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Background: Remote patient monitoring (RPM) aims to improve patient access to care and communication with clinical providers. Overall, understanding the usability of RPM applications and their influence on clinical care workflows is limited from the perspectives of clinician end users at a cancer center in the Northeastern United States., Objective: This study aims to explore the usability and functionality of RPM and elicit the perceptions and experiences of oncology clinicians using RPM for oncology patients after hospital discharge., Methods: The sample included 30 of 98 clinicians (31% response rate) managing at least 5 patients in the RPM program and responding to the mHealth usability between March 2021 and October 2021. Overall, clinicians responded positively to the survey. Item responses with the highest proportion of disagreement were explored further. A nested sample of 5 clinicians who responded to the study survey (30% response rate) participated in interview sessions conducted from November 2021 to February 2022, averaging 60 minutes each., Results: Survey responses highlighted that RPM was easy to use and learn and verified symptom alerts during follow-up phone calls. Areas to improve identified practice changes from reporting RPM alerts through digital portals and its influence on clinicians' workload burden. Interview sessions revealed 3 main themes: clinician understanding and usability constraints, patient constraints, and suggestions for improving the program. Subthemes for each theme were explored, characterizing technical and functional limitations that could be addressed to enhance efficiency, workflow, and user experience., Conclusions: Clinicians support the value of RPM for improving symptom management and engaging with providers. Improvements to address RPM challenges include functional changes to enhance the program's utility, such as input from patients about temporal changes in their symptoms and technical resources for home monitoring devices., (© Ann Marie Mazzella-Ebstein, Robert Daly, Jennie Huang, Camila Bernal, Clare Wilhelm, Katherine S Panageas, Jessie Holland, Rori Salvaggio, Jill Ackerman, Jennifer Cracchiolo, Gilad Kuperman, Jun Mao, Aaron Begue, Margaret Barton-Burke. Originally published in JMIR Human Factors (https://humanfactors.jmir.org).)

Pretreatment prognostication, on-treatment monitoring, and early detection of physiological symptoms are considerable challenges in cancer. We describe the feasibility of high-resolution wearable data (steps per day, walking speed) to longitudinally profile physiological trajectories extracted from Apple Health data in three patients with lung cancer from diagnosis through cancer treatment after obtaining informed consent. We used descriptive statistics to describe our approach of building longitudinal physiological profiles. The wearable data monitoring period ranged from 58 to 135 weeks, with between 34,319 and 103,535 distinct digital physiological measures collected during this period-the equivalent to 41 measures per day/patient. Longitudinal profiling revealed that wearable data accurately captured physiological changes linked with clinical events such as surgery and hospitalizations as well as initiation (and cessation) of systemic cancer treatment in all three patients. These findings suggest that wearable devices could play a critical role in the management of lung cancer, although larger studies are needed to confirm these preliminary observations and validate their generalizability. Wearable devices hold significant promise for the development of personalized "digital biomarkers," which may enhance risk stratification and management in oncology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bliss, Underwood, Carlson, Scott, Daly, Li, Drilon, Stetson, Boutros and Jones.)

Background: Remote patient monitoring (RPM) aims to improve patient access to care and communication with clinical providers. Overall, understanding the usability of RPM applications and their influence on clinical care workflows is limited from the perspectives of clinician end users at a cancer center in the Northeast, United States., Objective: Explore the usability and functionality of RPM and elicit the perceptions and experiences of oncology clinicians using RPM for oncology patients after hospital discharge., Methods: The sample included 30 of 98 clinicians (31% response rate) managing at least five patients in the RPM program and responding to the m-Health Usability between March 2021- October 2021. Overall, clinicians responded positively to the survey. Item responses with the highest proportion of disagreement were explored further. A nested sample of five clinicians who responded to the study survey (30% response rate) participated in interview sessions conducted from November 2021 to February 2022, and averaged 60 minutes each., Results: Survey responses highlighted that RPM was easy to use and learn and verified symptom alerts during follow-up phone calls. Areas to improve identified practice changes from reporting RPM alerts through digital portals and its influence on clinicians' workload burden. Interview sessions revealed three main themes: clinician understanding and usability constraints, patient constraints, and suggestions for improving the program. Subthemes for each theme were explored, characterizing technical and functional limitations that could be addressed to enhance efficiency, workflow, and user experience., Conclusions: Clinicians support the value of RPM for improving symptom management and engaging with providers. Functional changes to enhance the program's utility, such as input from patients about temporal changes in their symptoms and technical resources for home monitoring devices.

The COVID-19 pandemic placed a spotlight on the potential to dramatically increase the use of telehealth across the cancer care continuum, but whether and how telehealth can be implemented in practice in ways that reduce, rather than exacerbate, inequities are largely unknown. To help fill this critical gap in research and practice, we developed the Framework for Integrating Telehealth Equitably (FITE), a process and evaluation model designed to help guide equitable integration of telehealth into practice. In this manuscript, we present FITE and showcase how investigators across the National Cancer Institute's Telehealth Research Centers of Excellence are applying the framework in different ways to advance digital and health equity. By highlighting multilevel determinants of digital equity that span further than access alone, FITE highlights the complex and differential ways structural determinants restrict or enable digital equity at the individual and community level. As such, achieving digital equity will require strategies designed to not only support individual behavior but also change the broader context to ensure all patients and communities have the choice, opportunity, and resources to use telehealth across the cancer care continuum., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Modern cancer care is costly and logistically burdensome for patients and their families despite an expansion of technology and medical advances that create the opportunity for novel approaches to care. Therefore, there is a growing appreciation for the need to leverage these innovations to make cancer care more patient centered and convenient. The Memorial Sloan Kettering Making Telehealth Delivery of Cancer Care at Home Efficient and Safe Telehealth Research Center is a National Cancer Institute-designated and funded Telehealth Research Center of Excellence poised to generate the evidence necessary to inform the appropriate use of telehealth as a strategy to improve access to cancer services that are convenient for patients. The center will evaluate telehealth as a strategy to personalize cancer care delivery to ensure that it is not only safe and effective but also convenient and efficient. In this article, we outline this new center's research strategy, as well as highlight challenges that exist in further integrating telehealth into standard oncology practice based on early experiences., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Surface enhanced Raman spectroscopy (SERS) is a powerful analytical technique that has found application in the trace detection of a wide range of contaminants. In this paper, we report on the fabrication of 2D silver nanodendrites, on silicon chips, synthesized by electrochemical reduction of AgNO 3 at microelectrodes. The formation of nanodendrites is tentatively explained in terms of electromigration and diffusion of silver ions. Electrochemical characterization suggests that the nanodendrites do not stay electrically connected to the microelectrode. The substrates show SERS activity with an enhancement factor on the order of 10 6 . Density functional theory simulations were carried out to investigate the suitability of the fabricated substrate for pesticide monitoring. These substrates can be functionalized with cyclodextrin macro molecules to help with the detection of molecules with low affinity with silver surfaces. A proof of concept is demonstrated with the detection of the herbicide 2-methyl-4-chlorophenoxyacetic acid (MCPA)., (Creative Commons Attribution license.)

Objective: To analyse the relationship between health app quality with user ratings and the number of downloads of corresponding health apps., Materials and Methods: Utilising a dataset of 881 Android-based health apps, assessed via the 300-point objective Organisation for the Review of Care and Health Applications (ORCHA) assessment tool, we explored whether subjective user-level indicators of quality (user ratings and downloads) correlate with objective quality scores in the domains of user experience, data privacy and professional/clinical assurance. For this purpose, we applied spearman correlation and multiple linear regression models., Results: For user experience, professional/clinical assurance and data privacy scores, all models had very low adjusted R squared values (< .02). Suggesting that there is no meaningful link between subjective user ratings or the number of health app downloads and objective quality measures. Spearman correlations suggested that prior downloads only had a very weak positive correlation with user experience scores (Spearman = .084, p = .012) and data privacy scores (Spearman = .088, p = .009). There was a very weak negative correlation between downloads and professional/clinical assurance score (Spearman = -.081, p = .016). Additionally, user ratings demonstrated a very weak correlation with no statistically significant correlations observed between user ratings and the scores (all p > 0.05). For ORCHA scores multiple linear regression had adjusted R-squared = -.002., Conclusion: This study highlights that widely available proxies which users may perceive to signify the quality of health apps, namely user ratings and downloads, are inaccurate predictors for estimating quality. This indicates the need for wider use of quality assurance methodologies which can accurately determine the quality, safety, and compliance of health apps. Findings suggest more should be done to enable users to recognise high-quality health apps, including digital health literacy training and the provision of nationally endorsed "libraries"., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: This study is funded by a DfE Cast award and ORCHA. Simon Leigh, Anna Frey and Robert Daly are/were employees at ORCHA when this study was conducted. Other authors have no conflict of interest to declare., (Copyright: © 2024 Hyzy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: There are more than 350,000 digital health interventions (DHIs) in the app stores. To ensure that they are effective and safe to use, they should be assessed for compliance with best practice standards., Objective: The objective of this paper was to examine and compare the compliance of DHIs with best practice standards and adherence to user experience (UX), professional and clinical assurance (PCA), and data privacy (DP)., Methods: We collected assessment data from 1574 DHIs using the Organisation for the Review of Care and Health Apps Baseline Review (OBR) assessment tool. As part of the assessment, each DHI received a score out of 100 for each of the abovementioned areas (ie, UX, PCA, and DP). These 3 OBR scores are combined to make up the overall ORCHA score (a proxy for quality). Inferential statistics, probability distributions, Kruskal-Wallis, Wilcoxon rank sum test, Cliff delta, and Dunn tests were used to conduct the data analysis., Results: We found that 57.3% (902/1574) of the DHIs had an Organisation for the Review of Care and Health Apps (ORCHA) score below the threshold of 65. The overall median OBR score (ORCHA score) for all DHIs was 61.5 (IQR 51.0-73.0) out of 100. A total of 46.2% (12/26) of DHI's health care domains had a median equal to or above the ORCHA threshold score of 65. For the 3 assessment areas (UX, DP, and PCA), DHIs scored the highest for the UX assessment 75.2 (IQR 70.0-79.6), followed by DP 65.1 (IQR 55.0-73.4) and PCA 49.6 (IQR 31.9-76.1). UX scores had the least variance (SD 13.9), while PCA scores had the most (SD 24.8). Respiratory and urology DHIs were consistently highly ranked in the National Institute for Health and Care Excellence Evidence Standards Framework tiers B and C based on their ORCHA score., Conclusions: There is a high level of variability in the ORCHA scores of DHIs across different health care domains. This suggests that there is an urgent need to improve compliance with best practices in some health care areas. Possible explanations for the observed differences might include varied market maturity and commercial interests within the different health care domains. More investment to support the development of higher-quality DHIs in areas such as ophthalmology, allergy, women's health, sexual health, and dental care may be needed., (©Maciej Hyzy, Raymond Bond, Maurice Mulvenna, Lu Bai, Alan Dix, Robert Daly, Anna-Lena Frey, Simon Leigh. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 23.11.2023.)

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma., Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT., Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2)., Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study., (© 2022 The Authors.)

Mental health clinicians frequently study the religion and spirituality (R/S) of their patients. There is, however, a paucity of empirical research concerning R/S of patients with bipolar disorder. This lack is exacerbated by the absence of an evaluation of how these studies relate to each other. Reviews to date concern almost exclusively quantitative studies; a review that synthesizes quantitative and qualitative research is needed. The aim of this paper is to provide a synthesis of empirical studies that is useful in clinical practice. Systematic searches for relevant journal articles in SCOPUS, PubMed, and PsycInfo found 14 quantitative and four qualitative studies. The research reveals that intrinsic religiosity and positive religious coping are the dimensions of R/S that have the most positive correlations with improvement of bipolar disorder symptoms as revealed by measures of clinical outcomes. Patients struggle with their religious experiences, and they wish that R/S would be taken into account by mental health professionals. The quantitative studies are not in conflict with the patient/person-centered focus of qualitative studies. This integration of quantitative data with a patient/person-centered focus shows how belief and illness affect each other. The tensions inherent in such an integration provide new insights for research and treatment. Unfortunately, the qualitative literature has not caught up with quantitative approaches in terms of diagnostic rigor., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Seagrasses are considered indicators of anthropogenic impact but surprisingly little is known about their temporal and spatial dynamics in impacted seascapes. In this study, we used three decades of Landsat imagery (1988-2018) off the coast of Adelaide, South Australia, to investigate how seagrass cover over 501 km 2 responds to changes in land-based inputs, including breakpoints in system trajectory and associated timelags, and the identification of vulnerable meadows. Field data was used to help train benthic classification of summer imagery and define its accuracy. Temporal dynamics of seagrass cover were investigated in relation to annual and multi-year nitrogen and suspended solids loads. Spatial dynamics were inferred from maps of benthic cover persistence and trajectory for each decade. The region experienced a net regrowth of some 11,000 ha of seagrasses since the early 2000s, with the initial large-scale recruitment visible in the imagery 6 years after the closure of sludge outfalls. Seagrass expansion occurred primarily in deeper waters (>10 m) of the central coast and at the seaward edge of the distribution. Recovery continued until 2011 assisted by a window of opportunity created by a decade-long drought and further reductions in nitrogen loads from wastewater treatment plants and industry. Localized seagrass losses however continued to be observed as a result of either permanent or transient increases in suspended solids loads. Seagrass area in the central coast was well correlated (r 2  = 0.88) with 5-year running averages of nitrogen and suspended solids loads. Meadows particularly vulnerable to changes in land-based discharges were located at the edges of the distribution, along erosional scarps and at depths >10 m south of the Torrens River. These areas were identified as useful indicators of seagrass status. Overall, seagrass persistence expanded from 48 to 69% of the mapped area, with the region now mostly covered by stable seagrasses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Early phase cancer clinical trials have become increasingly complicated in terms of patient selection and trial procedures-this is reflected in the increasing length of participant information sheets (PIS). Informed consent for early phase clinical trials has been contentious due to the potential ethical issues associated with performing experimental research on a terminally ill population which has exhausted standard treatment options. Empirical studies have demonstrated significant gaps in patient understanding regarding the nature and intent of these trials. This study aims to test whether enhanced informed consent for patient education can improve patient scores on a validated questionnaire testing clinical trial comprehension., Methods and Analysis: This is a randomised controlled trial that will allocate patients who are eligible to participate in one of four investigator-initiated clinical trials at the Royal Marsden Drug Development Unit to either a standard arm or an experimental arm, stratified by age and educational level. The standard arm will involve the full length trial PIS, followed by electronic or paper administration of the Quality of Informed Consent Questionnaire Parts A and B (QuIC-A and QuIC-B). The experimental arm will involve the full length trial PIS, exposure to a two-page study aid and 10 online educational videos, followed by administration of the QuIC-A and QuIC-B. The primary endpoint will be the difference (using a one-sided two-sample t-test) in the QuIC-A score, which measures objective understanding, between the standard and experimental arm. Accrual target is at least 17 patients per arm to detect an 8 point difference (80% power, alpha 0.05)., Ethics and Dissemination: Ethics approval was granted by the National Health Service Health Research Authority on 15 June 2020-IRAS Project ID 277065, Protocol Number CCR5165, REC Reference 20/EE/0155. Results will be disseminated via publication in a relevant journal., Trial Registration Number: NCT04407676; Pre-results., Competing Interests: Competing interests: This study has not received a specific grant and is not externally funded and has not undergone peer review by the funding body. The authors declare the following competing interests, none of which are directly related to this study. AP, DM, BRB, RD, JL-K, SS: none declared; CY has received fees from Celgene and Faron unrelated to this work, is an associate editor for Trials; AM has served on advisory boards and received fees from Merck, Faron, Novartis, Bayer and Janssen, all unrelated to this work; UB has received honoraria from Astellas, Novartis, Karus Therapuetics, Pheonix Solutions, Eli Lilly, Astex, Vernalis, Boehringer Ingelheim, is a recipient of a National Institute for Health Research (NIHR) Research Professorship Award and has received CRUK funding: Cancer Research UK Scientific Executive Board, Cancer Research UK Centre Award, Cancer Research UK Drug Discovery Committee—Programme Award, all unrelated to this work; JDB has served on advisory boards and received fees from many companies including AstraZeneca, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho and Vertex Pharmaceuticals. He is an employee of The ICR, which have received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). He was named as an inventor, with no financial interest, for patent 8822438. He has been the chief investigator (CI)/principal investigator (PI) of many industry sponsored clinical trials. JDB is an NIHR Senior Investigator. All unrelated to this work; DK: none declared; FB received fees for Advisory Boards for Roche, Novartis, Eisai, Pfizer and Eli Lilly. She has been the site PI/CI for many industry sponsored clinical trials, all unrelated to this work. Friends of the Mater Foundation support her academic appointment at the University of Sydney and her supervision of this work. JL: research grant funding from Roche, Basilea and Genmab, all unrelated to this work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: NRG1 rearrangements produce chimeric ligands that subvert the ERBB pathway to drive tumorigenesis. A better understanding of the signaling networks that mediate transformation by NRG1 fusions is needed to inform effective therapeutic strategies. Unfortunately, this has been hampered by a paucity of patient-derived disease models that faithfully recapitulate this molecularly defined cancer subset., Methods: Patient-derived xenograft (PDX) and cell line models were established from NRG1-rearranged lung adenocarcinoma samples. Transcriptomic, proteomic, and biochemical analyses were performed to identify activated pathways. Efficacy studies were conducted to evaluate HER3- and MTOR-directed therapies., Results: We established a pair of PDX and cell line models of invasive mucinous lung adenocarcinoma (LUAD) (LUAD-0061AS3, SLC3A2-NRG1), representing the first reported paired in vitro and in vivo model of NRG1-driven tumors. Growth of LUAD-0061AS3 models was reduced by the anti-HER3 antibody GSK2849330. Transcriptomic profiling revealed activation of the MTOR pathway in lung tumor samples with NRG1 fusions. Phosphorylation of several MTOR effectors (S6 and 4EBP1) was higher in LUAD-0061AS3 cells compared with human bronchial epithelial cells and the breast cancer cell line MDA-MB-175-VII (DOC4-NRG1 fusion). Accordingly, LUAD-0061AS3 cells were more sensitive to MTOR inhibitors than MDA-MB-175-VII cells and targeting the MTOR pathway with rapamycin blocked growth of LUAD-0061AS3 PDX tumors in vivo. In contrast, MDA-MB-175-VII breast cancer cells had higher MAPK pathway activation and were more sensitive to MEK inhibition., Conclusions: We identify the MTOR pathway as a candidate vulnerability in NRG1 fusion-positive lung adenocarcinoma that may warrant further preclinical evaluation, with the eventual goal of finding additional therapeutic options for patients in whom ERBB-directed therapy fails. Moreover, our results uncover heterogeneity in downstream oncogenic signaling among NRG1-rearranged cancers, possibly tumor type-dependent, the therapeutic significance of which requires additional investigation., (Copyright © 2021. Published by Elsevier Inc.)

Water is a precious resource that is under threat from a number of pressures, including, for example, release of toxic compounds, that can have damaging effect on ecology and human health. The current methods of water quality monitoring are based on sample collection and analysis at dedicated laboratories. Recently, electrochemical-based methods have attracted a lot of attention for environmental sensing owing to their versatility, sensitivity and their ease of integration with cost effective, smart and portable readout systems. In the present work, we report on the fabrication and characterization of platinum-based interdigitated microband electrodes arrays, and their application for trace detection of copper. Using square wave voltammetry after acidification with mineral acids, a limit of detection of 0.8 μg/L was achieved. Copper detection was also undertaken on river water samples and compared with standard analytical techniques. The possibility of controlling the pH at the surface of the sensors-thereby avoiding the necessity to add mineral acids-was investigated. By applying potentials to drive the water splitting reaction at one comb of the sensor's electrode (the protonator), it was possible to lower the pH in the vicinity of the sensing electrode. Detection of standard copper solutions down to 5 μg/L (ppb) using this technique is reported. This reagent free method of detection opens the way for autonomous, in situ monitoring of pollutants in water bodies.

Patients with EGFR- mutant lung cancer have no approved targeted therapies after disease progression on first-line osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Preclinical studies suggest that tumors with both EGFR -sensitizing alteration and acquired second-site EGFR resistance alterations after treatment with osimertinib retain sensitivity to second-generation EGFR TKIs. We hypothesized that dacomitinib, a pan-human epidermal growth factor receptor TKI, may be effective in this setting., Methods: In this phase II study, patients who had progressed on first-line osimertinib were treated with dacomitinib 45 mg orally daily until disease progression or intolerability. The primary end point was objective response rate., Results: We enrolled 12 patients. Two partial responses were documented (17% objective response rate; 95% CI, 5 to 45). The median progression-free survival was 1.8 months (95% CI, 1.6 to not reached). One patient with an original sensitizing EGFR G719A mutation and one patient without molecular testing available had partial responses, whereas 0 of the 3 patients with second-site acquired EGFR resistance mutations (two C797S and one G724S) met the response criteria. The patient with EGFR G719A has an ongoing response at 17 months, which exceeds prior time on osimertinib (11 months)., Conclusion: In the first trial evaluating a second-generation EGFR TKI after first-line third-generation osimertinib, we found that dacomitinib after disease progression on osimertinib has limited benefit., (© 2021 by American Society of Clinical Oncology.)

Seagrasses are regarded as indicators and first line of impact for anthropogenic activities affecting the coasts. The underlying mechanisms driving seagrass cover however have been mostly studied on small scales, making it difficult to establish the connection to seagrass dynamics in an impacted seascape. In this study, hyperspectral airborne imagery, trained from field surveys, was used to investigate broadscale seagrass cover and genus distribution along the coast of Adelaide, South Australia. Overall mapping accuracy was high for both seagrass cover (98%, Kappa = 0.93), and genus level classification (85%, Kappa = 0.76). Spectral separability allowed confident genus mapping in waters up to 10 m depth, revealing a 3.5 ratio between the cover of the dominant Posidonia and Amphibolis. The work identified the absence of Amphibolis in areas historically affected by anthropogenic discharges, which occasionally contained Posidonia and might be recovering. The results suggest hyperspectral imagery as a useful tool to investigate the interplay between seagrass cover and genus distribution at large spatial scales.

Aim: The Suicide Crisis Assessment Nurse service has been developed as a Primary Care suicide intervention over the last decade. The current study aimed to describe the demographic details of users of this nurse led service, and to evaluate subsequent care pathways following this intervention., Methods: This study was conducted using a retrospective file review with a cross-sectional observational design investigating demographic details of service users and care pathways in a Suicide Crisis Assessment Nurse service within a defined catchment area of Ireland between June 2015 and May 2017., Results: The majority of referrals were managed in Primary Care following Suicide Crisis Assessment Nurse intervention. There was an increase in Primary Care management pathway in the second year of the service which was independent of age and gender., Conclusion: There was an increase in referrals to the service over time, and the majority of presentations were managed in primary care following Suicide Crisis Assessment Nurse intervention. The study suggests that primary care interventions for suicidal crises merit further research., (© 2019 John Wiley & Sons Australia, Ltd.)

Importance: Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib., Objective: To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia., Design, Setting, and Participants: For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly., Interventions: Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT., Main Outcomes and Measures: Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data., Results: Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%)., Conclusions and Relevance: In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms., Trial Registration: clinicaltrials.gov Identifier: NCT02055781.

Cardiac tamponade is a life-threatening emergency for which pericardiocentesis may be required. Real-time bedside ultrasound has obviated the need for routine blind procedures in cardiac arrest, and the number of pericardiocenteses being performed has declined. Despite this fact, pericardiocentesis remains an essential skill in emergency medicine. While commercially available training models exist, cost, durability, and lack of anatomical landmarks limit their usefulness. We sought to create a pericardiocentesis model that is realistic, simple to build, reusable, and cost efficient. We constructed the model using a red dye-filled ping pong ball (simulating the right ventricle) and a 250cc normal saline bag (simulating the effusion) encased in an artificial rib cage and held in place by gel wax. The inner saline bag was connected to a 1L saline bag outside of the main assembly to act as a fluid reservoir for repeat uses. The entire construction process takes approximately 16-20 hours, most of which is attributed to cooling of the gel wax. Actual construction time is approximately four hours at a cost of less than $200. The model was introduced to emergency medicine residents and medical students during a procedure simulation lab and compared to a model previously described by dell'Orto.1 The learners performed ultrasound-guided pericardiocentesis using both models. Learners who completed a survey comparing realism of the two models felt our model was more realistic than the previously described model. On a scale of 1-9, with 9 being very realistic, the previous model was rated a 4.5. Our model was rated a 7.8. There was also a marked improvement in the perceived recognition of the pericardium, the heart, and the pericardial sac. Additionally, 100% of the students were successful at performing the procedure using our model. In simulation, our model provided both palpable and ultrasound landmarks and held up to several months of repeated use. It was less expensive than commercial models ($200 vs up to $16,500) while being more realistic in simulation than other described "do-it-yourself models." This model can be easily replicated to teach the necessary skill of pericardiocentesis., Competing Interests: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. The authors disclosed none.

Unlabelled: We describe the rationale and design of the ongoing randomized, active-controlled, multicenter, Phase III study evaluating the efficacy of pixantrone and rituximab versus gemcitabine and rituximab in patients with diffuse large B-cell lymphoma or follicular grade 3 lymphoma, who are ineligible for high-dose chemotherapy and stem cell transplantation, and who failed front-line regimens containing rituximab. The administration schedule is pixantrone 50 mg/m(2) intravenously (iv.) or gemcitabine 1000 mg/m(2) iv. on days 1, 8 and 15, combined with rituximab 375 mg/m(2) iv. on day 1, up to six cycles. Pixantrone has a conditional European marketing approval for monotherapy in adults with multiple relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Our trial explores the efficacy of combining pixantrone with rituximab and completes postauthorization measures., Trial Registration Number: NCT01321541.

Global environmental change has influenced lake surface temperatures, a key driver of ecosystem structure and function. Recent studies have suggested significant warming of water temperatures in individual lakes across many different regions around the world. However, the spatial and temporal coherence associated with the magnitude of these trends remains unclear. Thus, a global data set of water temperature is required to understand and synthesize global, long-term trends in surface water temperatures of inland bodies of water. We assembled a database of summer lake surface temperatures for 291 lakes collected in situ and/or by satellites for the period 1985-2009. In addition, corresponding climatic drivers (air temperatures, solar radiation, and cloud cover) and geomorphometric characteristics (latitude, longitude, elevation, lake surface area, maximum depth, mean depth, and volume) that influence lake surface temperatures were compiled for each lake. This unique dataset offers an invaluable baseline perspective on global-scale lake thermal conditions as environmental change continues.

Protozoan pathogens present a significant human health concern, and prevention of contamination into potable networks remains a key focus for drinking water providers. Here, we monitored the change in Cryptosporidium concentration in source water during high flow events in a multi-use catchment. Furthermore, we investigated the diversity of Cryptosporidium species/genotypes present in the source water, and delivered an oocyst infectivity fraction. There was a positive and significant correlation between Cryptosporidium concentration and flow (ρ = 0.756) and turbidity (ρ = 0.631) for all rainfall-runoff events, despite variable source water pathogen concentrations. Cell culture assays measured oocyst infectivity and suggested an overall source water infectious fraction of 3.1%. No infectious Cryptosporidium parvum or Cryptosporidium hominis were detected, although molecular testing detected C. parvum in 7% of the samples analysed using PCR-based molecular techniques. Twelve Cryptosporidium species/genotypes were identified using molecular techniques, and were reflective of the host animals typically found in remnant vegetation and agricultural areas. The inclusion of molecular approaches to identify Cryptosporidium species and genotypes highlighted the diversity of pathogens in water, which originated from various sources across the catchment. We suggest this mixing of runoff water from a range of landuses containing diverse Cryptosporidium hosts is a key explanation for the often-cited difficulty forming strong pathogen-indicator relationships., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Cyanobacterial blooms are one of the main contaminants that can degrade drinking water quality with the associated taste, odour and toxic compounds. Although a wide range of techniques have shown promise for cyanobacterial bloom control and cyanobacterial cell/metabolite removal in reservoirs and water treatment plants (WTPs), these treatments may have negative consequences through release of intracellular metabolites into the surrounding water. This study assessed the impact of copper sulphate (CuSO4), chlorine, potassium permanganate (KMnO4), hydrogen peroxide (H2O2) and ozone on Microcystis aeruginosa culture and the toxins it produced. All of these agents induced the loss of cyanobacterial membrane integrity. However, no associated increase in dissolved toxins was detected during chlorine and H2O2 treatments which may be due to faster toxin oxidation rates than release rates. KMnO4 doses of 1 and 3mgL(-1) degraded dissolved toxins while having no impact on cyanobacterial membrane integrity. In contrast, ozone induced a significant increase in extracellular toxins but it was unable to degrade these toxins to the same degree as the other oxidants which may due to the lack of residual. All chemicals, except CuSO4, were able to reduce cyanotoxins and chlorine was the most effective with a rate up to 2161M(-1)s(-1)., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Potassium permanganate (KMnO4) is commonly used as a pre-treatment oxidant to remove soluble manganese (Mn) and iron (Fe) which can contribute to dirty water in drinking water supplies. Because Mn and Fe problems are commonly associated with thermal stratification in summer and autumn, they frequently coincide with the presence of cyanobacteria. The use of KMnO4 as an oxidant for Mn and Fe control therefore needs to consider the potential impacts on cyanobacterial cell integrity and toxin release. This study aims to assess the effect of KMnO4 on cyanobacteria cell integrity, toxin release and toxin oxidation. A toxic strain of Microcystis aeruginosa was exposed to various concentrations of KMnO4 and the cell integrity of cyanobacteria was measured with flow cytometry. Further the intra- and extra-cellular toxin concentrations were quantified and it was apparent that KMnO4 reduced both the intra- and extra-cellular toxins at low initial concentrations of 1 and 3 mg L(-1) without complete cell lysis. However, the cell integrity of cyanobacteria was compromised at KMnO4 concentrations of 5 mg L(-1) and 10 mg L(-1) and led to intracellular toxin release. In the 10 mg L(-1) KMnO4 treatment, the total toxin was oxidised after 7h contact time. A model describing the two step process of release and degradation was developed and may provide a tool to assess the risk water quality posed by toxin release. Consequently, it may be possible to use KMnO4 as a pre-treatment for Mn and Fe at concentrations<3 mg L(-1) and short contact time when cyanobacteria are also present., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The mantle of dead organic material ("canopy soil") associated with the mats of vascular and nonvascular epiphytes found on the branches of trees in the temperate rainforests along the southwestern coast of the South Island of New Zealand were examined for evidence of ectomycorrhizal fungi. DNA sequencing and cluster analysis were used to identify the taxa of fungi present in 74 root tips collected from the canopy soil microhabitat of three old growth Nothofagus menziesii trees in the South West New Zealand World Heritage Area. A diverse assemblage of ectomycorrhizal fungi was found to infect an extensive network of adventitious canopy roots of Nothofagus menziesii in this forest, including 14 phylotypes from nine genera of putative ectomycorrhizal fungi. Seven of the genera identified previously were known to form ectomycorrhizas with terrestrial roots of Nothofagus: Cortinarius, Russula, Cenococcum, Thelephora/Tomentella, Lactarius and Laccaria; two, Clavulina and Leotia, previously have not been reported forming ectomycorrhizas with Nothofagus. Canopy ectomycorrhizas provide an unexpected means for increased host nutrition that may have functional significance in some forest ecosystems. Presumably, canopy ectomycorrhizas on host adventitious roots circumvent the tree-ground-soil nutrient cycle by accessing a wider range of nutrients directly in the canopy than would be possible for non-mycorrhizal or arbuscular mycorrhizal canopy roots. In this system, both host and epiphytes would seem to be in competition for the same pool of nutrients in canopy soil.

Bipolar disorder can emerge in the context of organic brain pathology. In the case presented, long-standing hydrocephalus was diagnosed in a man with relatively late-onset bipolar illness who presented initially with somewhat atypical, treatment-resistant depressive symptoms. Hypomania, followed by a rapid-cycling bipolar course, subsequently developed. This report reviews the association between bipolar disorder and hydrocephalus, and examines possible neurobiological mechanisms implicated in both conditions.

Study Objectives: Hypocapnia is an important mediator of sleep-dependent respiratory instability. Positive pressure-associated ventilatory control instability results in poor control of sleep apnea and persistent sleep fragmentation. We tested the adjunctive efficacy of low volumes of dead space (enhanced expiratory rebreathing space [EERS]) using a non-vented mask to minimize sleep hypocapnia., Design: Retrospective chart review., Setting: American Academy of Sleep Medicine accredited sleep center and laboratory., Intervention: Enhanced expiratory rebreathing space, Measurements and Results: 204 patients diagnosed with continuous positive pressure (CPAP)-refractory sleep apnea between 1/1/04 and 7/1/06 were included in this retrospective review. All patients had in-lab attended polysomnography for diagnosis, conventional CPAP titration, and further assessments of added EERS. EERS volume was titrated to control of disease, which was typically obtained when end-tidal (ET) CO₂ during sleep was 1-2 mm Hg above wake eupneic CO₂ levels. The clinic records were reviewed for clinical outcomes. Poor laboratory response to, and initial clinical abandonment of CPAP, was very common (89.2%) in this group of patients, who as a group demonstrated mild resting wake hypocapnia (ETCO₂ = 38.1 ± 3.1 mm Hg). Minimizing sleep hypocapnia by adding 100-150 mL EERS (mean ETCO₂) at optimal therapy 38.6 ± 2.9 mm Hg) markedly improved polysomnographic control of sleep apnea, without inducing tachypnea or tachycardia. Follow-up (range 30-1872 days) showed improved clinical tolerance, compliance, and sustained clinical improvement. Leak and sleep fragmentation modified clinical outcomes., Conclusions: EERS is a potentially useful adjunctive therapy for positive pressure-associated respiratory instability and salvage of some CPAP treatment failures.

Surface water sources are increasingly subject to proliferation of toxic cyanobacteria. Direct chlorination of source water containing toxic cyanobacterial cells for different treatment purposes might cause cell damage and toxin release. There is limited information available on chlorination of saxitoxins (STXs: saxitoxin, C-toxins, and gonyautoxins) produced by Anabaena circinalis. This work: (1) investigated the impact of chlorination on cell lysis and toxin/odor compound release in natural waters; (2) assessed the rates of chlorination of total STXs, and (3) estimated apparent rate constants for STX oxidation in ultrapure and natural waters. With a chlorine exposure (CT) value of 7.0 mg x min/L all cells lost viability causing toxin release. Cell-membrane damage occurred faster than released STXs oxidation. All saxitoxin and more than 95% of other STX analogues were subsequently oxidized. Kinetic analysis of the oxidation of STX analogues revealed significant differences in the susceptibility to chlorine, saxitoxin being the easiest to oxidize. Also, concentrations of trihalomethanes, haloacetic acids, and N-nitrosodimethylamine as chlorination byproducts were respectively <50 μg/L and 11 ng/L even at the highest CT value (50.3 mg x min/L).

Absinthe is an alcoholic drink which is becoming more widely consumed after being banned for many decades. An association between absinthe use and psychiatric symptoms, ranging from impairment of concentration to marked hallucinations and seizures, has been suggested, but evidence remains unclear. Thujone, identified as a possible psychoactive ingredient, has recently been implicated in absinthe's putative neuropsychiatric effects. This report presents a case where acute suicidality emerged during absinthe consumption; possible neurobiological aetiological mechanisms and the history of absinthe use and associated adverse effects are reviewed.

Study Objectives: Complex sleep apnea is defined as sleep disordered breathing secondary to simultaneous upper airway obstruction and respiratory control dysfunction. The objective of this study was to assess the utility of an electrocardiogram (ECG)-based cardiopulmonary coupling technique to distinguish obstructive from central or complex sleep apnea., Design: Analysis of archived polysomnographic datasets., Setting: A laboratory for computational signal analysis., Interventions: None., Measurements and Results: The PhysioNet Sleep Apnea Database, consisting of 70 polysomnograms including single-lead ECG signals of approximately 8 hours duration, was used to train an ECG-based measure of autonomic and respiratory interactions (cardiopulmonary coupling) to detect periods of apnea and hypopnea, based on the presence of elevated low-frequency coupling (e-LFC). In the PhysioNet BIDMC Congestive Heart Failure Database (ECGs of 15 subjects), a pattern of "narrow spectral band" e-LFC was especially common. The algorithm was then applied to the Sleep Heart Health Study-I dataset, to select the 15 records with the highest amounts of broad and narrow spectral band e-LFC. The latter spectral characteristic seemed to detect not only periods of central apnea, but also obstructive hypopneas with a periodic breathing pattern. Applying the algorithm to 77 sleep laboratory split-night studies showed that the presence of narrow band e-LFC predicted an increased sensitivity to induction of central apneas by positive airway pressure., Conclusions: ECG-based spectral analysis allows automated, operator-independent characterization of probable interactions between respiratory dyscontrol and upper airway anatomical obstruction. The clinical utility of spectrographic phenotyping, especially in predicting failure of positive airway pressure therapy, remains to be more thoroughly tested.

The proliferation of cyanobacteria in drinking water sources is problematic for water authorities as they can interfere with water treatment processes. Studies have shown that oxidants such as chlorine can enhance the coagulation of cyanobacteria; however, chlorine can potentially lyse cyanobacterial cells, releasing toxic metabolites. Chlorine also has the potential to effectively degrade these toxins. This study evaluated the effect of chlorine on the cell integrity of toxic Microcystis aeruginosa in reservoir water using flow cytometry. In addition, the effect of chlorine on the subsequent release and degradation of microcystin toxins was systematically assessed. Cell lysis occurred at chlorine exposure values between 7 and 29 mg min/L, which is within the range of normal disinfection practices. Intracellular toxin was shown to be released from damaged cells at a rate three times faster than it was degraded by chlorine. The degradation of extracellular microcystin by chlorine was found to be dependent upon the pH, chlorine exposure, and the presence of cyanobacterial cells.

Platelet glycoprotein IIb-IIIa antagonists reduce cardiac events in acute coronary syndromes (ACSs), but their use is limited during coronary artery bypass grafting (CABG) because of bleeding concerns. Patients with ACS, however, are at increased risk for cardiac events after CABG. The use of short-acting glycoprotein IIbIIIa inhibitor eptifibatide in patients with ACS undergoing CABG was investigated. Fifteen patients with ACS and undergoing CABG with cardiopulmonary bypass were enrolled. One withdrew before surgery. Patients received heparin and eptifibatide preoperatively. Eptifibatide concentration and receptor occupancy (RO) at termination of infusion were similar in the two groups. Immediately before surgery, eptifibatide levels in the 2-hour group were twice that in the 4-hour group, and platelet RO was higher. Cessation of eptifibatide 4 hours before surgery results in less bleeding and transfusions than 2 hours before surgery. The optimal balance between bleeding and platelet inhibition is approximately 60% platelet RO. Further investigation of upstream therapy should target this threshold.

Given renewed interest in the role of human action in the development of depression, I re-examine a tradition in the West which interpreted phenomena akin to the symptoms and signs of modern depression as "a spiritual disease." In medieval Europe, acedia was a vice, an undesirable trait of character acquired in the course of living a life. Persons suffering from the vice of acedia were implicated as agents in its development and to some extent responsible for overcoming it. In Part I of this paper, I note the contemporary interest of psychiatrists and others in this vice, consider the warrants for asserting that it is akin to some forms of depression, and recount, in brief, the history of this vice from the fourth to the fifteenth centuries. In Part II, I discuss how medieval scholars, confessors, and spiritual guides understood the question of responsibility for acedia and how they distinguished between this vice and melancholia. I argue that acedia was a vice that could be distinguished from melancholia and that, while akin to clinical depression, this vice should not be identified with depression. This investigation of and commentary on acedia is intended as a contribution to the contemporary discussion of the role of human agency in the development of depression and in its treatment.

Objective: The role of ovarian steroids in both premenstrual dysphoria and perimenopausal depression has led to the suggestion that these conditions represent expressions of the same underlying disorder. Premenstrual mood symptoms were evaluated in women with perimenopause-related depression., Method: Self-reports and daily symptom ratings during one menstrual cycle were examined in 70 depressed perimenopausal women attending a menopause clinic and 35 nondepressed perimenopausal women., Results: Twenty-six percent of the depressed and 9% of the nondepressed women reported premenstrual symptoms. Thirty-one percent of the depressed and 20% of the nondepressed women met criteria for significant menses-related symptom cyclicity (at least a 30% increase in the average ratings of at least two of four measured negative mood symptoms in the premenstrual versus the postmenstrual week); 5 of these depressed women and none of the comparison subjects described premenstrual symptoms on self-reports. Finally, 21% of the depressed and 3% of the nondepressed women met criteria for premenstrual dysphoria (symptom cyclicity and at least moderate severity, with symptoms exceeding a minimum luteal symptom severity threshold of 2.5)., Conclusions: A higher-than-expected rate of menses-related symptom cyclicity and premenstrual dysphoria was observed in perimenopausal depressed women. However, neither menses-related symptom cyclicity nor premenstrual dysphoria was an invariant accompaniment of perimenopausal depression. Additionally, the rate of premenstrual dysphoria was not predicted by initial self-reports.

Purpose of Review: The recent rapid evolution of our understanding of the mechanisms involved in control of respiration during sleep has yielded new insights to guide our care of difficult-to-treat sleep apnea patients with complex sleep-disordered breathing. This review will describe these recent advances in the literature and suggest a model for their incorporation into clinical practice., Recent Findings: Control of respiration during sleep shows amplified instability relative to that seen during wake in these difficult patients. Baseline (eupneic) carbon dioxide levels as well as the responsiveness of the ventilatory system to changes in carbon dioxide are all-important in this relative instability. Furthermore, the instability seen during sleep varies widely across sleep states. A further refinement of our definition of stable and unstable sleep has been developed that directly informs our understanding of the control of respiration across a night of sleep., Summary: Complex sleep-disordered breathing is a distinct form of sleep apnea. It has recognizable characteristics that are present without, and often worsened during, positive airway pressure treatment. Both sleep state stability and the behavior of the respiratory control system contribute to this complexity. It is only with a clear understanding of the factors contributing to complex sleep-disordered breathing that implementation of truly effective clinical therapy can be achieved for this disorder, which to date is poorly controlled.

Context: Alternative and over-the-counter medicines have become increasingly popular choices for many patients who prefer not to take traditional antidepressants. The adrenal androgen and neurosteroid dehydroepiandrosterone (DHEA) is available as over-the-counter hormonal therapy and previously has been reported to have antidepressant-like effects., Objective: To evaluate the efficacy of DHEA as a monotherapy treatment for midlife-onset depression., Design: A double-blind, randomized, placebo-controlled, crossover treatment study was performed from January 4, 1996, through August 31, 2002. Settings The National Institute of Mental Health Midlife Outpatient Clinic in the National Institutes of Health Clinical Center, Bethesda, Md. Patients Men (n = 23) and women (n = 23) aged 45 to 65 years with midlife-onset major or minor depression participated in this study. None of the subjects received concurrent antidepressant medications. Intervention Six weeks of DHEA therapy, 90 mg/d for 3 weeks and 450 mg/d for 3 weeks, and 6 weeks of placebo., Main Outcome Measures: The 17-Item Hamilton Depression Rating Scale and Center for Epidemiologic Studies Depression Scale. Additional measures included the Derogatis Interview for Sexual Functioning. Results were analyzed by means of repeated-measures analysis of variance and post hoc Bonferroni t tests., Results: Six weeks of DHEA administration was associated with a significant improvement in the 17-Item Hamilton Depression Rating Scale and the Center for Epidemiologic Studies Depression Scale ratings compared with both baseline (P<.01) and 6 weeks of placebo treatment (P<.01). A 50% or greater reduction in baseline Hamilton Depression Rating Scale scores was observed in 23 subjects after DHEA and in 13 subjects after placebo treatments. Six weeks of DHEA treatment also was associated with significant improvements in Derogatis Interview for Sexual Functioning scores relative to baseline and placebo conditions., Conclusion: We find DHEA to be an effective treatment for midlife-onset major and minor depression.

Objectives: To assess the efficacy of added carbon dioxide as adjunctive therapy to positive airway pressure-refractory mixed obstructive and central sleep-disordered breathing, using a prototype device-the positive airway pressure gas modulator., Design: Open-label evaluation of low concentrations of carbon dioxide added to a positive airway pressure circuit., Setting: Physician-attended polysomnographic titration in a free-standing sleep laboratory with end-tidal and transcutaneous carbon-dioxide monitoring., Patients: Six adult men (age 54 +/- 5.7 years) with severe poorly controlled mixed sleep-disordered breathing in the absence of renal or heart failure., Interventions: Flow-independent addition of incremental concentrations of carbon dioxide during sleep., Measurements and Results: The respiratory disturbance index before treatment was 66 +/- 14.5 events per hour of sleep, with a nocturnal desaturation low of 84.6% +/- 10.1%. Residual respiratory disturbance index on best treatment was 43 +/- 9 events per hour of sleep. There was an immediate (<1 minute) response to the addition of 0.5% to 1% carbon dioxide, and minimal changes were required to be made across the night. There was no discomfort, shortness of breath, palpitations, headache, or significant increase in respiratory or heart rate. The residual respiratory disturbance index on carbon dioxide, scored irrespective of desaturations, was in the normal range (< 5 / hour of sleep). Two subjects had a second night at the concentration of carbon dioxide determined to be efficacious, with no required concentration change. No adverse effects on overall sleep architecture were noted., Conclusions: Low concentrations of carbon dioxide added to conventional positive airway pressure effectively control severe treatment-resistant mixed obstructive and central sleep-disordered breathing.

Abnormalities in quality of life and cognitive measures have been observed in women with Turner syndrome (TS), and a relationship between these phenomena and chromosomal constitution has been suggested. In contrast, few studies have systematically evaluated the presence of mood and behavioral syndromes in these women. In this study, 100 TS women were administered the Structured Clinical Interview for DSM IV after a two-week period during which their hormone replacement had been discontinued. The majority of women who met criteria for a psychiatric condition had a mood or anxiety disorder. Overall, 52 (52%) of the TS women met criteria for a current or a past depressive or anxiety disorder. Eighteen of the women with TS met criteria for a current Axis I psychiatric disorder [Depression--major (n = 5), minor (n = 5), dysthymia (n = 1); Anxiety (n = 9)]. Forty-six of the women with TS met criteria for a past Axis I psychiatric illness [Depression: unipolar (n = 41), bipolar (n = 3); Anxiety (n= 7); eating disorder (n =6); substance dependence (n = 3)]. Five women with TS met criteria for an Axis II personality disorder. Women with TS reported a higher rate of lifetime depression compared with rates observed in community-based studies but similar to those obtained from gynecologic clinic samples.

Objective: Despite reports of estradiol's therapeutic efficacy in perimenopausal depression, the relationship between ovarian function and mood in perimenopausal depression remains unclear. The purpose of this study was to examine changes in mood and pituitary-ovarian axis function in women exhibiting perimenopausal depression., Method: Depression ratings (from the Center for Epidemiologic Studies-Depression Scale [CES-D Scale]) and follicle-stimulating hormone (FSH) plasma levels of depressed perimenopausal women (N=110) attending a menopause clinic were obtained at baseline and after a 6-week screening period., Results: Eighteen women experienced an improvement in depression (50% decline in CES-D Scale scores) at week 6, which was associated with a significant decrease in FSH plasma levels (baseline: mean=73.3 IU/liter [SD=42.0]; week 6: mean=42.2 IU/liter [SD=28.6]). Similarly, those subjects experiencing a 50% drop in FSH plasma levels had significant decreases in CES-D Scale scores (baseline: mean=23.3 [SD=6.8]; week 6: mean=18.1 [SD=10.9]). However, between women with CES-D Scale scores > or = 15 and those with CES-D Scale scores <15, no significant differences in FSH levels were observed either at baseline (mean=65.5 IU/liter [SD=35.7] and 60.9 IU/liter [SD=34.9], respectively) or at week 6 (mean=56.2 IU/liter [SD=36.6] and 51.5 IU/liter [SD=34.2])., Conclusions: Mood variability in women with perimenopausal depression may reflect episodic alterations in ovarian function that are best detected by longitudinal study designs.

This article reviews the literature regarding endocrine factors postulated or presumed to be relevant in postpartum depression (PPD), a condition affecting at least 10% of childbearing women. The phenomenology and epidemiology of PPD are also described. Data suggest that parturition-related endocrine changes are causally implicated in PPD in a vulnerable subgroup of women. More specifically, studies by our group and others suggest a role for changes in estradiol and progesterone in precipitating mood symptoms among women with PPD. The mechanisms underlying such differential sensitivities remain undetermined. Future directions for research are explored.

Thrombocytopenia is a relatively common side effect observed during glycoprotein (GP) IIb/IIIa antagonist therapy. With the oral antagonist roxifiban, we observed thrombocytopenia, defined as 50% reduction of platelets over predose values or below 90 000/microL (9 x 10(10)/L), with a frequency of 2% (8 of 386). Thrombocytopenia occurred either early (days 2 to 4) or delayed (days 11 to 16). No additional cases were observed with up to 6 months of treatment. Retrospective analysis provided evidence for drug-dependent antibodies (DDABs) to GP IIb/IIIa in 5 of 6 subjects, suggestive of an immune etiology of thrombocytopenia. The hypothesis that excluding patients based on positive DDAB reaction would reduce the frequency of thrombocytopenia was tested. Patients were screened for DDABs during the study qualification period and, overall, 3.9% of the patients were excluded based on pre-existing DDAB concentrations above a statistically defined medical decision limit. An additional 2.6% were excluded based on therapy-related antibody production during the first 2 weeks. With antibody testing, 0.2% of patients (2 of 1044) developed immune-mediated thrombocytopenia. One case developed a rapidly increasing antibody concentration and presented with thrombocytopenia despite discontinuation of roxifiban therapy. The second case was related to a false-negative test result. The frequency of thrombocytopenia was statistically significantly reduced from 2% to 0.2% (P =.0007) comparing nonscreened and screened patients. Testing for DDABs can reduce the frequency of thrombocytopenia in patients treated with roxifiban and, by analogy, other GP IIb/IIIa antagonists. Thus, DDAB testing may be employed to increase the safety of GP IIb/IIIa antagonists.

Introduction: Intravenous platelet glycoprotein (GP) IIb/IIIa receptor inhibitors have a significant beneficial impact on the outcomes of patients undergoing high-risk coronary interventions and in the stabilization of patients with unstable angina pectoris refractory to conventional medical treatment. The role of long-term treatment with oral platelet GP IIb/IIIa receptor inhibitors in patients with coronary artery disease is unproven. This study examined the dose-response effect on inhibition of platelet aggregation by roxifiban (DMP754), a novel oral platelet GP IIb/IIIa receptor inhibitor, and its safety and tolerability in patients with a history of chronic stable angina pectoris., Methods: Ninety-eight patients were randomized to receive either a placebo or 1 of 8 oral dosages of roxifiban. Twenty-two patients were enrolled in multiple-dose regimens, bringing the total study population to 120. The oral dosages were 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, or 2.5 mg/day for up to 30 days., Results: Pharmacodynamic response of roxifiban was clearly dose-dependent. Platelet aggregation inhibition in response to 10 micromol/L slope adenosine diphosphate was sustained throughout the study period (up to 1 month). No serious adverse events, including significant major bleeding events, were associated with roxifiban treatment. Minor bleeding was reported in 5% of participants in the placebo group (1 of 21 cases) versus 26% in the study group (26 of 99 cases). Incidence of minor bleeding associated with roxifiban 2 and 2.5 mg/day was significantly (p < or = 0.05) greater than that with placebo. Adverse events, including gastrointestinal disorders, platelet and clotting disorders, and urinary tract disorders, were observed in 1 of 21 cases (5%) in the placebo group and in 12 of 99 cases (12%) in the study group. Reversible thrombocytopenia without other complications developed in two patients., Conclusions: Roxifiban-induced inhibition of platelet aggregation was dose-dependent and sustained throughout the study period: higher drug dosages correlated with higher levels of platelet inhibition and higher incidence of minor bleeding events. No serious adverse events were observed at any dosage. Thus, roxifiban appears to be a potent oral platelet GP IIb/IIIa receptor inhibitor that is clinically well-tolerated and deserves further study as a new treatment strategy in patients with chronic stable angina pectoris.

Background: Several authors have reported increased soluble interleukin 2 receptor (sIL2Ralpha) concentrations in schizophrenia. The aim of this work was to examine serum sIL2Ralpha in the first degree relatives of patients with schizophrenia., Methods: We sampled 51 first degree relatives of patients with DSM IIIR schizophrenia. These relatives were unaffected by psychosis and included nine fathers, thirteen mothers, seventeen sisters and twelve brothers. They were compared to 126 controls who were not pregnant, had no known autoimmune disorder and no intercurrent illness. Neither the controls, nor their first degree relatives, suffered from a psychotic illness. Serum sIL2Ralpha was analysed using a commercial ELISA preparation (Quantikine sIL2Ralpha immunoassay - R and D Systems, Inc.). We used non-parametric Mann Whitney U test and Spearman correlation throughout. SIL2Ralpha levels were adjusted for higher levels in females and with increasing age., Results: Adjusted mean sIL2Ralpha values of unaffected siblings, averaged within their families, were higher than controls (n=14, one-tailed p=0.027). There was no difference in sIL2Ralpha values between fathers or mothers and controls following regression for age and sex., Conclusion: Soluble interleukin 2 receptoralpha levels are increased in siblings of patients with schizophrenia.

Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.