In this work, we propose methods to examine how the complex interrelationships between clinical symptoms and, separately, brain imaging biomarkers change over time leading up to the diagnosis of a ...disease in subjects with a known genetic near‐certainty of disease. We propose a time‐dependent undirected graphical model that ensures temporal and structural smoothness across time‐specific networks to examine the trajectories of interactions between markers aligned at the time of disease onset. Specifically, we anchor subjects relative to the time of disease diagnosis (anchoring time) as in a revival process, and we estimate networks at each time point of interest relative to the anchoring time. To use all available data, we apply kernel weights to borrow information across observations that are close to the time of interest. Adaptive lasso weights are introduced to encourage temporal smoothness in edge strength, while a novel elastic fused‐l0$$ {l}_0 $$ penalty removes spurious edges and encourages temporal smoothness in network structure. Our approach can handle practical complications such as unbalanced visit times. We conduct simulation studies to compare our approach with existing methods. We then apply our method to data from PREDICT‐HD, a large prospective observational study of pre‐manifest Huntington's disease (HD) patients, to identify symptom and imaging network changes that precede clinical diagnosis of HD.
On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to ...evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy.
Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon.
Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX.
After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.
To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC).
In this single-arm, phase II, ...multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC.
Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC.
High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC.
To estimate effects of gastric tube (G-tube) on survival and quality of life (QOL) in people with amyotrophic lateral sclerosis (ALS) correcting for confounding by indication inherent in ...nonrandomized observational data.
To complement a recent causal inference analysis, which concluded that G-tube placement increases the hazard of death, permanent assisted ventilation, or tracheostomy by 28%, we fit causal inference models on a different sample of 481 patients with ALS enrolled in a recent clinical trial of ceftriaxone. Forward selection identified predictors of G-tube placement. Effects of G-tube on survival and QOL were estimated using structural nested models and marginal structural models, accounting for predictors of G-tube treatment.
Forced vital capacity and the total score and bulbar subscale of the revised ALS Functional Rating Scale best predicted G-tube placement. Correcting for these confounders, G-tube placement decreased survival time by 46% (
< 0.001) and had no effect on QOL (
= 0.078). Sensitivity survival analyses varied in significance, but none revealed a survival benefit.
In the absence of randomization, causal inference methods are necessary to correct for time-varying confounding. G-tube placement may have a negative effect on survival with no QOL-related benefit for people with ALS. A randomized controlled trial is warranted to further evaluate the efficacy of this widely used intervention.
NCT00349622.
This study provides Class III evidence that for patients with ALS, G-tube placement decreases survival time and does not affect QOL.
Aspergillus section Nigri comprises filamentous fungi relevant to biomedicine, bioenergy, health, and biotechnology. To learn more about what genetically sets these species apart, as well as about ...potential applications in biotechnology and biomedicine, we sequenced 23 genomes de novo, forming a full genome compendium for the section (26 species), as well as 6 Aspergillus niger isolates. This allowed us to quantify both inter- and intraspecies genomic variation. We further predicted 17,903 carbohydrate-active enzymes and 2,717 secondary metabolite gene clusters, which we condensed into 455 distinct families corresponding to compound classes, 49% of which are only found in single species. We performed metabolomics and genetic engineering to correlate genotypes to phenotypes, as demonstrated for the metabolite aurasperone, and by heterologous transfer of citrate production to Aspergillus nidulans. Experimental and computational analyses showed that both secondary metabolism and regulation are key factors that are significant in the delineation of Aspergillus species.
Abstract
The default position in economic psychology is that consumers evaluate the fairness of firms' pricing strategies based on a widely shared schema of market morality, operationalized by ...analysing the average response within a respondent pool to a given price-change scenario. Conversely, drawing on economic and cultural sociology, we argue that there are multiple, distinctive schemas that pattern consumers’ moral evaluation of market pricing practices. We identify distinctive moral schemas by replicating and reanalysing scenarios from the foundational study of the fairness in pricing field (Kahneman et al., 1986) with a new online survey of American adults. Using correlational class analysis, we find respondents orient to one of four different configurations of moral judgement about price-change fairness: dual-entitlement principles, free-market proponents (and opponents), retail-labour domain specificity and procedural (un)fairness. This research gives analysts new tools for more precisely specifying variation in consumer moral sentiment and raises new questions about the causes, consequences and contours of multiple market moralities.
Background
Patients who present to the emergency department (ED) with acute chest pain should receive a thorough history and exam to rule out rare, life-threatening conditions, such as drug-induced ...acute aortic dissections (AD).
Case presentation
A 34-year-old man with a history of uncontrolled hypertension, smoking, and “ecstasy” use presented to the ED with an acute type A aortic dissection (AD). Following surgery to repair the dissection, he developed compartment syndrome of the lower extremity requiring muscle excision and neurolysis with subsequent wound debridement procedures.
Conclusion
Physicians treating adults with symptoms and signs of aortic dissection should take a focused history about substance use and include AD on their differential. In addition, the extremities should be monitored for signs and symptoms of ischemia throughout the acute peri-surgical period(s).
By collecting data continuously over 24 hours, accelerometers and other wearable devices can provide novel insights into circadian rhythms and their relationship to human health. Existing approaches ...for analyzing diurnal patterns using these data, including the cosinor model and functional principal component analysis, have revealed and quantified population-level diurnal patterns, but considerable subject-level variability remained uncaptured in features such as wake/sleep times and activity intensity. This remaining informative variability could provide a better understanding of chronotypes, or behavioral manifestations of one's underlying 24-hour rhythm. Curve registration, or alignment, is a technique in functional data analysis that separates "vertical" variability in activity intensity from "horizontal" variability in time-dependent markers like wake and sleep times; this data-driven approach is well-suited to studying chronotypes using accelerometer data. We develop a parametric registration framework for 24-hour accelerometric rest-activity profiles represented as dichotomized into epoch-level states of activity or rest. Specifically, we estimate subject-specific piecewise linear time-warping functions parametrized with a small set of parameters. We apply this method to data from the Baltimore Longitudinal Study of Aging and illustrate how estimated parameters give a more flexible quantification of chronotypes compared to traditional approaches.
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