Examining Change in Symptoms of Depression, Anxiety, and Stress in Adults after Treatment of Chronic Cough: A Dissertation

Background: Chronic cough is a common health problem with variable success rates to standardized treatment. Psychologic symptoms of depression, anxiety, and stress have been reported in association with chronic cough. The purpose of this study was to examine changes in the psychologic symptoms of depression, anxiety, and stress in adults with chronic cough 3 months after management using the ACCP cough treatment guidelines. Methods: This study used a descriptive longitudinal observation design. The major tenets associated with the Theory of Unpleasant Symptoms were examined. Intervention fidelity to the study components was measured. Results: A sample of 80 consecutive patients with chronic cough of greater than 8 weeks duration was recruited from one cough specialty clinic. Mean age of subjects was 58.54 years; 68.7% were female; 98.7% were white, and 97.5% were non-smokers. Mean cough duration was 85.99 months and mean cough severity was 6.11 (possible 0 –10; higher scores equal greater cough severity). Cough severity improved post treatment (n=65, M=2.32, (SE =.291), t (64) =7.98, p=.000); cough-specific quality-of-life also improved (n=65, M=9.17, (SE=1.30), t (64) =7.02, p=.000). Physiologic (urge-to-cough r=.360, ability to speak r=.469) and psychologic factors (depression r=.512, anxiety r=.507, stress r=.484) were significantly related to cough-specific quality-of-life and to cough severity (urge-to-cough r=.643, ability to speak r=.674 and depression r=.356, anxiety r=.419, stress r=.323) (all r, p=.01); social support and number of diagnoses were not related to either variable. Those experiencing greater financial strain had worse cough severity. Women, those experiencing financial strain, and those taking self-prescribed therapy had worse cough-specific quality-of-life. Intervention fidelity to the study plan was rated as high according to observation, participant receipt, and patient/physician concordance. Qualitative review identified potential areas of variability with intervention fidelity. Conclusions: By measuring the factors related to the major tenets of the Theory of Unpleasant Symptoms, this theory has helped to explain why those with chronic cough may have symptoms of depression, anxiety, and stress and why these symptoms improve as cough severity and cough-specific quality-of-life improve. Moreover, by measuring intervention fidelity, it may be possible to determine why cough guidelines may not be yielding consistently favorable results

Communications Biophysics

Contains research objectives and reports on three research projects.National Science Foundation (Grant G-16526)National Institutes of Health (Grant MH-04737-02

Benthic assemblages are more predictable than fish assemblages at an island scale

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Sandin, S. A., Alcantar, E., Clark, R., de Leon, R., Dilrosun, F., Edwards, C. B., Estep, A. J., Eynaud, Y., French, B. J., Fox, M. D., Grenda, D., Hamilton, S. L., Kramp, H., Marhaver, K. L., Miller, S. D., Roach, T. N. F., Seferina, G., Silveira, C. B., Smith, J. E., Zgliczynski, B. J., & Vermeij, M. J. A. Benthic assemblages are more predictable than fish assemblages at an island scale. Coral Reefs, 41, (2022.): 1031–1043, https://doi.org/10.1007/s00338-022-02272-5.Decades of research have revealed relationships between the abundance of coral reef taxa and local conditions, especially at small scales. However, a rigorous test of covariation requires a robust dataset collected across wide environmental or experimental gradients. Here, we surveyed spatial variability in the densities of major coral reef functional groups at 122 sites along a 70 km expanse of the leeward, forereef habitat of Curaçao in the southern Caribbean. These data were used to test the degree to which spatial variability in community composition could be predicted based on assumed functional relationships and site-specific anthropogenic, physical, and ecological conditions. In general, models revealed less power to describe the spatial variability of fish biomass than cover of reef builders (R2 of best-fit models: 0.25 [fish] and 0.64 [reef builders]). The variability in total benthic cover of reef builders was best described by physical (wave exposure and reef relief) and ecological (turf algal height and coral recruit density) predictors. No metric of anthropogenic pressure was related to spatial variation in reef builder cover. In contrast, total fish biomass showed a consistent (albeit weak) association with anthropogenic predictors (fishing and diving pressure). As is typical of most environmental gradients, the spatial patterns of both fish biomass density and reef builder cover were spatially autocorrelated. Residuals from the best-fit model for fish biomass retained a signature of spatial autocorrelation while the best-fit model for reef builder cover removed spatial autocorrelation, thus reinforcing our finding that environmental predictors were better able to describe the spatial variability of reef builders than that of fish biomass. As we seek to understand spatial variability of coral reef communities at the scale of most management units (i.e., at kilometer- to island-scales), distinct and scale-dependent perspectives will be needed when considering different functional groups.This research and the larger efforts of Blue Halo Curacao were supported by funding from the Waitt Institute and with permissions from the Government of Curacao, Ministry of Health, Environment, and Nature. Field logistics were further supported by the Waitt Institute vessel crew, CARMABI Foundation, The Dive Shop Curacao, and Dive Charter Curacao

Pattern of Relapse and Treatment Response in WNT- Activated Medulloblastoma

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% +/- 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% +/- 2% vs. 57.4% +/- 1.8% (p < 0.01)). In contrast, beta-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% +/- 1.5% in lithium treated cells vs. 56.6 +/- 3% (p < 0.01)) accompanied by increased number of.H2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% +/- 8% for lithium treated cells vs. 27% +/- 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.B.R.A.I.N Child Canada; Cancer Research UK; Brain Tumour Charity; Hungarian Brain Research Program [KTIA_13_NAP-A-V/3]; Janos Bolyai Scholarship of the Hungarian Academy of Sciences [TAMOP-4.2.2. A-11/1/KONV-2012-0025]; German Cancer Aid/Dr. Mildred Scheel Foundation for Cancer Research; Cure Childhood Cancer Foundation; St. Baldrick's Foundation; Southeastern Brain Tumor Foundation; Action Medical Research; [CZ.1.05/2.1.00/03.0101]; [CZ.1.07/2.3.00/20.0183

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Federated learning enables big data for rare cancer boundary detection.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing

Author Correction: Federated learning enables big data for rare cancer boundary detection.

10.1038/s41467-023-36188-7NATURE COMMUNICATIONS14

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders