Structural Analytics (United States)

BackgroundEnhanced cognitive behavioral therapy (CBT-E) is the prevailing treatment approach for adult eating disorders. CBT-E is a variant of cognitive behavioral therapy, modified specifically to treat an eating disorder. Systematic reviews have established the effectiveness of CBT-E for adults when delivered face to face. However, few studies have evaluated evidence-based eating disorder treatment outcomes for programs intentionally designed to be delivered remotely.ObjectiveThe objective of this study was to examine the clinical utility of CBT-E for adults with eating disorders using data from a national treatment program designed specifically for remote delivery.MethodsThis was a pre-post observational cohort study conducted in a naturalistic setting where patients received treatment through standard clinical pathways, including typical referral, intake, and treatment processes. The participant sample for the study was identified through retrospective chart review and included adult patients (aged ≥18 y) diagnosed with anorexia nervosa, bulimia nervosa, binge eating disorder, or other specified feeding or eating disorder. For adult patients with these diagnoses, CBT-E is generally the first line of care in the program. CBT-E was developed to be transdiagnostic, and rather than focusing on a specific diagnosis, treatment focuses on treating the problematic beliefs related to weight, shape, and eating that maintain the eating disorder. CBT-E is highly individualized, and the treatment provider creates a treatment plan to match the specific eating disorder symptoms experienced by the patient. The recommended cadence of sessions is weekly. The criterion of utility was the magnitude and consistency of symptom change in weight gain and eating disorder, depression, and anxiety symptoms during CBT-E treatment. Survival analyses assessed patient and treatment characteristics. Multilevel models assessed the changes in outcomes both over time and at weeks 20 and 40, as these time points generally aligned with CBT-E clinical trial end points.ResultsThe patient sample (N=1629) predominantly consisted of White (n=1166, 71.6%), cisgender women (n=1403, 86.1%), with a mean age of 30 (SD 12) years. The overall median length of stay was 22 (95% CI 20-25) weeks. In all, 416 (25.5%) patients required weight restoration. The estimated probability of achieving weight restoration was 0.50 (95% CI 0.43-0.57) just before week 40 of treatment. By 40 weeks of treatment, the probability of achieving subclinical status for eating disorder symptoms was 0.48 (95% CI 0.44-0.51); for depression, the probability was 0.55 (95% CI 0.51-0.59), and for anxiety, the probability was 0.56 (95% CI 0.51-0.60). Time in treatment was significantly associated with improved symptoms across all outcomes (all P<.001).ConclusionsCBT-E delivered via telehealth is clinically useful, resulting in meaningful improvements in weight and eating disorder, depression, and anxiety symptoms in an outpatient setting. However, the absence of a comparison group and inclusion of a single treatment setting may limit generalizability.

BACKGROUNDWe aimed to evaluate the precision of Alzheimer's disease (AD) and neurodegeneration biomarker measurements from venous dried plasma spots (DPSvenous) for the diagnosis and monitoring of neurodegenerative diseases in remote settings.METHODSIn a discovery (n = 154) and a validation cohort (n = 115), glial fibrillary acidic protein (GFAP); neurofilament light (NfL); amyloid beta (Aβ) 40, Aβ42; and phosphorylated tau (p‐tau181 and p‐tau217) were measured in paired DPSvenous and ethylenediaminetetraacetic acid plasma samples with single‐molecule array. In the validation cohort, a subset of participants (n = 99) had cerebrospinal fluid (CSF) biomarkers.RESULTSAll DPSvenous and plasma analytes correlated significantly, except for Aβ42. In the validation cohort, DPSvenous GFAP, NfL, p‐tau181, and p‐tau217 differed between CSF Aβ‐positive and ‐negative individuals and were associated with worsening cognition.DISCUSSIONOur data suggest that measuring blood biomarkers related to AD pathology and neurodegeneration from DPSvenous extends the utility of blood‐based biomarkers to remote settings with simplified sampling conditions, storage, and logistics.HighlightsA wide array of biomarkers related to Alzheimer's disease (AD) and neurodegeneration were detectable in dried plasma spots (DPSvenous).DPSvenous biomarkers correlated with standard procedures and cognitive status.DPSvenous biomarkers had a good diagnostic accuracy discriminating amyloid status.Our findings show the potential interchangeability of DPSvenous and plasma sampling.DPSvenous may facilitate remote and temperature‐independent sampling for AD biomarker measurement.Innovative tools for blood biomarker sampling may help recognizing the earliest changes of AD.

Supplementary Methods, Figure Legends, Figures 1 - 9, Tables 1 - 8 from Multiclonality and Marked Branched Evolution of Low-Grade Endometrioid Endometrial Carcinoma

In the History of Ideas discipline, the relation between freedom and ethics begins with Zarathustra and becomes transmitted through Plotinus to the Christianity of Augustine where it becomes enmeshed with the “problem of evil.” There is both a “natural evil,” pain and suffering, plagues, and floods and droughts, and an ethical, “human evil” wrought by man’s free will. And the question arises if God is in any way responsible for either or both these evils? But in Plato and Aristotle there is no evil but there is goodness through knowledge in Plato and virtue in Aristotle achieved through the training of voluntary choices. Just so epistemic spontaneity rules in the domain of knowledge, as Aristotle recruits the acts of dynamis (potentiality), energeia (actuality), and entelecheia (completion). This conception of spontaneity is picked up by Leibniz’s conception of his “windowless Monad,” since according to him nothing can enter the Monad from without and nothing can escape from within, it follows that the Monad can only spontaneously act from within. In his turn Kant subscribes via Leibniz’s spontaneity for his transcendental theory of immanent time-consciousness and the reflexive unity of self-consciousness. Dutifully, Fichte follows suit. Plato aesthetically summons spontaneity in the Ion for accounting for the rhapsode’s artistic genius in interpreting the Homeric myths. Both Kant in the Critique of Judgement and Schopenhauer in The World as Will and Representations appeal to the principle of spontaneity in their aesthetic as well.

The penultimate chapter philosophically asks the reader to decide for himself or herself whether Leibniz is right in his optimistic conviction that “this world is the best of all possible worlds?” or whether instead Schopenhauer is correct and that “this world is the worst of all possible worlds?”

As viral vector-based gene therapies move toward indications with larger patient populations, the pressure to improve manufacturing efficiency is rising. To support efficient manufacturing, therapeutic developers must begin by putting a robust process development (PD) plan in place. The industry has been working towards a robust PD plan using innovations such as templated processes to improve yield whilst reducing costs of goods sold (COGS) and time-to-clinic. Templates will help, but there will always be a need for PD to optimize the upstream/transfection, as well as downstream due to differences in the gene of interest (GOI). In this article, we will discuss the PD innovations that Merck’s teams have worked on to improve manufacturability, robustness of analytical testing, and scale-down models, all with a view to meeting the needs of large-scale viral vector manufacturing.

Background: The goal of the study was to assess the safety and tolerability of atogepant, an oral, calcitonin gene-related peptide receptor antagonist in development for migraine preventive treatment, once daily over 1 year. Methods: Multicenter, open-label trial (NCT03700320). Adults with migraine were randomized 5:2 to atogepant or oral standard-of-care (SOC) migraine prevention. Results: 744 randomized participants (n=546 atogepant), 739 safety population participants (n=543 atogepant). Adverse events (AEs) were reported by 67.0% of atogepant participants; 18.0% had AEs considered related to atogepant. AEs reported by ≥5% of atogepant-treated participants were upper respiratory tract infection (10.3%), constipation (7.2%), nausea (6.3%), and urinary tract infection (5.2%). 4.4% of atogepant participants reported serious AEs that included various, common medical conditions; no event occurred in ≥1 participant and none were atogepant-related. Two deaths were reported in atogepant-treated participants (homicide victim; toxic shock syndrome); both were considered not treatment-related. 5.7% of atogepant participants discontinued due to AEs. Alanine aminotransferase/aspartate aminotransferase levels ≥3X upper limit of normal were reported for 2.4% of atogepant participants (n=13/531) and 3.2% of SOC participants (n=6/190). No cases of potential Hy’s Law were reported. Conclusions: Once-daily use of atogepant for preventive treatment of migraine over 1 year was safe and well-tolerated with no safety concerns identified.