Depth of Anesthesia and Postoperative Delirium Abbott, Thomas E. F; Pearse, Rupert M
JAMA : the journal of the American Medical Association,
02/2019, Letnik:
321, Številka:
5
Journal Article
Abstract GWSkyNet-Multi is a machine learning model developed for the classification of candidate gravitational-wave events detected by the LIGO and Virgo observatories. The model uses limited ...information released in the low-latency Open Public Alerts to produce prediction scores indicating whether an event is a merger of two black holes (BHs), a merger involving a neutron star (NS), or a non-astrophysical glitch. This facilitates time-sensitive decisions about whether to perform electromagnetic follow-up of candidate events during LIGO-Virgo-KAGRA (LVK) observing runs. However, it is not well understood how the model is leveraging the limited information available to make its predictions. As a deep learning neural network, the inner workings of the model can be difficult to interpret, impacting our trust in its validity and robustness. We tackle this issue by systematically perturbing the model and its inputs to explain what underlying features and correlations it has learned for distinguishing the sources. We show that the localization area of the 2D sky maps and the computed coherence versus incoherence Bayes factors are used as strong predictors for distinguishing between real events and glitches. The estimated distance to the source is further used to discriminate between binary BH mergers and mergers involving NSs. We leverage these findings to show that events misclassified by GWSkyNet-Multi in LVK’s third observing run have distinct sky areas, coherence factors, and distance values that influence the predictions and explain these misclassifications. The results help identify the model’s limitations and inform potential avenues for further optimization.
Abstract
Compact object mergers which produce both detectable gravitational waves and electromagnetic (EM) emission can provide valuable insights into the neutron star equation of state, the tension ...in the Hubble constant, and the origin of the
r
-process elements. However, EM follow-up of gravitational wave sources is complicated by false-positive detections, and the transient nature of the associated EM emission.
GWSkyNet-Multi
is a machine learning model that attempts facilitate EM follow-up by providing real-time predictions of the source of a gravitational wave detection. The model uses information from Open Public Alerts (OPAs) released by LIGO–Virgo within minutes of a gravitational wave detection.
GWSkyNet
was introduced in Cabero et al. as a binary classifier and uses the OPA skymaps to classify sources as either astrophysical or as glitches. In this paper, we introduce
GWSkyNet-Multi
, an extension of
GWSkyNet
which further distinguishes sources as binary black hole mergers, mergers involving a neutron star, or non-astrophysical glitches.
GWSkyNet-Multi
is a sequence of three one-versus-all classifiers trained using a class-balanced and physically motivated source mass distribution. Training on this data set, we obtain test set accuracies of 93.7% for binary black hole-versus-all, 94.4% for neutron star-versus-all, and 95.1% for glitch-versus-all. We obtain an overall accuracy of 93.4% using a hierarchical classification scheme. Furthermore, we correctly identify 36 of the 40 gravitational wave detections from the first half of LIGO–Virgo’s third observing run (O3a) and present predictions for O3b sources. As gravitational wave detections increase in number and frequency,
GWSkyNet-Multi
will be a powerful tool for prioritizing successful EM follow-up.
L-Histidine Decarboxylase and Tourette's Syndrome Ercan-Sencicek, A. Gulhan; Stillman, Althea A; Ghosh, Ananda K ...
Nature reviews. Neuroscience,
05/2010, Letnik:
362, Številka:
20
Journal Article
Recenzirano
Odprti dostop
Susceptibility to Tourette's syndrome is known to have a genetic influence. This study, of a nonconsanguineous family in which the father and his eight children are affected by the disorder, ...implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder.
This study of a nonconsanguineous family in which the father and his eight children are affected by Tourette's syndrome implicates a deficit in L-histidine decarboxylase activity as one potential cause of the disorder.
Tourette's syndrome is characterized by childhood onset, waxing and waning symptomatology, and typically, improvement in adulthood. The molecular underpinnings of the disorder remain uncertain, although multiple lines of evidence suggest involvement of dopaminergic neurotransmission and abnormalities involving cortical–striatal–thalamic–cortical circuitry.
1
Current treatment focuses on tic reduction and management of prevalent coexisting conditions such as obsessive–compulsive disorder and attention deficit–hyperactivity disorder. However, therapeutic options have limited efficacy and may carry clinically significant side effects. Consequently, the development of new treatments based on an improved understanding of disease pathophysiology is a high priority.
2
The large genetic contribution to Tourette's syndrome is well established. . . .
To characterize the relationships between adherence (compliance and persistence) to bisphosphonate therapy and risk of specific fracture types in postmenopausal women.
Data were collected from 45 ...employers and 100 health plans in the continental United States from 2 claims databases during a 5-year period (January 1, 1999, through December 31, 2003). Claims from patients receiving a bisphosphonate prescription (alendronate or risedronate) were evaluated for 6 months before the index prescription and during 24 months of follow-up to determine total, vertebral, and nonvertebral osteoporotic fractures, persistence (no gap in refills for >30 days during 24 months), and refill compliance (medication possession ratio ≥0.80).
The eligible cohort included 35,537 women (age, ≥45 years) who received a bisphosphonate prescription. A subgroup with a specified diagnosis of postmenopausal osteoporosis was also evaluated. Forty-three percent were refill compliant, and 20% persisted with bisphosphonate therapy during the 24-month study period. Total, vertebral, nonvertebral, and hip fractures were significantly lower in refill-compliant and persistent patients, with relative risk reductions of 20% to 45%. The relationship between adherence and fracture risk remained significant after adjustment for baseline age, concomitant medications, and fracture history. There was a progressive relationship between refill compliance and fracture risk reduction, commencing at refill compliance rates of approximately 50% and becoming more pronounced at compliance rates of 75% and higher.
Adherence to bisphosphonate therapy was associated with significantly fewer fractures at 24 months. Increasing refill compliance levels were associated with progressively lower fracture rates. These findings suggest that incremental changes in medication-taking habits could improve clinical outcomes of osteoporosis treatment.
Abstract Objectives Major guidelines regarding the application of cost-effectiveness analysis (CEA) have recommended the common and widespread use of the “societal perspective” for purposes of ...consistency and comparability. The objective of this Task Force subgroup report (one of six reports from the International Society for Pharmacoeconomics and Outcomes Research ISPOR Task Force on Good Research Practices—Use of Drug Costs for Cost Effectiveness Analysis Drug Cost Task Force (DCTF)) was to review the definition of this perspective, assess its specific application in measuring drug costs, identify any limitations in theory or practice, and make recommendations regarding potential improvements. Methods Key articles, books, and reports in the methodological literature were reviewed, summarized, and integrated into a draft review and report. This draft report was posted for review and comment by ISPOR membership. Numerous comments and suggestions were received, and the report was revised in response to them. Results The societal perspective can be defined by three conditions: 1) the inclusion of time costs, 2) the use of opportunity costs, and 3) the use of community preferences. In practice, very few, if any, published CEAs have met all of these conditions, though many claim to have taken a societal perspective. Branded drug costs have typically used actual acquisition cost rather than the much lower social opportunity costs that would reflect only short-run manufacturing and distribution costs. This practice is understandable, pragmatic, and useful to current decision-makers. Nevertheless, this use of CEA focuses on static rather than dynamic efficacy and overlooks the related incentives for innovation. Conclusions Our key recommendation is that current CEA practice acknowledge and embrace this limitation by adopting a new standard for the reference case as one of a “limited societal” or “health systems” perspective, using acquisition drug prices while including indirect costs and community preferences. The field of pharmacoeconomics also needs to acknowledge the limitations of this perspective when it comes to important questions of research and development costs, and incentives for innovation.
Osteoporosis and 1‐year fracture risk were studied in 197,848 postmenopausal American women from five ethnic groups. Weight explained differences in BMD, except among blacks, who had the highest BMD. ...One SD decrease in BMD predicted a 50% increased fracture risk in each group. Despite similar relative risks, absolute fracture rates differed.
Introduction: Most information about osteoporosis comes from studies of white women. This study describes the frequency of osteoporosis and the association between BMD and fracture in women from five ethnic groups.
Materials and Methods: This study was made up of a cohort of 197,848 community‐dwelling postmenopausal women (7784 blacks, 1912 Asians, 6973 Hispanics, and 1708 Native Americans) from the United States, without known osteoporosis or a recent BMD test. Heel, forearm, or finger BMD was measured, and risk factor information was obtained; 82% were followed for 1 year for new fractures. BMD and fracture rates were compared, adjusting for differences in covariates.
Results: By age 80, more than one‐fifth of women in each ethnic group had peripheral BMD T scores <−2.5. Black women had the highest BMD; Asian women had the lowest. Only the BMD differences for blacks were not explained by differences in weight. After 1 year, 2414 new fractures of the spine, hip, forearm, wrist, or rib were reported. BMD at each site predicted fractures equally well within each ethnic group. After adjusting for BMD, weight, and other covariates, white and Hispanic women had the highest risk for fracture (relative risk ‘RR’ 1.0 ‘referent group’ and 0.95, 95% CI, 0.76, 1.20, respectively), followed by Native Americans (RR, 0.87; 95% CI, 0.57, 1.32), blacks (RR, 0.52; 95% CI, 0.38, 0.70), and Asian Americans (RR, 0.32; 95% CI, 0.15, 0.66). In age‐ and weight‐adjusted models, each SD decrease in peripheral BMD predicted a 1.54 times increased risk of fracture in each ethnic group (95% CI, 1.48‐1.61). Excluding wrist fractures, the most common fracture, did not materially change associations.
Conclusions: Ethnic differences in BMD are strongly influenced by body weight; fracture risk is strongly influenced by BMD in each group. Ethnic differences in absolute fracture risk remain, which may warrant ethnic‐specific clinical recommendations.
Successful addiction treatment depends on maintaining long-term abstinence, making relapse prevention an essential therapeutic goal. However, exposure to environmental cues associated with drug use ...often thwarts abstinence efforts by triggering drug using memories that drive craving and relapse. We sought to develop a dual approach for weakening cocaine memories through phosphoproteomic identification of targets regulated in opposite directions by memory extinction compared with reconsolidation in male Sprague-Dawley rats that had been trained to self-administer cocaine paired with an audiovisual cue. We discovered a novel, inversely regulated, memory-dependent phosphorylation event on calcium-calmodulin-dependent kinase II α (CaMKIIα) at serine (S)331. Correspondingly, extinction-associated S331 phosphorylation inhibited CaMKIIα activity. Intra-basolateral amygdala inhibition of CaMKII promoted memory extinction and disrupted reconsolidation, leading to a reduction in subsequent cue-induced reinstatement. CaMKII inhibition had no effect if the memory was neither retrieved nor extinguished. Therefore, inhibition of CaMKII represents a novel mechanism for memory-based addiction treatment that leverages both extinction enhancement and reconsolidation disruption to reduce relapse-like behavior.
Preventing relapse to drug use is an important goal for the successful treatment of addictive disorders. Relapse-prevention therapies attempt to interfere with drug-associated memories, but are often hindered by unintentional memory strengthening. In this study, we identify phosphorylation events that are bidirectionally regulated by the reconsolidation versus extinction of a cocaine-associated memory, including a novel site on CaMKIIα. Additionally, using a rodent model of addiction, we show that CaMKII inhibition in the amygdala can reduce relapse-like behavior. Together, our data supports the existence of mechanisms that can be used to enhance current strategies for addiction treatment.
CONTEXT Large segments of the population at risk for osteoporosis and fracture
have not been evaluated, and the usefulness of peripheral measurements for
short-term prediction of fracture risk is ...uncertain. OBJECTIVES To describe the occurrence of low bone mineral density (BMD) in postmenopausal
women, its risk factors, and fracture incidence during short-term follow-up. DESIGN The National Osteoporosis Risk Assessment, a longitudinal observational
study initiated September 1997 to March 1999, with approximately 12 months
of subsequent follow-up. SETTING AND PARTICIPANTS A total of 200 160 ambulatory postmenopausal women aged 50 years
or older with no previous osteoporosis diagnosis, derived from 4236 primary
care practices in 34 states. MAIN OUTCOME MEASURES Baseline BMD T scores, obtained from peripheral bone densitometry performed
at the heel, finger, or forearm; risk factors for low BMD, derived from questionnaire
responses; and clinical fracture rates at 12-month follow-up. RESULTS Using World Health Organization criteria, 39.6% had osteopenia (T score
of –1 to –2.49) and 7.2% had osteoporosis (T score ≤−2.5).
Age, personal or family history of fracture, Asian or Hispanic heritage, smoking,
and cortisone use were associated with significantly increased likelihood
of osteoporosis; higher body mass index, African American heritage, estrogen
or diuretic use, exercise, and alcohol consumption significantly decreased
the likelihood. Among the 163 979 participants with follow-up information,
osteoporosis was associated with a fracture rate approximately 4 times that
of normal BMD (rate ratio, 4.03; 95% confidence interval CI, 3.59-4.53)
and osteopenia was associated with a 1.8-fold higher rate (95% CI, 1.49-2.18). CONCLUSIONS Almost half of this population had previously undetected low BMD, including
7% with osteoporosis. Peripheral BMD results were highly predictive of fracture
risk. Given the economic and social costs of osteoporotic fractures, strategies
to identify and manage osteoporosis in the primary care setting need to be
established and implemented.
Protein fouling is a critical problem for ultrafiltration (UF) and microfiltration (MF). In the latest decade, a Fourier-transform infrared (FT-IR) spectroscopic method has been developed to quantify ...protein secondary structure by employing the amide I spectral region. The most attractive feature of FT-IR analysis is its ability to analyze proteins in various conditions. In this study, we employed FT-IR to quantify the conformational change of protein fouled on polysulfone (PS) UF membrane and polytetrafluoroethylene (PTFE) MF membrane. Bovine serum albumin (BSA) was adopted as a model protein. BSA adsorption onto the membranes was performed at 4°C and gel-like BSA deposits on the membranes were prepared by filtration at room temperature. FT-IR analysis revealed that the BSA adsorbed onto PS UF membrane had little change in the secondary structure, whereas the BSA adsorbed onto PTFE MF membrane had remarkable changes in the secondary structure, which were a decrease in α-helix content from 66 to 50% and an increase in β-sheet content from 21 to 36%. In addition, gel-like BSA deposits on both of the membranes had marked changes in secondary structure, which were similar to the changes in the BSA adsorbed onto the PTFE MF membrane. And the BSA concentration did not significantly affect the changes in the secondary structure of BSA fouled on both the UF and MF membranes.
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