Non-pharmaceutical interventions to optimize cancer immunotherapy.

The traditional picture of cancer patients as weak individuals requiring maximum rest and protection is beginning to dissolve. Too much focus on the medical side and one's own vulnerability and mortality might be counterproductive and not doing justice to the complexity of human nature. Unlike cytotoxic and lympho-depleting treatments, immune-engaging therapies strengthen the immune system and are typically less harmful for patients. Thus, cancer patients receiving checkpoint inhibitors are not viewed as being vulnerable per se, at least not in immunological and physical terms. This perspective article advocates a holistic approach to cancer immunotherapy, with an empowered patient in the center, focusing on personal resources and receiving domain-specific support from healthcare professionals. It summarizes recent evidence on non-pharmaceutical interventions to enhance the efficacy of immune checkpoint blockade and improve quality of life. These interventions target behavioral factors such as diet, physical activity, stress management, circadian timing of checkpoint inhibitor infusion, and waiving unnecessary co-medication curtailing immunotherapy efficacy. Non-pharmaceutical interventions are universally accessible, broadly applicable, instantly actionable, scalable, and economically sustainable, creating value for all stakeholders involved. Most importantly, this holistic framework re-emphasizes the patient as a whole and harnesses the full potential of anticancer immunity and checkpoint blockade, potentially leading to survival benefits. Digital therapeutics are proposed to accompany the patients on their mission toward change in lifestyle-related behaviors for creating optimal conditions for treatment efficacy and personal growth.

Gender-specific disease trajectories prior to the onset of COPD allow individualized screening and early intervention.

BACKGROUND: Nation-wide hospitalization databases include diagnostic information at the level of an entire population over an extended period of time. Comorbidity network and early disease development can be unveiled. Chronic obstructive pulmonary disease (COPD) is an underdiagnosed condition for which it is crucial to identify early disease indicators. The identification of gender-specific conditions preceding the onset of COPD may reveal disease progression patterns allowing for early diagnosis and intervention. The objective of the study was to investigate the antecedent hospitalization history of patients newly diagnosed with COPD and to retrace a gender-specific trajectory of coded entities prior to the onset of COPD. MATERIAL AND METHODS: A population-wide hospitalization database including information about all hospitalizations in Switzerland between 2002 and 2018 was used. COPD cases were extracted from the database and comorbidities occurring prior to the onset of COPD identified. Comorbidities significantly over-represented in COPD compared with a 1:1, age- and sex-matched control population were identified and their longitudinal evolution was analyzed. RESULTS: Between 2002 and 2018, 697,714 hospitalizations with coded COPD were recorded in Switzerland. Sixty-two diagnoses were significantly over-represented before onset of COPD. These preceding comorbidities included both well-established conditions and novel links to COPD. Early pre-conditions included nicotine and alcohol abuse, obesity and cardiovascular diseases. Later comorbidities included atrial fibrillation, diseases of the genitourinary system and pneumonia. Atherosclerotic heart diseases were more prevalent in males, whereas hypothyroidism, varicose and intestinal disorders were more frequent in females. Disease trajectories were validated using an independent data set. CONCLUSIONS: Gender-specific disease trajectories highlight early indicators and pathogenetic links between COPD and antecedent diseases and could allow for early detection and intervention.

Smartphone-based cough monitoring as a near real-time digital pneumonia biomarker.

Background: Cough represents a cardinal symptom of acute respiratory tract infections. Generally associated with disease activity, cough holds biomarker potential and might be harnessed for prognosis and personalised treatment decisions. Here, we tested the suitability of cough as a digital biomarker for disease activity in coronavirus disease 2019 (COVID-19) and other lower respiratory tract infections. Methods: We conducted a single-centre, exploratory, observational cohort study on automated cough detection in patients hospitalised for COVID-19 (n=32) and non-COVID-19 pneumonia (n=14) between April and November 2020 at the Cantonal Hospital St Gallen, Switzerland. Cough detection was achieved using smartphone-based audio recordings coupled to an ensemble of convolutional neural networks. Cough levels were correlated to established markers of inflammation and oxygenation. Measurements and main results: Cough frequency was highest upon hospital admission and declined steadily with recovery. There was a characteristic pattern of daily cough fluctuations, with little activity during the night and two coughing peaks during the day. Hourly cough counts were strongly correlated with clinical markers of disease activity and laboratory markers of inflammation, suggesting cough as a surrogate of disease in acute respiratory tract infections. No apparent differences in cough evolution were observed between COVID-19 and non-COVID-19 pneumonia. Conclusions: Automated, quantitative, smartphone-based detection of cough is feasible in hospitalised patients and correlates with disease activity in lower respiratory tract infections. Our approach allows for near real-time telemonitoring of individuals in aerosol isolation. Larger trials are warranted to decipher the use of cough as a digital biomarker for prognosis and tailored treatment in lower respiratory tract infections.

Nighttime Continuous Contactless Smartphone-Based Cough Monitoring for the Ward: Validation Study.

BACKGROUND: Clinical deterioration can go unnoticed in hospital wards for hours. Mobile technologies such as wearables and smartphones enable automated, continuous, noninvasive ward monitoring and allow the detection of subtle changes in vital signs. Cough can be effectively monitored through mobile technologies in the ward, as it is not only a symptom of prevalent respiratory diseases such as asthma, lung cancer, and COVID-19 but also a predictor of acute health deterioration. In past decades, many efforts have been made to develop an automatic cough counting tool. To date, however, there is neither a standardized, sufficiently validated method nor a scalable cough monitor that can be deployed on a consumer-centric device that reports cough counts continuously. These shortcomings limit the tracking of coughing and, consequently, hinder the monitoring of disease progression in prevalent respiratory diseases such as asthma, chronic obstructive pulmonary disease, and COVID-19 in the ward. OBJECTIVE: This exploratory study involved the validation of an automated smartphone-based monitoring system for continuous cough counting in 2 different modes in the ward. Unlike previous studies that focused on evaluating cough detection models on unseen data, the focus of this work is to validate a holistic smartphone-based cough detection system operating in near real time. METHODS: Automated cough counts were measured consistently on devices and on computers and compared with cough and noncough sounds counted manually over 8-hour long nocturnal recordings in 9 patients with pneumonia in the ward. The proposed cough detection system consists primarily of an Android app running on a smartphone that detects coughs and records sounds and secondarily of a backend that continuously receives the cough detection information and displays the hourly cough counts. Cough detection is based on an ensemble convolutional neural network developed and trained on asthmatic cough data. RESULTS: In this validation study, a total of 72 hours of recordings from 9 participants with pneumonia, 4 of whom were infected with SARS-CoV-2, were analyzed. All the recordings were subjected to manual analysis by 2 blinded raters. The proposed system yielded a sensitivity and specificity of 72% and 99% on the device and 82% and 99% on the computer, respectively, for detecting coughs. The mean differences between the automated and human rater cough counts were -1.0 (95% CI -12.3 to 10.2) and -0.9 (95% CI -6.5 to 4.8) coughs per hour within subject for the on-device and on-computer modes, respectively. CONCLUSIONS: The proposed system thus represents a smartphone cough counter that can be used for continuous hourly assessment of cough frequency in the ward.

Inhaled aviptadil for the possible treatment of COVID-19 in patients at high risk for ARDS: study protocol for a randomized, placebo-controlled, and multicenter trial.

BACKGROUND: Despite the fast establishment of new therapeutic agents in the management of COVID-19 and large-scale vaccination campaigns since the beginning of the SARS-CoV-2 pandemic in early 2020, severe disease courses still represent a threat, especially to patients with risk factors. This indicates the need for alternative strategies to prevent respiratory complications like acute respiratory distress syndrome (ARDS) associated with COVID-19. Aviptadil, a synthetic form of human vasoactive intestinal peptide, might be beneficial for COVID-19 patients at high risk of developing ARDS because of its ability to influence the regulation of exaggerated pro-inflammatory proteins and orchestrate the lung homeostasis. Aviptadil has recently been shown to considerably improve the prognosis of ARDS in COVID-19 when applied intravenously. An inhaled application of aviptadil has the advantages of achieving a higher concentration in the lung tissue, fast onset of activity, avoiding the hepatic first-pass metabolism, and the reduction of adverse effects. The overall objective of this project is to assess the efficacy and safety of inhaled aviptadil in patients hospitalized for COVID-19 at high risk of developing ARDS. METHODS: This multicenter, placebo-controlled, double-blinded, randomized trial with 132 adult patients hospitalized for COVID-19 and at high risk for ARDS (adapted early acute lung injury score ≥ 2 points) is conducted in five public hospitals in Europe. Key exclusion criteria are mechanical ventilation at baseline, need for intensive care at baseline, and severe hemodynamic instability. Patients are randomly allocated to either inhale 67 µg aviptadil or normal saline (three times a day for 10 days), in addition to standard care, stratified by center. The primary endpoint is time from hospitalization to clinical improvement, defined as either hospital discharge, or improvement of at least two levels on the nine-level scale for clinical status suggested by the World Health Organization. DISCUSSION: Treatment strategies for COVID-19 are still limited. In the context of upcoming new variants of SARS-CoV-2 and possible inefficacy of the available vaccines and antibody therapies, the investigation of alternative therapy options plays a crucial role in decreasing associated mortality and improving prognosis. Due to its unique immunomodulating properties also targeting the SARS-CoV-2 pathways, inhaled aviptadil may have the potential to prevent ARDS in COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04536350 . Registered 02 September 2020.

TripletCough: Cougher Identification and Verification From Contact-Free Smartphone-Based Audio Recordings Using Metric Learning.

Cough, a symptom associated with many prevalent respiratory diseases, can serve as a potential biomarker for diagnosis and disease progression. Consequently, the development of cough monitoring systems and, in particular, automatic cough detection algorithms have been studied since the early 2000s. Recently, there has been an increased focus on the efficiency of such algorithms, as implementation on consumer-centric devices such as smartphones would provide a scalable and affordable solution for monitoring cough with contact-free sensors. Current algorithms, however, are incapable of discerning between coughs of different individuals and, thus, cannot function reliably in situations where potentially multiple individuals have to be monitored in shared environments. Therefore, we propose a weakly supervised metric learning approach for cougher recognition based on smartphone audio recordings of coughs. Our approach involves a triplet network architecture, which employs convolutional neural networks (CNNs). The CNNs of the triplet network learn an embedding function, which maps Mel spectrograms of cough recordings to an embedding space where they are more easily distinguishable. Using audio recordings of nocturnal coughs from asthmatic patients captured with a smartphone, our approach achieved a mean accuracyof 88 % ( ± 10 % SD) on two-way identification tests with 12 enrollment samples and accuracy of 80 % and an equal error rate (EER) of 20 % on verification tests. Furthermore, our approach outperformed human raters with regard to verification tests on average by 8% in accuracy, 4% in false acceptance rate (FAR), and 12% in false rejection rate (FRR). Our code and models are publicly available.

Text mining-based measurement of precision of polysomnographic reports as basis for intervention.

BACKGROUND: Text mining can be applied to automate knowledge extraction from unstructured data included in medical reports and generate quality indicators applicable for medical documentation. The primary objective of this study was to apply text mining methodology for the analysis of polysomnographic medical reports in order to quantify sources of variation - here the diagnostic precision vs. the inter-rater variability - in the work-up of sleep-disordered breathing. The secondary objective was to assess the impact of a text block standardization on the diagnostic precision of polysomnography reports in an independent test set. RESULTS: Polysomnography reports of 243 laboratory-based overnight sleep investigations scored by 9 trained sleep specialists of the Sleep Center St. Gallen were analyzed using a text-mining methodology. Patterns in the usage of discriminating terms allowed for the characterization of type and severity of disease and inter-rater homogeneity. The variation introduced by the inter-rater (technician/physician) heterogeneity was found to be twice as high compared to the variation introduced by effective diagnostic information. A simple text block standardization could significantly reduce the inter-rater variability by 44%, enhance the predictive value and ultimately improve the diagnostic accuracy of polysomnography reports. CONCLUSIONS: Text mining was successfully used to assess and optimize the quality, as well as the precision and homogeneity of medical reporting of diagnostic procedures - here exemplified with sleep studies. Text mining methodology could lay the ground for objective and systematic qualitative assessment of medical reports.

No evidence of harmful effects of steroids in severe exacerbations of COPD associated with influenza.

PURPOSE: COPD has large impact on patient morbidity and mortality worldwide. Acute exacerbations (AECOPD) are mostly triggered by respiratory infections including influenza. While corticosteroids are strongly recommended in AECOPD, they are potentially harmful during influenza. We aimed to evaluate if steroid treatment for AECOPD due to influenza may worsen outcomes. METHODS: A retrospective analysis of a Swiss nation-wide hospitalization database was conducted identifying all AECOPD hospitalisations between 2012 and 2017. In separate analyses, outcomes concerning length-of-stay (LOS), in-hospital mortality, rehospitalisation rate, empyema and aspergillosis were compared between AECOPD during and outside influenza season; AECOPD with and without laboratory-confirmed influenza; and AECOPD plus pneumonia with and without laboratory-confirmed influenza. RESULTS: Patients hospitalized for AECOPD during influenza season showed shorter LOS (11.3 vs. 11.6 day, p < 0.001) but higher rehospitalisation rates (33 vs 31%, p < 0.001) compared to those hospitalized outside influenza season. Patients with confirmed influenza infection had lower in-hospital mortality (3.3 vs. 5.5%, p = 0.010) and rehospitalisation rates (29 vs. 37%, p < 0.001) than those without confirmed influenza. CONCLUSION: Using different indicators for influenza as the likely cause of AECOPD, we found no consistent evidence of worse outcomes of AECOPD due to influenza for hospitalized patients. Assuming that most of these patients received corticosteroids, as it is accepted standard of care in Switzerland, this study gives no evidence to change the current practice of using corticosteroids for hospitalized AECOPD independent of the influenza status.

Diagnostic precision and identification of rare diseases is dependent on distance of residence relative to tertiary medical facilities.

BACKGROUND: Diagnostic precision and the identification of rare diseases is a daily challenge, which needs specialized expertise. We hypothesized, that there is a correlation between the distance of residence to the next tertiary medical facility with highly specialized care and the diagnostic precision, especially for rare diseases. RESULTS: Using a nation-wide hospitalization database, we found a negative association between diagnostic diversity and travel time to the next tertiary referral hospital when including all cases throughout the overall International Classification of Diseases version 10 German Modification (ICD-10-GM) diagnosis codes. This was paralleled with a negative association of standardized incidence rates in all groups of rare diseases defined by the Orphanet rare disease nomenclature, except for rare teratologic and rare allergic diseases. CONCLUSION: Our findings indicate a higher risk of being mis-, under- or late diagnosed especially in rare diseases when living more distant to a tertiary medical facility. Greater distance to the next tertiary medical facility basically increases the chance for hospitalization in a non-comprehensive regional hospital with less diagnostic capacity, and, thus, impacts on adapted health care access. Therefore, solutions for overcoming the distance to specialized care as an indicator of health care access are a major goal in the future.

Characteristics of Asthma-related Nocturnal Cough: A Potential New Digital Biomarker.

INTRODUCTION: The nature of nocturnal cough is largely unknown. It might be a valid marker for asthma control but very few studies characterized it as a basis for better defining its role and its use as clinical marker. This study investigated prevalence and characteristics of nocturnal cough in asthmatics over the course of four weeks. METHODS: In two centers, 94 adult patients with physician-diagnosed asthma were recruited. Patient-reported outcomes and nocturnal sensor data were collected by a smartphone with a chat-based study app. RESULTS: Patients coughed in 53% of 2212 nights (range: 0-345 coughs/night). Median coughs per hour were 0 (IQR 0-1). Nocturnal cough rates showed considerable inter-individual variance. The highest counts were measured in the first 30 min in bed (4.5-fold higher than rest of night). Eighty-six percent of coughs were part of a cough cluster. Clusters consisted of a median of two coughs (IQR 2-4). Nocturnal cough was persistent within patient. CONCLUSION: To the best of the authors' knowledge, this study is the first to describe prevalence and characteristics of nocturnal cough in asthma over a period of one month, demonstrating that it was a prevalent symptom with large variance between patients and high persistence within patients. Cough events in asthmatics were 4.5 times more frequent within the first 30 min in bed indicating a potential role of positional change, and not more frequent during the early morning hours. An important next step will investigate the association between nocturnal cough and asthma control.

Nocturnal Cough and Sleep Quality to Assess Asthma Control and Predict Attacks.

INTRODUCTION: Objective markers for asthma, that can be measured without extra patient effort, could mitigate current shortcomings in asthma monitoring. We investigated whether smartphone-recorded nocturnal cough and sleep quality can be utilized for the detection of periods with uncontrolled asthma or meaningful changes in asthma control and for the prediction of asthma attacks. METHODS: We analyzed questionnaire and sensor data of 79 adults with asthma. Data were collected in situ for 29 days by means of a smartphone. Sleep quality and nocturnal cough frequencies were measured every night with the Pittsburgh Sleep Quality Index and by manually annotating coughs from smartphone audio recordings. Primary endpoint was asthma control assessed with a weekly version of the Asthma Control Test. Secondary endpoint was self-reported asthma attacks. RESULTS: Mixed-effects regression analyses showed that nocturnal cough and sleep quality were statistically significantly associated with asthma control on a between- and within-patient level (p < 0.05). Decision trees indicated that sleep quality was more useful for detecting weeks with uncontrolled asthma (balanced accuracy (BAC) 68% vs 61%; Δ sensitivity -12%; Δ specificity -2%), while nocturnal cough better detected weeks with asthma control deteriorations (BAC 71% vs 56%; Δ sensitivity 3%; Δ specificity -34%). Cut-offs using both markers predicted asthma attacks up to five days ahead with BACs between 70% and 75% (sensitivities 75 - 88% and specificities 57 - 72%). CONCLUSION: Nocturnal cough and sleep quality have useful properties as markers for asthma control and seem to have prognostic value for the early detection of asthma attacks. Due to the limited study duration per patient and the pragmatic nature of the study, future research is needed to comprehensively evaluate and externally validate the performance of both biomarkers and their utility for asthma self-management.

Laryngopharyngeal reflux in chronic obstructive pulmonary disease - a multi-centre study.

Reflux of gastric content has been associated with recurrent exacerbations of chronic obstructive pulmonary disease (COPD). We aimed to assess the prevalence of laryngopharyngeal reflux (LPR) in COPD and if LPR is a contributing factor to clinically relevant outcomes in COPD. We evaluated a total of 193 COPD patients (GOLD I-IV) with a 24-h laryngo-pharyngeal pΗ-monitor. LPR was observed in 65.8% of COPD patients and it was not significantly associated with clinically relevant outcomes of COPD. Treatment with PPI significantly decreased the upright RYAN score (p = 0.047) without improving lung function. Furthermore, the presence or severity of LPR cannot be diagnosed based solely on symptoms and questionnaires.

Automatic Recognition, Segmentation, and Sex Assignment of Nocturnal Asthmatic Coughs and Cough Epochs in Smartphone Audio Recordings: Observational Field Study.

BACKGROUND: Asthma is one of the most prevalent chronic respiratory diseases. Despite increased investment in treatment, little progress has been made in the early recognition and treatment of asthma exacerbations over the last decade. Nocturnal cough monitoring may provide an opportunity to identify patients at risk for imminent exacerbations. Recently developed approaches enable smartphone-based cough monitoring. These approaches, however, have not undergone longitudinal overnight testing nor have they been specifically evaluated in the context of asthma. Also, the problem of distinguishing partner coughs from patient coughs when two or more people are sleeping in the same room using contact-free audio recordings remains unsolved. OBJECTIVE: The objective of this study was to evaluate the automatic recognition and segmentation of nocturnal asthmatic coughs and cough epochs in smartphone-based audio recordings that were collected in the field. We also aimed to distinguish partner coughs from patient coughs in contact-free audio recordings by classifying coughs based on sex. METHODS: We used a convolutional neural network model that we had developed in previous work for automated cough recognition. We further used techniques (such as ensemble learning, minibatch balancing, and thresholding) to address the imbalance in the data set. We evaluated the classifier in a classification task and a segmentation task. The cough-recognition classifier served as the basis for the cough-segmentation classifier from continuous audio recordings. We compared automated cough and cough-epoch counts to human-annotated cough and cough-epoch counts. We employed Gaussian mixture models to build a classifier for cough and cough-epoch signals based on sex. RESULTS: We recorded audio data from 94 adults with asthma (overall: mean 43 years; SD 16 years; female: 54/94, 57%; male 40/94, 43%). Audio data were recorded by each participant in their everyday environment using a smartphone placed next to their bed; recordings were made over a period of 28 nights. Out of 704,697 sounds, we identified 30,304 sounds as coughs. A total of 26,166 coughs occurred without a 2-second pause between coughs, yielding 8238 cough epochs. The ensemble classifier performed well with a Matthews correlation coefficient of 92% in a pure classification task and achieved comparable cough counts to that of human annotators in the segmentation of coughing. The count difference between automated and human-annotated coughs was a mean -0.1 (95% CI -12.11, 11.91) coughs. The count difference between automated and human-annotated cough epochs was a mean 0.24 (95% CI -3.67, 4.15) cough epochs. The Gaussian mixture model cough epoch-based sex classification performed best yielding an accuracy of 83%. CONCLUSIONS: Our study showed longitudinal nocturnal cough and cough-epoch recognition from nightly recorded smartphone-based audio from adults with asthma. The model distinguishes partner cough from patient cough in contact-free recordings by identifying cough and cough-epoch signals that correspond to the sex of the patient. This research represents a step towards enabling passive and scalable cough monitoring for adults with asthma.

Influence of Older Age and Other Risk Factors on Pneumonia Hospitalization in Switzerland in the Pneumococcal Vaccine Era.

Background: Pneumococcal pneumonia is a disease of the extremes of age. However, as other traditional risk factors for pneumococcal pneumonia also increase with older age, it is unclear if older age itself should be an indication for pneumococcal vaccination. Therefore, we assessed the effect of age on risk for hospitalization for pneumonia and for pneumococcal pneumonia. Methods: Using a national hospitalization dataset, all patients ≥16 years hospitalized in a Swiss hospital with a diagnosis of pneumonia or pneumococcal pneumonia between 2002 and 2015 were included. Multivariable logistic regression analysis was used to test the association between age (≥50 or ≥65 years) and hospitalization for pneumonia or pneumococcal pneumonia after adjusting for pneumococcal vaccine indications. Similar analyses were performed for effect of age on length of stay (LOS) and mortality. Results: Among a total of 17,619,016 hospitalizations a diagnosis of pneumonia was present in 421,760 (2.4%) and a diagnosis of pneumococcal pneumonia in 21,610 (0.12%). Age ≥50 years (OR: 3.52 and 2.12, respectively; p for both <0.001) and age ≥65 years (OR: 2.98 and 1.80, respectively; p for both <0.001) as well as most Swiss pneumococcal vaccine indications were independent predictors of hospitalization with a pneumonia and pneumococcal pneumonia diagnosis, respectively. Older age with both age cut-offs were associated with increased LOS (≥50 years: aRR: 1.19 and 1.24, respectively; age ≥65 years: aRR: 1.60 and 1.20, respectively; p < 0.001 for all) and mortality (≥50 years: aOR: 4.73 and 2.84, respectively; age ≥65 years: aOR: 2.38 and 2.69, respectively, p < 0.001 for all) in patients with a pneumonia and pneumococcal pneumonia diagnosis, respectively. The effects of pneumococcal vaccine indications decreased with older age. The incidences of hospitalizations with a pneumonia diagnosis and a pneumococcal pneumonia diagnosis increased significantly from the pre-vaccine era to the PCV7 era and the PCV13 era (p for trend for both analyses <0.001). Conclusion: This study confirms the Swiss indications for pneumococcal vaccination as independent risk factors for pneumonia hospitalizations. Older age itself should be considered as an additional vaccine indication. Pneumonia and pneumococcal pneumonia in adults have increased despite pneumococcal vaccination in children.

Prevalence of nocturnal cough in asthma and its potential as a marker for asthma control (MAC) in combination with sleep quality: protocol of a smartphone-based, multicentre, longitudinal observational study with two stages.

INTRODUCTION: Nocturnal cough is a burdensome asthma symptom. However, knowledge about the prevalence of nocturnal cough in asthma is limited. Furthermore, prior research has shown that nocturnal cough and impaired sleep quality are associated with asthma control, but the association between these two symptoms remains unclear. This study further investigates the potential of these symptoms as markers for asthma control and the accuracy of automated, smartphone-based passive monitoring for nocturnal cough detection and sleep quality assessment. METHODS AND ANALYSIS: The study is a multicentre, longitudinal observational study with two stages. Sensor and questionnaire data of 94 individuals with asthma will be recorded for 28 nights by means of a smartphone. On the first and the last study day, a participant's asthma will be clinically assessed, including spirometry and fractionated exhaled nitric oxide levels. Asthma control will be assessed by the Asthma Control Test and sleep quality by means of the Pittsburgh Sleep Quality Index. In addition, nocturnal coughs from smartphone microphone recordings will be labelled and counted by human annotators. Relatively unrestrictive eligibility criteria for study participation are set to support external validity of study results. Analysis of the first stage is concerned with the prevalence and trends of nocturnal cough and the accuracies of smartphone-based automated detection of nocturnal cough and sleep quality. In the second stage, patient-reported asthma control will be predicted in a mixed effects regression model with nocturnal cough frequencies and sleep quality of past nights as the main predictors. ETHICS AND DISSEMINATION: The study was reviewed and approved by the ethics commission responsible for research involving humans in eastern Switzerland (BASEC ID: 2017-01872). All study data will be anonymised on study termination. Results will be published in medical and technical peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03635710; Pre-results.

Digitalizing multidisciplinary pulmonary rehabilitation in COPD with a smartphone application: an international observational pilot study.

BACKGROUND: Concerning COPD, pulmonary rehabilitation (PR) has a positive effect on disease progression and mortality, is cost-effective, and is a part of recommendations of international guidelines. Only a minority of patients profit from conventional PR due to a lack of resources, physicians' guideline adherence, or patients' motivation. Novel digital therapies like Kaia COPD, a smartphone application that digitizes PR in COPD, are promising solutions to fill this void. METHODS: Kaia COPD provides a digital version of PR and is certified as a class-I medical device in the European Union. We investigated anonymized data from users of the Kaia COPD app on in-app retention and the change in health-related quality of life (COPD assessment test and Chronic Respiratory Disease Questionnaire [CRQ]) during a period of 20 exercise days with the app. RESULTS: Of 349 app downloads, 56 users fulfilled inclusion criteria and 34 (61%) had finished day 20 at the time of analysis and were included. Users took 33±11 days to complete the 20-day core program. Users finishing the program reduced their COPD assessment test scores (mean 2.5 units from 21.6±7.7 to 19.1±8.4 units, P=0.008). In finishers, there was a statistically significant effect above the minimum clinically important threshold of the CRQ score on the domains of fatigue, mastery, and emotional function. There was a statistically significant but not clinically relevant effect on the domain of dyspnea of CRQ. CONCLUSION: Digitalizing PR with a smartphone app is feasible and accepted by selected patients. The app leads to short-term improvement of health-related quality of life in patients completing a 20-day core program. Due to its observational character, this study has several methodological limitations and was intended to show the feasibility and to extrapolate effect sizes for planned prospective randomized-controlled trials to confirm these findings.

Diagnostic diversity - an indicator of institutional and regional healthcare quality.

AIM: Our aim was to estimate the diagnostic performance of institutions and healthcare regions from a nationwide hospitalisation database. METHODS: The Shannon diversity index was used as an indicator of diagnostic performance based on the International Classification of Disease, 10th revision, German Modification (ICD-10-GM codes). The dataset included a total of 9,325,326 hospitalisation cases from 2009 to 2015 and was provided by the Swiss Federal Office for Statistics. A total of 16,435 diagnostic items from the ICD-10-GM codes were taken as the basis for the calculation of the diagnostic diversity index (DDI). Numerical simulations were performed to evaluate the effect of misdiagnoses in the DDI. We arbitrarily defined the minimum clinically important difference (MCID) as 10% misdiagnoses. The R statistical software was used for all analyses. RESULTS: Diagnostic performance of institutions and healthcare regions as measured by the DDI were strongly associated with caseload and number of inhabitants, respectively. A caseload of >7217 hospitalisations per year for institutions and a population size >363,522 for healthcare regions were indicators of an acceptable diagnostic performance. Among hospitals, there was notable heterogeneity of diagnostic diversity, which was strongly associated with caseload. Application of misdiagnosis-thresholds within each ICD-10-GM category allowed classification of hospitals in four distinct groups: high-volume hospitals with an all-over comprehensive diagnostic performance; high- to mid-volume hospitals with extensive to relevant basic diagnostic performance in most categories; low-volume specialised hospitals with a high diagnostic performance in a single category; and low-volume hospitals with inadequate diagnostic performance in all categories. The diagnostic diversity observed in the 26 Swiss healthcare regions showed relevant heterogeneity, an association with ICD-10-GM code utilisation, and was strongly associated with the size of the healthcare region. The limited diagnostic performance in small healthcare regions was partially, but not fully, compensated for by consumption of health services outside of their own healthcare region. CONCLUSION: Calculation of the DDI from ICD-10 codes is easy and complements the information derived from other quality indicators as it sheds a light on the fitness of the institutionalised interplay between primary and specialised medical inpatient care.  .

Longitudinal change of COPD assessment test (CAT) in a telehealthcare cohort is associated with exacerbation risk.

BACKGROUND: There are only scarce data regarding the evolution of the chronic obstructive pulmonary disease (COPD) assessment test (CAT) over time. Our aim was to investigate the evolution of the CAT in a telehealthcare (THC) cohort and to evaluate its potential to predict exacerbations. PATIENTS AND METHODS: The CAT was measured weekly over up to 1 year in 40 COPD patients undergoing a THC intervention. The evolution of the CAT was analyzed using linear regression. The association between this evolution and the occurrence of exacerbations was evaluated using the Andersen-Gill formulation of the Cox proportional hazards model for the analysis of recurrent time-to-event data with time-varying predictors. RESULTS: The median CAT at inclusion was 17 (interquartile range 13-22) points. During the study, 25% of patients had a significant negative slope (median -7 points per year [ppy]), 38% were stable (median +0 ppy) and 38% had a significant positive slope (median +6 ppy). The median slope of the CAT in the overall cohort was +1 (interquartile range -3 to +6) ppy. A significant positive association was found between the change in CAT scores and the risk of exacerbations (hazard ratio =1.08, 95% CI: 1.03-1.13; p<0.001). There was an 8% increase of the risk of exacerbation per unit increase in CAT. We detected a significant learning effect in filling out the CAT in 18.4% of patients with a median learning phase of five filled questionnaires. CONCLUSION: Sixty-three percent of the COPD patients monitored by THC experienced a stable or improved CAT during 1-year follow-up. We found a significant positive association between the evolution of the CAT over time and the risk of exacerbations. In about one-fifth of patients, there was a significant learning effect in filling out the CAT, before reliable results could be obtained. The evolution of the CAT could help to assess the risk for future exacerbations.