422) factor analysis. Invariance methods were used to assess potential sex differences.
The HRSD-17 was psychometrically sub-optimal and non-invariant for all models. High item variances and low variance explained suggested redundancy in each model. EFA failed at baseline and produced four item models for outcome groups (five for placebo-outcome), which were metric but not scalar invariant.
In antidepressant trial data, the HRSD-17 was psychometrically inadequate and scores were not sex invariant. Neither full nor abbreviated HRSD models are suitable for use in clinical trial settings and the HRSD's status as the gold standard should be reconsidered.
Abstract
Context
Bisphosphonates have been reported to be cardioprotective in some, but not all, studies. It is unknown whether denosumab (Dmab) use protects against cardiovascular events (CVEs).
...Objective
To determine whether oral bisphosphonate (oBP) or Dmab use is associated with CVEs in persons with incident fracture.
Methods
Participants with an incident minimal trauma fracture from the Sax Institute’s 45 and Up Study, a population-based cohort from NSW, Australia, were followed between 2005/2009 and 2017. Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection APDC) by the Centre for Health Record Linkage). Medicare Benefit Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data sets were provided by Services Australia. Data was stored in a secure computing environment (Secure Unified Research Environment). Fractures, CVEs, and comorbidities were identified from the APDC and oBP and Dmab medication from the PBS. oBP and Dmab users were matched to never users (NoRx) by propensity scores. The main outcome measures were association between oBP and Dmab with CVE (acute myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) and were determined using a stratified Cox's proportional hazards model.
Results
There were 880 pairs of oBP and NoRx (616 women) and 770 pairs of Dmab and NoRx (615 women) followed for ∼4.3 years. CVE risk was similar for oBP and NoRx Hazard Ratios (HR) women, 0.88 95% CI 0.65-1.18; men, 1.07 95% CI 0.72-1.57). Similar findings were obtained for Dmab (Hazard Ratios (HR) women, 1.08 95% CI 0.78-1.50; men, 1.55 95% CI 0.96-2.48).
Conclusion
oBP and Dmab use was not associated with CVEs.
Reviewing three relevant streams of extant literature reveals a marked absence of a generic framework composed of a full range of negative manager/leader behaviors (from moderate to extreme) across ...sectors and countries, a void particularly detrimental to the effectiveness of management and leadership development (MLD) programs. To address this concern, we conduct a multiple cross‐case/cross‐nation comparative analysis (MCCA) of data collected from our own 13 previous empirical replication studies (using the critical incident technique) of effective/ineffective managerial/leader behavior across nine culturally diverse countries and varied private sector industries, resulting in a comprehensive framework of perceived negative manager/leader behavior. Our generic framework is composed of five behavioral dimensions: inadequate functional behavior, unethical behavior, impersonal domineering behavior, depriving behavior, and closed/negative‐minded behavior, and lends support to the universal school of culture in business literature by showing that neither national culture nor sectorial specificities influence people's perceptions of negative manager/leader behavior. It also stresses the importance of the mundane (as opposed to the glorious) in managerial/leadership work by revealing that employees' perceptions of negative manager/leader behavior include not only conspicuously “bad” behaviors but also less conspicuous “poor” behaviors.
Most chromosomal deletions and duplications (copy-number variants) that are associated with neurodevelopmental disorders are known to result in a wide variation of clinical phenotypes. This study ...describes a genetic mechanism for such variation.
Genomic rearrangements are an important source of genetic and phenotypic variation. Rare, recurrent copy-number variants of pathogenic significance, termed genomic disorders, were originally identified in persons with a characteristic set of clinically recognizable features, such as the Smith–Magenis syndrome, the Sotos syndrome, and the Williams–Beuren syndrome. Although unexplained phenotypic variation and differences in severity have long been recognized among patients with the same genomic disorder,
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comparatively recent discoveries of potentially pathogenic copy-number variants have broadened the phenotypic range associated with a given variant to include entirely distinct diseases. High-throughput analyses of patient populations have implicated the same copy-number variants . . .
Translocator protein (TSPO) is upregulated in activated microglia and thus can serve as a marker of neuroinflammation. Recently, a novel radioligand, ...(11)C-N,N-diethyl-2-2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo1,5-apyrimidin-3-yl-acetamide ((11)C-DPA-713), has been described that binds to TSPO with high affinity. Here, we report the first examination of (11)C-DPA-713 in human subjects using PET.
Five healthy controls were studied with PET for 90 min after a bolus injection of high-specific-activity (11)C-DPA-713. For comparison, 2 additional healthy controls were studied with (11)C-R-PK11195. Arterial blood sampling and metabolite analysis were performed to allow the accurate quantification of tracer kinetics. Tracer uptake was evaluated for several brain regions. Tissue time-activity curves were fitted using 1- and 2-tissue-compartment models, with goodness-of-fit tests showing a preference for the 2-tissue model.
In the healthy brain, the average plasma-to-tissue clearance and the total volume of distribution were an order of magnitude larger than measured for (11)C-R-PK11195. Accordingly, dose-normalized time-activity curves showed that (11)C-DPA-713 gives a larger brain signal.
Studies in patient populations will help determine whether (11)C-DPA-713 provides better sensitivity for evaluating increased TSPO expression. This initial study in humans shows that (11)C-DPA-713 is a promising ligand for evaluating TSPO binding with PET.
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