Cannabis policy in The Netherlands: Rationale and design of an experiment with a controlled legal ('closed') cannabis supply chain.

Since the Dutch tolerance policy, allowing the purchase of cannabis in 'coffeeshops', is associated with problems of public order and safety as well as health risks, there has been a long debate about legalisation of cannabis production and supply. It was therefore decided to conduct an experiment with a controlled legal ('closed') cannabis supply chain for recreational use. This is of international relevance in view of the current illegal cannabis exports from the Netherlands, the importance of sharing knowledge about the effectiveness of cannabis policies, and the accumulation of evidence needed to evaluate and update international treaties. Here we describe and discuss the background, general approach and design of the experiment. An independent expert committee elaborated how the closed chain will operate and be evaluated, based on the experience with the medicinal cannabis chain, and round table discussions with stakeholders (mayors, coffeeshop owners, cannabis consumers, growers, regulators, scientists, and addiction experts). Ten trusted cannabis growers are contracted to produce and supply cannabis to the coffeeshops in intervention municipalities, with product quality control, law enforcement against criminal interference, and preventive efforts to reduce health risks being implemented. No changes will be made in the cannabis supply to the coffeeshops in participating control municipalities. A process evaluation will assess whether the chain from production to sale in the intervention municipalities was really closed. In a quasi-experimental study comparing intervention and control municipalities, the chain's effects on public health, cannabis-related crime, safety and public nuisance will be estimated. The fieldwork period is expected to start early 2024 and will take four years, including reporting to the government and parliament. These will then decide whether and what further steps towards legalisation of the production and supply of cannabis will be taken.

Impact of influenza vaccination on GP-diagnosed COVID-19 and all-cause mortality: a Dutch cohort study.

OBJECTIVES: As clinical presentation and complications of both viruses overlap, it was hypothesised that influenza vaccination was associated with lower general practitioner (GP)-diagnosed COVID-19 rates and lower all-cause mortality rates. STUDY DESIGN: From a primary care population-based cohort in the Netherlands, GP-diagnosed COVID-19 (between 10 March and 22 November 2020) and all-cause mortality events (between 30 December 2019 and 22 November 2020) were recorded. 223 580 persons were included, representing the influenza vaccination 2019 target group (all aged ≥60 years, and those <60 years with a medical indication). Proportional hazards regression analyses evaluated associations between influenza vaccination in 2019 and two outcomes: GP-diagnosed COVID-19 and all-cause mortality. Covariables were sex, age, comorbidities and number of acute respiratory infection primary care consultations in 2019. RESULTS: A slightly positive association (HR 1.15; 95% CI 1.08 to 1.22) was found between influenza vaccination in 2019 and GP-diagnosed COVID-19, after adjusting for covariables. A slightly protective effect for all-cause mortality rates (HR 0.90; 95% CI 0.83 to 0.97) was found for influenza vaccination, after adjusting for covariables. A subgroup analysis among GP-diagnosed COVID-19 cases showed no significant association between influenza vaccination in 2019 and all-cause mortality. CONCLUSIONS: Our hypothesis of a possibly negative association between influenza vaccination in 2019 and GP-diagnosed COVID-19 was not confirmed as we found a slightly positive association. A slightly protective effect on all-cause mortality was found after influenza vaccination, possibly by a wider, overall protective effect on health. Future research designs should include test-confirmed COVID-19 cases and controls, adjustments for behavioural, socioeconomic and ethnic factors and validated cause-specific mortality cases.

Detection of atrial fibrillation in primary care with radial pulse palpation, electronic blood pressure measurement and handheld single-lead electrocardiography: a diagnostic accuracy study.

OBJECTIVE: To determine the diagnostic accuracy of three tests-radial pulse palpation, an electronic blood pressure monitor and a handheld single-lead ECG device-for opportunistic screening for unknown atrial fibrillation (AF). DESIGN: We performed a diagnostic accuracy study in the intention-to-screen arm of a cluster randomised controlled trial aimed at opportunistic screening for AF in general practice. We performed radial pulse palpation, followed by electronic blood pressure measurement (WatchBP Home A) and handheld ECG (MyDiagnostick) in random order. If one or more index tests were positive, we performed a 12-lead ECG at shortest notice. Similarly, to limit verification bias, a random sample of patients with three negative index tests received this reference test. Additionally, we analysed the dataset using multiple imputation. We present pooled diagnostic parameters. SETTING: 47 general practices participated between September 2015 and August 2018. PARTICIPANTS: In the electronic medical record system of the participating general practices (n=47), we randomly marked 200 patients of ≥65 years without AF. When they visited the practice for any reason, we invited them to participate. Exclusion criteria were terminal illness, inability to give informed consent or visit the practice or having a pacemaker or an implantable cardioverter-defibrillator. OUTCOMES: Diagnostic accuracy of individual tests and test combinations to detect unknown AF. RESULTS: We included 4339 patients; 0.8% showed new AF. Sensitivity and specificity were 62.8% (range 43.1%-69.7%) and 91.8% (91.7%-91.8%) for radial pulse palpation, 70.0% (49.0%-80.6%) and 96.5% (96.3%-96.7%) for electronic blood pressure measurement and 90.1% (60.8%-100%) and 97.9% (97.8%-97.9%) for handheld ECG, respectively. Positive predictive values were 5.8% (5.3%-6.1%), 13.8% (12.2%-14.8%) and 25.2% (24.2%-25.8%), respectively. All negative predictive values were ≥99.7%. CONCLUSION: In detecting AF, electronic blood pressure measurement (WatchBP Home A), but especially handheld ECG (MyDiagnostick) showed better diagnostic accuracy than radial pulse palpation. TRIAL REGISTRATION NUMBER: Netherlands Trial Register No. NL4776 (old NTR4914).

Coronavirus disease 2019 scenarios for a long-term strategy under fundamental uncertainty.

Early on, scientists have pointed out that coronavirus disease 2019 is most likely here to stay, although its course and development are uncertain. This requires a long-term strategy of living with the virus. However, the urgency of new waves of infection and the emergence of new variants have invoked an approach of acute crisis management over and over, hindering the design of a structural approach for the long term. Exploratory scenarios can provide scientific strategic guidance to policy processes to be better prepared in this situation of fundamental uncertainty. We have therefore developed five scenarios, which describe the possible long-term development of the pandemic from an epidemiological, virological, and broader societal perspective. These scenarios are based on four driving forces that are both important and uncertain: immunity, vaccination, mutations, and human behavior. The scenarios are (1) return to normal, (2) flu+, (3) external threat, (4) continuous struggle, and (5) worst case. Working with scenarios is crucial for appropriate public communication and provides guidance for anticipating the various conceivable possibilities for the further course of the pandemic.

Decision-making given surrogate outcomes.

BACKGROUND: Opinions differ about the extent to which intervention research should and can directly assess the main patient-important health outcomes, what role surrogate endpoints can play, and which requirements should then apply to the scientific underpinning of clinical and policy decisions. METHOD: In a commentary we elaborate on this and provide guidance for dealing with related dilemmas. CONCLUSIONS: Ethical, methodological and practical reasons for decision making based on surrogate endpoints can be that (1) reaching the intended patient-important health outcome would take too long to await direct RCT-based evidence, (2) experimental conditions have limited sustainability over time; and (3) the plausibility of an intervention's clinical efficacy, given the already available evidence regarding surrogate endpoints, goes beyond equipoise. Given an expected increase of interventions with a long term patient-important health outcome perspective, dealing with surrogate endpoints will remain an important challenge. Appropriately dealing with a surrogate endpoint includes (1) the assessment of its predictive value for the intended patient-important outcome, where GRADE guidelines for assessing 'indirectness' and 'causal chain analysis' can be helpful; (2) transparency of (absence of) evidence; (3) adequately updating the 'knowledge mosaic'; (4) weighing different perspectives and values, and (5) monitoring whether adjustments need to be made. The remaining level of uncertainty must be balanced against the urgency of clinical or societal decision making and the disadvantages of postponing this. Criteria for using surrogate endpoints are suggested. Patients, citizens and policy makers can be involved in agreeing upon these criteria.

Measuring the success of blinding in placebo-controlled trials: Should we be so quick to dismiss it?

'Blinding' involves concealing knowledge of which trial participants received the interventions from participants themselves and other trial personnel throughout the trial. Blinding reduces bias arising from the beliefs and expectations of these groups. It is agreed that where possible, blinding should be attempted, for example by ensuring that experimental and control treatments look the same. However, there is a debate about if we should measure whether blinding has been successful, this manuscript will discuss this controversy, including the benefits and risks of measuring blinding within the randomised controlled trial.

The Effect of a Comprehensive, Interdisciplinary Medication Review on Quality of Life and Medication Use in Community Dwelling Older People with Polypharmacy.

Background: We conducted a comprehensive medication review at the patients' home, using data from electronic patient records, and with input from relevant specialists, general practitioners and pharmacists formulated and implemented recommendations to optimize medication use in patients aged 60+ years with polypharmacy. We evaluated the effect of this medication review on quality of life (QoL) and medication use. Methods: Cluster randomized controlled trial (stepped wedge), randomly assigning general practices to one of three consecutive steps. Patients received usual care until the intervention was implemented. Primary outcome was QoL (SF-36 and EQ-5D); secondary outcomes were medication changes, medication adherence and (instrumental) activities of daily living (ADL, iADL) which were measured at baseline, and around 6- and 12-months post intervention. Results: Twenty-four general practices included 360 women and 410 men with an average age of 75 years (SD 7.5). A positive effect on SF-36 mental health (estimated mean was stable in the intervention, but decreased in the control condition with -6.1, p = 0.009,) was found with a reduced number of medications at follow-up compared to the control condition. No significant effects were found on other QoL subscales, ADL, iADL or medication adherence. Conclusion: The medication review prevented decrease of mental health (SF36), with no significant effects on other outcome measures, apart from a reduction in the number of prescribed medications.

Individual point-of-care trials: a new approach to incorporate patient's preferences into personalized pragmatic clinical trials.

Although Evidence-based medicine (EBM) and Patient-centered medicine (PCM) are often perceived as two conflicting paradigms that speak the language of populations and the language of individuals, respectively, both share the common objective of improving the care of individual patients. As physicians should not practice an EBM that is away from the individual patient nor a PCM that is not based on the best available evidence, it is crucial to connect and combine both movements, promoting the fruitful and natural interaction between research and care. Achieving such interaction requires developing new individual-patient centric research methods. In this commentary, we propose an innovative clinical research design oriented to personalize point-of-care trials-integrating clinical research and medical care-through the incorporation of individual patients' preferences to build personalized research protocols. Building on the framework of N-of-1 studies, in "individual point-of-care trials," each protocol could be personalized for each patient so that the therapeutic objectives, the outcome variables analyzed, and the (operationalization of the) compared interventions would be based not only on the clinical and biological characteristics of each patient but also on their individual preferences, goals, and values. If patient preferences are being progressively integrated into medical practice, it makes sense that they also are incorporated into clinical trials embedded in care delivery. The proposal to perform individual point of care trials may be an optimal way to combine EBM and PCM while preserving their foundational principles, and to ensure the connection between "personalized" and "personal" care.

Opportunistic screening versus usual care for detection of atrial fibrillation in primary care: cluster randomised controlled trial.

OBJECTIVE: To investigate whether opportunistic screening in primary care increases the detection of atrial fibrillation compared with usual care. DESIGN: Cluster randomised controlled trial. SETTING: 47 intention-to-screen and 49 usual care primary care practices in the Netherlands, not blinded for allocation; the study was carried out from September 2015 to August 2018. PARTICIPANTS: In each practice, a fixed sample of 200 eligible patients, aged 65 or older, with no known history of atrial fibrillation in the electronic medical record system, were randomly selected. In the intention-to-screen group, 9218 patients eligible for screening were included, 55.0% women, mean age 75.2 years. In the usual care group, 9526 patients were eligible for screening, 54.3% women, mean age 75.0 years. INTERVENTIONS: Opportunistic screening (that is, screening in patients visiting their general practice) consisted of three index tests: pulse palpation, electronic blood pressure measurement with an atrial fibrillation algorithm, and electrocardiography (ECG) with a handheld single lead electrocardiographic device. The reference standard was 12 lead ECG, performed in patients with at least one positive index test and in a sample of patients (10%) with three negative tests. If 12 lead ECG showed no atrial fibrillation, patients were invited for more screening by continuous monitoring with a Holter electrocardiograph for two weeks. MAIN OUTCOME MEASURES: Difference in the detection rate of newly diagnosed atrial fibrillation over one year in intention-to-screen versus usual care practices. RESULTS: Follow-up was complete for 8874 patients in the intention-to-screen practices and for 9102 patients in the usual care practices. 144 (1.62%) new diagnoses of atrial fibrillation in the intention-to-screen group versus 139 (1.53%) in the usual care group were found (adjusted odds ratio 1.06 (95% confidence interval 0.84 to 1.35)). Of 9218 eligible patients in the intention-to-screen group, 4106 (44.5%) participated in the screening protocol. In these patients, 12 lead ECG detected newly diagnosed atrial fibrillation in 26 patients (0.63%). In the 266 patients who continued with Holter monitoring, four more diagnoses of atrial fibrillation were found. CONCLUSIONS: Opportunistic screening for atrial fibrillation in primary care patients, aged 65 and over, did not increase the detection rate of atrial fibrillation, which implies that opportunistic screening for atrial fibrillation is not useful in this setting. TRIAL REGISTRATION: Netherlands Trial Register No NL4776 (old NTR4914).

Describing deprescribing trials better: an elaboration of the CONSORT statement.

OBJECTIVE: The objective of this study was to identify key features to be addressed in the reporting of deprescribing trials and to elaborate and explain CONSORT items in this regard. STUDY DESIGN AND SETTING: As a first step in a multistage process and based on a systematic review of deprescribing trials, we elaborated variation in design, intervention, and reporting of the included trials of the review. We identified items that were missed or insufficiently described, using the CONSORT and TIDieR checklists. The resulting list of items, which we considered relevant to be reported in deprescribing trials, were discussed in a single-round Delphi exercise and subsequently in a full-day face-to-face meeting with an international panel of 14 experts. We agreed on CONSORT items for further elaboration with regard to design and reporting of deprescribing trials. RESULTS: We identified seven CONSORT items on trial design, participants, intervention, outcomes, flowchart, and harms, where the investigators of deprescribing trials should take into consideration specific aspects, such as whether or not to use placebo or how to inform participants. CONCLUSION: This article presents an elaboration to the CONSORT statement for the reporting of deprescribing trials. It may also support investigators in motivated design choices.

Magnitude and determinants of multimorbidity and health care utilization among patients attending public versus private primary care: a cross-sectional study from Odisha, India.

BACKGROUND: Multimorbidity in primary care is a challenge not only for developing countries but also for low and medium income countries (LMIC). Health services in LMIC countries are being provided by both public and private health care providers. However, a critical knowledge gap exists on understanding the true extent of multimorbidity in both types of primary care settings. METHODS: We undertook a study to identify multimorbidity prevalence and healthcare utilization among both public and private primary care attendees in Odisha state of India. A total of 1649 patients attending 40 primary care facilities were interviewed using a structured multimorbidity assessment questionnaire collecting information on 22 chronic diseases, medication use, number of hospitalization and number of outpatient visits. RESULT: The overall prevalence of multimorbidity was 28.3% and nearly one third of patients of public facilities and one fourth from private facilities had multimorbidity. Leading diseases among patients visiting public facilities included acid peptic diseases, arthritis and chronic back pain. No significant difference in reporting of hypertension and diabetes across the facilities was seen. Besides age, predictors of multimorbidity among patients attending public facilities were, females [AOR: 1.6; 95% CI 1.1-1.3] and non-aboriginal groups [AOR: 1.6; 95%CI 1.1-2.3] whereas, in private females [AOR: 1.6; 95%CI 1.1-2.4], better socioeconomic conditions [AOR 1.4; 95% CI 1.0-2.1] and higher educational status [primary school completed [AOR 2.6; 95%CI 1.6-4.2] and secondary schooling and above [AOR 2.0; 95%CI 1.1-3.6] with reference to no education were seen to be the determinants of multimorbidity. Increased number of hospital visits to public facilities were higher among lower educational status patients [IRR: 1.57; 95% CI 1.13-2.18] whereas, among private patients, the mean number of hospital visits was 1.70 times more in higher educational status [IRR: 1.70; 95%CI 1.01-3.69]. The mean number of medicines taken per day was higher among patients attending private hospitals. CONCLUSION: Our findings suggest that, multimorbidity is being more reported in public primary care facilities. The pattern and health care utilization in both types of settings are different. A comprehensive care approach must be designed for private care providers.