How effective is topical miconazole or amorolfine for mild to moderately severe onychomycosis in primary care: the Onycho Trial - a randomised double-blind placebo-controlled trial.

OBJECTIVES: To evaluate the efficacy of topical miconazole or amorolfine compared to placebo for mild to moderately severe onychomycosis. DESIGN: Randomised, double-blind, placebo-controlled trial, with computer-generated treatment allocation at a 1:1:1 ratio. SETTING: Primary care, recruitment from February 2020 to August 2022. PARTICIPANTS: 193 patients with suspected mild to moderately severe onychomycosis were recruited via general practices and from the general public, 111 of whom met the study criteria. The mean age of participants was 51 (SD 13.1), 51% were female and onychomycosis was moderately severe (mean OSI 12.1 (SD 8.0)). INTERVENTIONS: Once-daily miconazole 20 mg/g or once-weekly amorolfine 5% nail lacquer solution was compared with placebo (denatonium benzoate solution). MAIN OUTCOME MEASURES: Complete, clinical and mycological cure at 6 months. Secondary outcomes were clinical improvement, symptom burden, quality of life, adverse effects, compliance, patient-perceived improvement and treatment acceptability. RESULTS: Based on intention-to-treat analysis, none of the participants receiving miconazole or amorolfine reached complete cure compared with two in the placebo group (OR not estimable (n.e.), p=0.493 and OR n.e., p=0.240, respectively). There was no evidence of a significant difference between groups regarding clinical cure (OR n.e., p=0.493 and OR 0.47, 95% CI 0.04 to 5.45, p=0.615) while miconazole and amorolfine were less effective than placebo at reaching both mycological cure (OR 0.25, 95% CI 0.06 to 0.98, p=0.037 and OR 0.23, 95% CI 0.06 to 0.92, p=0.029, respectively) and clinical improvement (OR 0.26, 95% CI 0.08 to 0.91, p=0.028 and OR 0.25, 95% CI 0.07 to 0.85, p=0.021, respectively). There was no evidence of a significant difference in disease burden, quality of life, adverse reactions, compliance, patient-perceived improvement or treatment acceptability. CONCLUSIONS: Topical miconazole and amorolfine were not effective in achieving a complete, clinical or mycological cure of mild to moderately severe onychomycosis, nor did they significantly alleviate the severity or symptom burden. These treatments should, therefore, not be advised as monotherapy to treat onychomycosis. TRIAL REGISTRATION NUMBER: WHO ICTRP NL8193.

Association between onychomycosis and ulcerative complications in patients with diabetes: a longitudinal cohort study in Dutch general practice.

INTRODUCTION: Diabetic foot ulcers are feared complications of diabetes mellitus (DM), requiring extensive treatment and hospital admissions, ultimately leading to amputation and increased mortality. Different factors contribute to the development of foot ulcers and related complications. Onychomycosis, being more prevalent in patients with diabetes, could be an important risk factor for developing ulcers and related infections. However, the association between onychomycosis and diabetic complications has not been well studied in primary care. RESEARCH DESIGN AND METHODS: To determine the impact of onychomycosis on ulcer development and related complications in patients with diabetes in primary care, a longitudinal cohort study was carried out using routine care data from the Extramural Leiden University Medical Center Academic Network. Survival analyses were performed through Cox proportional hazards models with time-dependent covariates. RESULTS: Data from 48 212 patients with a mean age of 58 at diagnosis of DM, predominantly type 2 (87.8%), were analysed over a median follow-up of 10.3 years. 5.7% of patients developed an ulcer. Onychomycosis significantly increased the risk of ulcer development (HR 1.37, 95% CI 1.13 to 1.66), not affected by antimycotic treatment, nor after adjusting for confounders (HR 1.23, 95% CI 1.01 to 1.49). The same was found for surgical interventions (HR 1.54, 95% CI 1.35 to 1.75) and skin infections (HR 1.48, CI 95% 1.28 to 1.72), again not affected by treatment and significant after adjusting for confounders (HR 1.32, 95% CI 1.16 to 1.51 and HR 1.27, 95% CI 1.10 to 1.48, respectively). CONCLUSIONS: Onychomycosis significantly increased the risk of ulcer development in patients with DM in primary care, independently of other risk factors. In addition, onychomycosis increased the risk of surgeries and infectious complications. These results underscore the importance of giving sufficient attention to onychomycosis in primary care and corresponding guidelines. Early identification of onychomycosis during screening and routine care provides a good opportunity for timely recognition of increased ulcer risk.

Severe drug eruption from oral terbinafine for mild onychomycosis-A case report from family practice and literature review: "Just an innocent little pill?"

Onychomycosis is the most prevalent nail disease and is frequently encountered in clinical practice. Despite having multiple therapeutic options, of which systemic antifungals are the most effective, treatment is not always mandatory in all patients. Especially when considering systemic treatment, the risk of adverse reactions may outweigh the potential benefits of treatment. In this case report, we present a clinical case of a 49-year-old male patient with a blank past medical history who experienced a severe drug eruption from terbinafine prescribed for mild onychomycosis that required discontinuation of terbinafine, additional evaluation, and treatment of this adverse reaction.

[Loss of contact between doctor and patient: early signaling can prevent escalation]. / Verbroken arts-patiëntcontact.

A good therapeutic relationship leads to better outcomes. In the event of an imminent break in contact, discussing the alliance rupture can be helpful. Optimal use of the countertransference also contributes. Metacommunication can be useful. In this article, some cases illustrating these concepts, are being discussed.

Molluscum contagiosum survey - common approach and attitude towards treatment and research in Dutch general practice.

BACKGROUND: Molluscum contagiosum (MC) can cause significant burden in children. So far, pharmacological treatment has not been proven beneficial. More rigorous interventions have not been well studied. Current guidelines advise a "wait and see" policy. However, children and their parents frequently visit their GP requesting intervention. Therefore, the aim of this study was to gain insight into the approach to MC by GPs and parents' expectations and to investigate willingness to participate in an interventional study. METHODS: A survey study was carried out among GPs and parents using a questionnaire for each group inquiring about MC and potential study participation. Descriptive statistics were used to analyze results and logistical regression to investigate factors influencing participation. RESULTS: The majority of GPs (88%) preferred an expectative approach; only 21% were willing to participate in a trial as proposed. GPs estimating ≥ 50% of parents would request treatment, were more likely to participate. Most responding parents did or would visit their GP requesting treatment. In contrast to GPs, 58% were willing to participate. Parents preferring cryotherapy or curettage were more likely to participate. CONCLUSION: Our study demonstrated that the majority of GPs preferred a conservative approach, adhering to current guidelines. However, most parents preferred treatment to resolve MC and symptoms. Parents' willingness to participate was much higher than GP's, reflecting parents' desire for treatment. These findings underscore the need for continued therapeutic research. Careful preparation and selection of GPs and patients will be essential to ensure the feasibility of such an endeavor. TRIAL REGISTRATION: This survey study was not part of a clinical trial.

Home-based initiatives for acute management of COVID-19 patients needing oxygen: differences across The Netherlands.

OBJECTIVE: During the COVID-19 pandemic new collaborative-care initiatives were developed for treating and monitoring COVID-19 patients with oxygen at home. Aim was to provide a structured overview focused on differences and similarities of initiatives of acute home-based management in the Netherlands. METHODS: Initiatives were eligible for evaluation if (i) COVID-19 patients received oxygen treatment at home; (ii) patients received structured remote monitoring; (iii) it was not an 'early hospital discharge' program; (iv) at least one patient was included. Protocols were screened, and additional information was obtained from involved physicians. Design choices were categorised into: eligible patient group, organization medical care, remote monitoring, nursing care, and devices used. RESULTS: Nine initiatives were screened for eligibility; five were included. Three initiatives included low-risk patients and two were designed specifically for frail patients. Emergency department (ED) visit for an initial diagnostic work-up and evaluation was mandatory in three initiatives before starting home management. Medical responsibility was either assigned to the general practitioner or hospital specialist, most often pulmonologist or internist. Pulse-oximetry was used in all initiatives, with additional monitoring of heart rate and respiratory rate in three initiatives. Remote monitoring staff's qualification and authority varied, and organization and logistics were covered by persons with various backgrounds. All initiatives offered remote monitoring via an application, two also offered a paper diary option. CONCLUSIONS: We observed differences in the organization of interprofessional collaboration for acute home management of hypoxemic COVID-19 patients. All initiatives used pulse-oximetry and an app for remote monitoring. Our overview may be of help to healthcare providers and organizations to set up and implement similar acute home management initiatives for critical episodes of COVID-19 (or other acute disorders) that would otherwise require hospital care.

[Acute chest pain in out-of-hours primary care]. / Acute pijn op de borst op de huisartsenpost.

Out-of-hours primary care (OOH-PC) facilities act as a first point of contact in acute care in the Netherlands, including acute chest pain. The facilities perform initial triage to assess the patient's urgency using standardized triage protocols (Netherlands Triage Standard). The performance of the current protocol for chest pain assessment was recently evaluated and showed only moderate discriminatory properties. Although final triage decision-making is improved by the clinical experience of triage assistants and general practitioners, substantial over- and under-triage persists. Improving the care of patients with chest pain in OOH-PC should primarily be sought in improving the triage software, followed by the use of innovative diagnostic tools (such as troponine measurements).

Implementation of a group-based lifestyle intervention programme (Healthy Heart) in general practices in The Netherlands: a mixed-methods study.

BACKGROUND: Lifestyle intervention programmes target behavioural risk factors that contribute to cardiovascular diseases (CVDs). Unfortunately, sustainable implementation of these programmes can be challenging. Gaining insights into the barriers and facilitators for successful implementation is important for maximising public health impact of these interventions. The Healthy Heart (HH) programme is an example of a combined lifestyle intervention programme. AIM: To analyse the reach, adoption, and implementation of the HH programme. DESIGN & SETTING: A mixed-methods study conducted in a general practice setting in The Netherlands. METHOD: Quantitative data were collected from the Healthy Heart study (HH study), a non-randomised cluster stepped-wedge trial to assess the effect of the HH programme on patients at high risk of developing CVDs at practice level. Qualitative data were obtained through focus groups. RESULTS: Out of 73 approached general practices, 55 implemented the HH programme. A total of 1082 patients agreed to participate in the HH study, of whom 64 patients were referred to the HH programme and 41 patients participated. Several barriers for participation were identified such as time investment, lack of risk perception, and being confident in changing lifestyle on their own. Important barriers for healthcare providers (HCPs) to refer a patient were time investment, lack of information to sufficiently inform patients, and preconceived notions regarding which patients the programme was suitable for. CONCLUSION: This study has offered insights from a patient and HCP perspective regarding barriers and facilitators for implementation of the group-based lifestyle intervention programme. The identified barriers and facilitators, and the suggested improvements, can be used by others who wish to implement a similar programme.

Added Predictive Value of Female-Specific Factors and Psychosocial Factors for the Risk of Stroke in Women Under 50.

BACKGROUND AND OBJECTIVES: Female-specific factors and psychosocial factors may be important in the prediction of stroke but are not included in prediction models that are currently used. We investigated whether addition of these factors would improve the performance of prediction models for the risk of stroke in women younger than 50 years. METHODS: We used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20-49 years without a history of cardiovascular disease. Analyses were stratified by 10-year age intervals at cohort entry. Cox proportional hazards models to predict stroke risk were developed, including traditional cardiovascular factors, and compared with models that additionally included female-specific and psychosocial factors. We compared the risk models using the c-statistic and slope of the calibration curve at a follow-up of 10 years. We developed an age-specific stroke risk prediction tool that may help communicating the risk of stroke in clinical practice. RESULTS: We included 409,026 women with a total of 3,990,185 person-years of follow-up. Stroke occurred in 2,751 women (incidence rate 6.9 [95% CI 6.6-7.2] per 10,000 person-years). Models with only traditional cardiovascular factors performed poorly to moderately in all age groups: 20-29 years: c-statistic: 0.617 (95% CI 0.592-0.639); 30-39 years: c-statistic: 0.615 (95% CI 0.596-0.634); and 40-49 years: c-statistic: 0.585 (95% CI 0.573-0.597). After adding the female-specific and psychosocial risk factors to the reference models, the model discrimination increased moderately, especially in the age groups 30-39 (Δc-statistic: 0.019) and 40-49 years (Δc-statistic: 0.029) compared with the reference models, respectively. DISCUSSION: The addition of female-specific factors and psychosocial risk factors improves the discriminatory performance of prediction models for stroke in women younger than 50 years.

Ruling out acute coronary syndrome in primary care with a clinical decision rule and a capillary, high-sensitive troponin I point of care test: study protocol of a diagnostic RCT in the Netherlands (POB HELP).

INTRODUCTION: Chest pain is a common reason for consultation in primary care. To rule out acute coronary syndrome (ACS), general practitioners (GP) refer 40%-70% of patients with chest pain to the emergency department (ED). Only 10%-20% of those referred, are diagnosed with ACS. A clinical decision rule, including a high-sensitive cardiac troponin-I point-of-care test (hs-cTnI-POCT), may safely rule out ACS in primary care. Being able to safely rule out ACS at the GP level reduces referrals and thereby alleviates the burden on the ED. Moreover, prompt feedback to the patients may reduce anxiety and stress. METHODS AND ANALYSIS: The POB HELP study is a clustered randomised controlled diagnostic trial investigating the (cost-)effectiveness and diagnostic accuracy of a primary care decision rule for acute chest pain, consisting of the Marburg Heart Score combined with a hs-cTnI-POCT (limit of detection 1.6 ng/L, 99th percentile 23 ng/L, cut-off value between negative and positive used in this study 3.8 ng/L). General practices are 2:1 randomised to the intervention group (clinical decision rule) or control group (regular care). In total 1500 patients with acute chest pain are planned to be included by GPs in three regions in The Netherlands. Primary endpoints are the number of hospital referrals and the diagnostic accuracy of the decision rule 24 hours, 6 weeks and 6 months after inclusion. ETHICS AND DISSEMINATION: The medical ethics committee Leiden-Den Haag-Delft (the Netherlands) has approved this trial. Written informed consent will be obtained from all participating patients. The results of this trial will be disseminated in one main paper and additional papers on secondary endpoints and subgroup analyses. TRIAL REGISTRATION NUMBERS: NL9525 and NCT05827237.

The accuracy of clinical diagnosis of onychomycosis in Dutch general practice: a diagnostic accuracy study.

BACKGROUND: Onychomycosis, the most common cause of nail dystrophy, is generally diagnosed by clinical examination. Current guidelines for Dutch general practice advise confirmatory testing only in cases of doubt or insufficient response to treatment. However, making a correct diagnosis can be challenging given the wide variety of clinical features and differential diagnosis. AIM: To establish accuracy of clinical diagnosis of onychomycosis by GPs. DESIGN & SETTING: A diagnostic accuracy study based on GPs' clinical diagnosis of primary care patients suspected of onychomycosis. METHOD: Using 137 complete datasets from the Onycho Trial, diagnostic accuracy of clinical diagnosis as the index test was compared with confirmatory testing as the reference test. A sensitivity analysis was performed to determine diagnostic values for different combinations of index and reference test. Logistical regression was used to assess which clinical characteristics were associated with the positive predictive value (PPV) of the index test. RESULTS: Clinical accuracy, that is the PPV of the index test, was 74.5%. Sensitivity analysis showed no significant difference in diagnostic values. Male sex and a history of any previous treatment significantly increased clinical accuracy with an odds ratio (OR) of 3.873 (95% confidence interval [CI] = 1.230 to 12.195, P = 0.021) and OR 4.022 (95% CI = 1.075 to 15.040, P = 0.039), respectively. CONCLUSION: The study demonstrated that the GPs' clinical diagnosis of onychomycosis was insufficiently accurate to initiate treatment without confirmatory testing. Further research is needed to investigate how to increase clinical accuracy and reduce potentially unnecessary exposure to treatment.

The Effect and Cost-Effectiveness of Offering a Combined Lifestyle Intervention for the Prevention of Cardiovascular Disease in Primary Care: Results of the Healthy Heart Stepped-Wedge Trial.

OBJECTIVE: To evaluate the effectiveness and cost-effectiveness of offering the combined lifestyle programme "Healthy Heart", addressing overweight, diet, physical activity, smoking and alcohol, to improve lifestyle behaviour and reduce cardiovascular risk. DESIGN: A practice-based non-randomised stepped-wedge cluster trial with two-year follow-up. Outcomes were obtained via questionnaires and routine care data. A cost-utility analysis was performed. During the intervention period, "Healthy Heart" was offered during regular cardiovascular risk management consultations in primary care in The Hague, The Netherlands. The period prior to the intervention period served as the control period. RESULTS: In total, 511 participants (control) and 276 (intervention) with a high cardiovascular risk were included (overall mean ± SD age 65.0 ± 9.6; women: 56%). During the intervention period, 40 persons (15%) participated in the Healthy Heart programme. Adjusted outcomes did not differ between the control and intervention period after 3-6 months and 12-24 months. Intervention versus control (95% CI) 3-6 months: weight: ß -0.5 (-1.08-0.05); SBP ß 0.15 (-2.70-2.99); LDL-cholesterol ß 0.07 (-0.22-0.35); HDL-cholesterol ß -0.03 (-0.10-0.05); physical activity ß 38 (-97-171); diet ß 0.95 (-0.93-2.83); alcohol OR 0.81 (0.44-1.49); quit smoking OR 2.54 (0.45-14.24). Results were similar for 12-24 months. Mean QALYs and mean costs of cardiovascular care were comparable over the full study period (mean difference (95% CI) QALYs: -0.10 (-0.20; 0.002); costs: EUR 106 (-80; 293)). CONCLUSIONS: For both the shorter (3-6 months) and longer term (12-24 months), offering the Healthy Heart programme to high-cardiovascular-risk patients did not improve their lifestyle behaviour nor cardiovascular risk and was not cost-effective on a population level.

Cardiovascular Risk Prediction in Men and Women Aged Under 50 Years Using Routine Care Data.

Background Prediction models for risk of cardiovascular events generally do not include young adults, and cardiovascular risk factors differ between women and men. Therefore, this study aimed to develop prediction models for first-ever cardiovascular event risk in men and women aged 30 to 49 years. Methods and Results We included patients aged 30 to 49 years without cardiovascular disease from a Dutch routine care database. Outcome was defined as first-ever cardiovascular event. Our reference models were sex-specific Cox proportional hazards models based on traditional cardiovascular predictors, which we compared with models using 2 predictor subsets with the 20 or 50 most important predictors based on the Cox elastic net model regularization coefficients. We assessed the C-index and calibration curve slopes at 10 years of follow-up. We stratified our analyses based on 30- to 39-year and 40- to 49-year age groups at baseline. We included 542 141 patients (mean age 39.7, 51% women). During follow-up, 10 767 cardiovascular events occurred. Discrimination of reference models including traditional cardiovascular predictors was moderate (women: C-index, 0.648 [95% CI, 0.645-0.652]; men: C-index, 0.661 [95%CI, 0.658-0.664]). In women and men, the Cox proportional hazard models including 50 most important predictors resulted in an increase in C-index (0.030 and 0.012, respectively), and a net correct reclassification of 3.7% of the events in women and 1.2% in men compared with the reference model. Conclusions Sex-specific electronic health record-derived prediction models for first-ever cardiovascular events in the general population aged <50 years have moderate discriminatory performance. Data-driven predictor selection leads to identification of nontraditional cardiovascular predictors, which modestly increase performance of models.

Non-acute chest pain in primary care; referral rates, communication and guideline adherence: a cohort study using routinely collected health data.

BACKGROUND: The prevalence of coronary artery disease is increasing due to the aging population and increasing prevalence of cardiovascular risk factors. Non-acute chest pain often is the first symptom of stable coronary artery disease. To optimise care for patients with non-acute chest pain and make efficient use of available resources, we need to know more about the current incidence, referral rate and management of these patients. METHODS: We used routinely collected health data from the STIZON data warehouse in the Netherlands between 2010 and 2016. Patients > 18 years, with no history of cardiovascular disease, seen by the general practitioner (GP) for non-acute chest pain with a suspected cardiac origin were included. Outcomes were (i) incidence of new non-acute chest pain in primary care, (ii) referral rates to the cardiologist, (iii) correspondence from the cardiologist to the GP, (iv) registration by GPs of received correspondence and; (v) pharmacological guideline adherence after newly diagnosed stable angina pectoris. RESULTS: In total 9029 patients were included during the study period, resulting in an incidence of new non-acute chest pain of 1.01/1000 patient-years. 2166 (24%) patients were referred to the cardiologist. In 857/2114 (41%) referred patients, correspondence from the cardiologist was not available in the GP's electronic medical record. In 753/1257 (60%) patients with available correspondence, the GP did not code the conclusion in the electronic medical record. Despite guideline recommendations, 37/255 (15%) patients with angina pectoris were not prescribed antiplatelet therapy nor anticoagulation, 69/255 (27%) no statin and 67/255 (26%) no beta-blocker. CONCLUSION: After referral, both communication from cardiologists and registration of the final diagnosis by GPs were suboptimal. Both cardiologists and GPs should make adequate communication and registration a priority, as it improves health outcomes. Secondary pharmacological prevention in patients with angina pectoris was below guideline standards. So, proactive attention needs to be given to optimise secondary prevention in this high-risk group in primary care.

Impact of a Machine Learning-Based Decision Support System for Urinary Tract Infections: Prospective Observational Study in 36 Primary Care Practices.

BACKGROUND: There is increasing attention on machine learning (ML)-based clinical decision support systems (CDSS), but their added value and pitfalls are very rarely evaluated in clinical practice. We implemented a CDSS to aid general practitioners (GPs) in treating patients with urinary tract infections (UTIs), which are a significant health burden worldwide. OBJECTIVE: This study aims to prospectively assess the impact of this CDSS on treatment success and change in antibiotic prescription behavior of the physician. In doing so, we hope to identify drivers and obstacles that positively impact the quality of health care practice with ML. METHODS: The CDSS was developed by Pacmed, Nivel, and Leiden University Medical Center (LUMC). The CDSS presents the expected outcomes of treatments, using interpretable decision trees as ML classifiers. Treatment success was defined as a subsequent period of 28 days during which no new antibiotic treatment for UTI was needed. In this prospective observational study, 36 primary care practices used the software for 4 months. Furthermore, 29 control practices were identified using propensity score-matching. All analyses were performed using electronic health records from the Nivel Primary Care Database. Patients for whom the software was used were identified in the Nivel database by sequential matching using CDSS use data. We compared the proportion of successful treatments before and during the study within the treatment arm. The same analysis was performed for the control practices and the patient subgroup the software was definitely used for. All analyses, including that of physicians' prescription behavior, were statistically tested using 2-sided z tests with an α level of .05. RESULTS: In the treatment practices, 4998 observations were included before and 3422 observations (of 2423 unique patients) were included during the implementation period. In the control practices, 5044 observations were included before and 3360 observations were included during the implementation period. The proportion of successful treatments increased significantly from 75% to 80% in treatment practices (z=5.47, P<.001). No significant difference was detected in control practices (76% before and 76% during the pilot, z=0.02; P=.98). Of the 2423 patients, we identified 734 (30.29%) in the CDSS use database in the Nivel database. For these patients, the proportion of successful treatments during the study was 83%-a statistically significant difference, with 75% of successful treatments before the study in the treatment practices (z=4.95; P<.001). CONCLUSIONS: The introduction of the CDSS as an intervention in the 36 treatment practices was associated with a statistically significant improvement in treatment success. We excluded temporal effects and validated the results with the subgroup analysis in patients for whom we were certain that the software was used. This study shows important strengths and points of attention for the development and implementation of an ML-based CDSS in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04408976; https://clinicaltrials.gov/ct2/show/NCT04408976.

Clarifying responsibility: professional digital health in the doctor-patient relationship, recommendations for physicians based on a multi-stakeholder dialogue in the Netherlands.

BACKGROUND: Implementation of digital health (eHealth) generally involves adapting pre-established and carefully considered processes or routines, and still raises multiple ethical and legal dilemmas. This study aimed to identify challenges regarding responsibility and liability when prescribing digital health in clinical practice. This was part of an overarching project aiming to explore the most pressing ethical and legal obstacles regarding the implementation and adoption of digital health in the Netherlands, and to propose actionable solutions. METHODS: A series of multidisciplinary focus groups with stakeholders who have relevant digital health expertise were analysed through thematic analysis. RESULTS: The emerging general theme was 'uncertainty regarding responsibilities' when adopting digital health. Key dilemmas take place in clinical settings and within the doctor-patient relationship ('professional digital health'). This context is particularly challenging because different stakeholders interact. In the absence of appropriate legal frameworks and codes of conduct tailored to digital health, physicians' responsibility is to be found in their general duty of care. In other words: to do what is best for patients (not causing harm and doing good). Professional organisations could take a leading role to provide more clarity with respect to physicians' responsibility, by developing guidance describing physicians' duty of care in the context of digital health, and to address the resulting responsibilities. CONCLUSIONS: Although legal frameworks governing medical practice describe core ethical principles, rights and obligations of physicians, they do not suffice to clarify their responsibilities in the setting of professional digital health. Here we present a series of recommendations to provide more clarity in this respect, offering the opportunity to improve quality of care and patients' health. The recommendations can be used as a starting point to develop professional guidance and have the potential to be adapted to other healthcare professionals and systems.

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function.

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Selective prevention of cardiovascular disease using integrated lifestyle intervention in primary care: protocol of the Healthy Heart stepped-wedge trial.

INTRODUCTION: Lifestyle interventions are shown to be effective in improving cardiovascular disease (CVD) risk factors. It has been suggested that general practitioners can play an essential role in CVD prevention. However, studies into lifestyle interventions for primary care patients at high cardiovascular risk are scarce and structural implementation of lifestyle interventions can be challenging. Therefore, this study aims to (1) evaluate (cost-)effectiveness of implementation of an integrated group-based lifestyle programme in primary care practices; (2) identify effective intervention elements and (3) identify implementation determinants of an integrated group-based lifestyle intervention for patients with high cardiovascular risk. METHODS AND ANALYSIS: The Healthy Heart study is a non-randomised cluster stepped-wedge trial. Primary care practices will first offer standard care during a control period of 2-6 months, after which practices will switch (step) to the intervention, offering participants a choice between a group-based lifestyle programme or standard care. Participants enrolled during the control period (standard care) will be compared with participants enrolled during the intervention period (combined standard care and group-based lifestyle intervention). We aim to include 1600 primary care patients with high cardiovascular risk from 55 primary care practices in the area of The Hague, the Netherlands. A mixed-methods process evaluation will be used to simultaneously assess effectiveness and implementation outcomes. The primary outcome measure will be achievement of individual lifestyle goals after 6 months. Secondary outcomes include lifestyle change of five lifestyle components (smoking, alcohol consumption, diet, weight and physical activity) and improvement of quality of life and self-efficacy. Outcomes are assessed using validated questionnaires at baseline and 3, 6, 12 and 24 months of follow-up. Routine care data will be used to compare blood pressure and cholesterol levels. Cost-effectiveness of the lifestyle intervention will be evaluated. Implementation outcomes will be assessed using the RE-AIM model, to assesses five dimensions of implementation at different levels of organisation: reach, efficacy, adoption, implementation and maintenance. Determinants of adoption and implementation will be assessed using focus groups consisting of professionals and patients. ETHICS AND DISSEMINATION: This study is approved by the Ethics Committee of the Leiden University Medical Center (P17.079). Results will be shared with the primary care group, healthcare providers and patients, and will be disseminated through journal publications and conference presentations. TRIAL REGISTRATION NUMBER: NL60795.058.17. Status: pre-results.

COVID RADAR app: Description and validation of population surveillance of symptoms and behavior in relation to COVID-19.

BACKGROUND: Monitoring of symptoms and behavior may enable prediction of emerging COVID-19 hotspots. The COVID Radar smartphone app, active in the Netherlands, allows users to self-report symptoms, social distancing behaviors, and COVID-19 status daily. The objective of this study is to describe the validation of the COVID Radar. METHODS: COVID Radar users are asked to complete a daily questionnaire consisting of 20 questions assessing their symptoms, social distancing behavior, and COVID-19 status. We describe the internal and external validation of symptoms, behavior, and both user-reported COVID-19 status and state-reported COVID-19 case numbers. RESULTS: Since April 2nd, 2020, over 6 million observations from over 250,000 users have been collected using the COVID Radar app. Almost 2,000 users reported having tested positive for SARS-CoV-2. Amongst users testing positive for SARS-CoV-2, the proportion of observations reporting symptoms was higher than that of the cohort as a whole in the week prior to a positive SARS-CoV-2 test. Likewise, users who tested positive for SARS-CoV-2 showed above average risk social-distancing behavior. Per-capita user-reported SARS-CoV-2 positive tests closely matched government-reported per-capita case counts in provinces with high user engagement. DISCUSSION: The COVID Radar app allows voluntarily self-reporting of COVID-19 related symptoms and social distancing behaviors. Symptoms and risk behavior increase prior to a positive SARS-CoV-2 test, and user-reported case counts match closely with nationally-reported case counts in regions with high user engagement. These results suggest the COVID Radar may be a valid instrument for future surveillance and potential predictive analytics to identify emerging hotspots.