To determine the frequency and temporal changes in application of seven accepted methodological standards for the evaluation of diagnostic tests.
A search of the MEDLINE database yielded 1302 ...articles about diagnostic test studies, during a 16-year secular interval, 1978 through 1993, in four prominent general medical journals.
In the 112 eligible studies, the test was intended for clinical use, indexes of accuracy (sensitivity and specificity or likelihood ratios) were provided, and more than 10 patients were enrolled.
Although each study was critically reviewed by one primary observer, a subset was independently evaluated for interrater consistency.
The percentage of studies that fulfilled criteria for each of the seven methodological standards are as follows: (1) specify spectrum of evaluated patients, 27%; (2) report test indexes for clinical subgroups, 8%; (3) avoid workup bias, 46%; (4) avoid review bias, 38%; (5) provide numerical precision for test indexes, 11%; (6) report frequency and management of indeterminate results when calculating test indexes, 22%; and (7) specify test reproducibility, 23%. Secular increases were found for six of the seven standards in ranges of use from 14% to 31% during 1978-1981 to 1990-1993. Nevertheless, only one standard, avoidance of workup bias, was fulfilled by more than 50% of studies in the most recent secular interval.
These results indicate that most diagnostic tests are still inadequately appraised. The routine demand for methodological standards could raise the quality of diagnostic test information, and the careful predissemination evaluation of diagnostic tests could eliminate useless tests before they receive widespread application.
Despite the prominent use of complex survey data and the growing popularity of machine learning methods in epidemiologic research, few machine learning software implementations offer options for ...handling complex samples. A major challenge impeding the broader incorporation of machine learning into epidemiologic research is incomplete guidance for analyzing complex survey data, including the importance of sampling weights for valid prediction in target populations. Using data from 15, 820 participants in the 1988-1994 National Health and Nutrition Examination Survey cohort, we determined whether ignoring weights in gradient boosting models of all-cause mortality affected prediction, as measured by the F1 score and corresponding 95% confidence intervals. In simulations, we additionally assessed the impact of sample size, weight variability, predictor strength, and model dimensionality. In the National Health and Nutrition Examination Survey data, unweighted model performance was inflated compared to the weighted model (F1 score 81.9% 95% confidence interval: 81.2%, 82.7% vs 77.4% 95% confidence interval: 76.1%, 78.6%). However, the error was mitigated if the F1 score was subsequently recalculated with observed outcomes from the weighted dataset (F1: 77.0%; 95% confidence interval: 75.7%, 78.4%). In simulations, this finding held in the largest sample size (N = 10,000) under all analytic conditions assessed. For sample sizes <5,000, sampling weights had little impact in simulations that more closely resembled a simple random sample (low weight variability) or in models with strong predictors, but findings were inconsistent under other analytic scenarios. Failing to account for sampling weights in gradient boosting models may limit generalizability for data from complex surveys, dependent on sample size and other analytic properties. In the absence of software for configuring weighted algorithms, post-hoc re-calculations of unweighted model performance using weighted observed outcomes may more accurately reflect model prediction in target populations than ignoring weights entirely.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alagille syndrome (ALGS) is characterized by chronic cholestasis with associated pruritus and extrahepatic anomalies. Maralixibat, an ileal bile acid transporter inhibitor, is an approved ...pharmacologic therapy for cholestatic pruritus in ALGS. Since long-term placebo-controlled studies are not feasible or ethical in children with rare diseases, a novel approach was taken comparing 6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the G lobal AL agille A lliance (GALA) study.
Maralixibat trials comprise 84 patients with ALGS with up to 6 years of treatment. GALA contains retrospective data from 1438 participants. GALA was filtered to align with key maralixibat eligibility criteria, yielding 469 participants. Serum bile acids could not be included in the GALA filtering criteria as these are not routinely performed in clinical practice. Index time was determined through maximum likelihood estimation in an effort to align the disease severity between the two cohorts with the initiation of maralixibat. Event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods. Sensitivity analyses and adjustments for covariates were applied. Age, total bilirubin, gamma-glutamyl transferase, and alanine aminotransferase were balanced between groups with no statistical differences. Event-free survival in the maralixibat cohort was significantly better than the GALA cohort (HR, 0.305; 95% CI, 0.189-0.491; p <0.0001). Multiple sensitivity and subgroup analyses (including serum bile acid availability) showed similar findings.
This study demonstrates a novel application of a robust statistical method to evaluate outcomes in long-term intervention studies where placebo comparisons are not feasible, providing wide application for rare diseases. This comparison with real-world natural history data suggests that maralixibat improves event-free survival in patients with ALGS.
The aim of this study was to examine drivers of durable viral suppression (DVS) disparities among people with HIV (PWH) using quantitative intersectional approaches.
A retrospective cohort analysis ...from electronic health records informed by intersectionality to better capture the concept of interlocking and interacting systems of oppression.
We analyzed data of PWH seen at a LGBTQ federally qualified health center in Chicago (2012-2019) with at least three viral loads. We identified PWH who achieved DVS using latent trajectory analysis and examined disparities using three intersectional approaches: Adding interactions, latent class analysis (LCA), and qualitative comparative analysis (QCA). Findings were compared with main effects only regression.
Among 5967 PWH, 90% showed viral trajectories consistent with DVS. Main effects regression showed that substance use odds ratio (OR) 0.56, 0.46-0.68 and socioeconomic status like being unhoused (OR: 0.39, 0.29-0.53), but not sexual orientation or gender identity (SOGI) were associated with DVS. Adding interactions, we found that race and ethnicity modified the association between insurance and DVS ( P for interaction <0.05). With LCA, we uncovered four social position categories influenced by SOGI with varying rates of DVS. For example, the transgender women-majority class had worse DVS rates versus the class of mostly nonpoor white cisgender gay men (82 vs. 95%). QCA showed that combinations, rather than single factors alone, were important for achieving DVS. Combinations vary with marginalized populations (e.g. black gay/lesbian transgender women) having distinct sufficient combinations compared with historically privileged groups (e.g. white cisgender gay men).
Social factors likely interact to produce DVS disparities. Intersectionality-informed analysis uncover nuance that can inform solutions.
In pulmonary arterial hypertension (PAH), acute vasodilator response testing (AVT) is considered important to identify adult patients with favorable prognosis using calcium-channel blocker (CCB) ...therapy. However, in pediatric PAH, criteria used to identify acute responders and CCB use are insufficiently studied.
This study sought to describe current clinical practice of AVT and subsequent treatment decisions in pediatric PAH.
From January 2008 to May 2013, 529 consecutive children with confirmed pulmonary hypertension were enrolled in an international registry. We analyzed those children with evaluable AVT.
Of 382 children with evaluable AVT, 212 had idiopathic/familial PAH (IPAH/FPAH) and 105 had PAH associated with congenital heart disease (PAH-CHD). In 70% of the patients, AVT was performed using inhaled nitric oxide; other agents were used in the remaining patients. In IPAH/FPAH patients, 78 (37%) patients were acute responders according to their physician, 62 (30%) according to REVEAL (Registry-to-Evaluate-Early-And-Long-term PAH disease management)-pediatric criteria, and 32 (15%) according to Sitbon criteria. For PAH-CHD patients, the numbers of AVT responders were 38 (36%), 14 (13%), and 7 (7%) respectively. Correlation between AVT responder status as judged by the treating physician and by published response criteria was poor. Moreover, of the IPAH/FPAH patients judged by the treating physician as acute responders, only 23% were treated with CCB without additional PAH-targeted therapy. The Sitbon criteria selected patients with better prognosis who had excellent outcome when treated with CCB.
The current practice of identifying responders to AVT and subsequent treatment with CCB therapy demonstrated large discrepancies with current international guidelines. Also, in pediatric IPAH, the Sitbon criteria are the criteria of choice to identify patients with excellent survival when treated with CCB therapy.
Sexual orientation is a multidimensional construct which is increasingly recognized as an important demographic characteristic in population health research. For this study, weighted Youth Risk ...Behavior Survey data were pooled across 47 jurisdictions biennially from 2005 to 2015, resulting in a national sample of 98 jurisdiction-years (344,815 students). Respondents were a median of 15.5 years, 49.9% male, and 48.8% White. Sexual identity and behavior trends from 2005 to 2015 were assessed with logistic regression analysis. Overall, 13.9% of females and 7.0% of males identified as lesbian, gay, bisexual (LGB), or not sure, while 9.1% of females and 4.2% of males indicated both same-and-different-sex behavior or same-sex behavior. In total, 17.0% of female and 8.5% of male youth reported non-heterosexual (LGB or not sure) sexual identity, same-sex sexual behavior, or both. LGB youth were approximately twice as likely as other youth to report lifetime sexual behavior. White and Asian youth were less likely to report non-heterosexual identity and/or have engaged in same-sex sexual behaviors than youth of other races/ethnicities. Prevalence of non-heterosexual identities increased over time for both sexes, but only female youth reported significantly more same-sex behavior over time. This is the first study to simultaneously assess adolescent sexual identity and behavior over time within a national dataset. These findings are critical for understanding the sexual health needs of adolescents and for informing sexual health policy and practice.
Ultrasound contrast agents (UCAs) are currently used throughout the world in both clinical and research settings. The concept of contrast-enhanced ultrasound imaging originated in the late 1960s, and ...the first commercially available agents were initially developed in the 1980s. Today's microbubbles are designed for greater utility and are used for both approved and off-label indications. In October 2007, the US Food and Drug Administration (FDA) imposed additional product label warnings that included serious cardiopulmonary reactions, several new disease-state contraindications, and a mandated 30 min post-procedure monitoring period for the agents Optison and Definity. These additional warnings were prompted by reports of cardiopulmonary reactions that were temporally related but were not clearly attributable to these UCAs. Subsequent published reports over the following months established not only the safety but also the improved efficacy of clinical ultrasound applications with UCAs. The FDA consequently updated the product labeling in June 2008 and reduced contraindications, although it continued to monitor select patients. In addition, a post-marketing program was proposed to the sponsors for a series of safety studies to further assess the risk of UCAs. Then in October 2011, the FDA leadership further downgraded the warnings after hearing the results of the post-marketing data, which revealed continued safety and improved efficacy. The present review focuses on the use of UCAs in today's clinical practice, including the approved indications, a variety of off-label uses, and the most recent data, which affirms the safety and efficacy of UCAs.
ARTD1 (PARP1) is a key enzyme involved in DNA repair through the synthesis of poly(ADP-ribose) (PAR) in response to strand breaks, and it plays an important role in cell death following excessive DNA ...damage. ARTD1-induced cell death is associated with NAD+ depletion and ATP loss; however, the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Using real-time metabolic measurements, we compared the effects of ARTD1 activation and direct NAD+ depletion. We found that ARTD1-mediated PAR synthesis, but not direct NAD+ depletion, resulted in a block to glycolysis and ATP loss. We then established a proteomics-based PAR interactome after DNA damage and identified hexokinase 1 (HK1) as a PAR binding protein. HK1 activity is suppressed following nuclear ARTD1 activation and binding by PAR. These findings help explain how prolonged activation of ARTD1 triggers energy collapse and cell death, revealing insight into the importance of nucleus-to-mitochondria communication via ARTD1 activation.
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•ARTD1 activation-mediated ATP depletion initiates in the mitochondria•ARTD1 activation suppresses glycolysis and oxidative phosphorylation•NAD+ depletion does not affect glycolysis or cellular ATP levels•HK1 activity is inhibited by ARTD1 activation to suppress glycolysis
ARTD1-induced cell death is associated with NAD+ depletion and ATP loss, but the molecular mechanism of ARTD1-mediated energy collapse remains elusive. Fouquerel et al. show that ARTD1-mediated PAR synthesis, but not direct NAD+ depletion, blocks glycolysis and leads to ATP loss. These findings support a working model in which ARTD1 hyperactivation leads to inhibition and mislocalization of hexokinase-1, causing reduced glycolysis and depletion of cellular ATP pools.
Transmission spectroscopy
of exoplanets has revealed signatures of water vapour, aerosols and alkali metals in a few dozen exoplanet atmospheres
. However, these previous inferences with the Hubble ...and Spitzer Space Telescopes were hindered by the observations' relatively narrow wavelength range and spectral resolving power, which precluded the unambiguous identification of other chemical species-in particular the primary carbon-bearing molecules
. Here we report a broad-wavelength 0.5-5.5 µm atmospheric transmission spectrum of WASP-39b
, a 1,200 K, roughly Saturn-mass, Jupiter-radius exoplanet, measured with the JWST NIRSpec's PRISM mode
as part of the JWST Transiting Exoplanet Community Early Release Science Team Program
. We robustly detect several chemical species at high significance, including Na (19σ), H
O (33σ), CO
(28σ) and CO (7σ). The non-detection of CH
, combined with a strong CO
feature, favours atmospheric models with a super-solar atmospheric metallicity. An unanticipated absorption feature at 4 µm is best explained by SO
(2.7σ), which could be a tracer of atmospheric photochemistry. These observations demonstrate JWST's sensitivity to a rich diversity of exoplanet compositions and chemical processes.
Hemodynamic loading is known to contribute to the development and progression of pulmonary arterial hypertension (PAH). This loading drives changes in mechanobiological stimuli that affect cellular ...phenotypes and lead to pulmonary vascular remodeling. Computational models have been used to simulate mechanobiological metrics of interest, such as wall shear stress, at single time points for PAH patients. However, there is a need for new approaches that simulate disease evolution to allow for prediction of long-term outcomes. In this work, we develop a framework that models the pulmonary arterial tree through adaptive and maladaptive responses to mechanical and biological perturbations. We coupled a constrained mixture theory-based growth and remodeling framework for the vessel wall with a morphometric tree representation of the pulmonary arterial vasculature. We show that non-uniform mechanical behavior is important to establish the homeostatic state of the pulmonary arterial tree, and that hemodynamic feedback is essential for simulating disease time courses. We also employed a series of maladaptive constitutive models, such as smooth muscle hyperproliferation and stiffening, to identify critical contributors to development of PAH phenotypes. Together, these simulations demonstrate an important step toward predicting changes in metrics of clinical interest for PAH patients and simulating potential treatment approaches.
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