Search

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.

Background & aims: Medium chain triglyceride (MCT) supplementation is often recommended as treatment for patients with long-chain fatty acid β-oxidation (lcFAO) disorders, since they can be utilized as an energy source without the use of the defective enzyme. However, studies in mice and preterm infants suggest that not all medium-chain fatty acids (MCFA) are oxidized and may undergo elongation to long-chain fatty acids (LCFA). In this single blinded study, we explored the metabolic fates of MCT in healthy individuals using a 13C-labeled MCT tracer. Method: Three healthy males in rest received on two test days a primed continuous infusion of glyceryl tri[1,2,3,4–13C4]-octanoate with either an isocaloric supplementation of 1) exclusively MCT (MCT-only) or 2) a mixture of MCT, proteins and carbohydrates (MCT-mix). Gas chromatography - combustion - isotope ratio mass spectrometry (GC-C-IRMS) was used to determine 13C-enrichment of long-chain fatty acids in plasma and of 13CO2 in exhaled air. Results: When provided as single energy source, an estimated 42% of administered MCT was converted to CO2. In combination with carbohydrates and proteins in the diet, oxidation of MCT was higher (62%). In both diets

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. (c) 2020 Elsevier Inc. All rights reserved.

Atrial fibrillation (AF) is a common arrhythmia with serious potential consequences when left untreated. For timely treatment, early detection is imperative. We explored how new AF is detected in patients aged ≥ 65 years in Dutch healthcare.The study cohort consisted of 9526 patients from 49 Dutch general practices in the usual-care arm of the Detecting and Diagnosing Atrial Fibrillation study. We automatically extracted data from the electronic medical records and reviewed individual records of patients who developed AF. Patient selection started in 2015, and data collection ended in 2019.We included 258 patients with newly diagnosed AF. In 55.0% of the patients, the irregular heartbeat was first observed in general practice and in 16.3% in the cardiology department. Cardiologists diagnosed most cases (47.3%), followed by general practitioners (GPs; 33.7%). AF detection was triggered by symptoms in 64.7% of the patients and by previous stroke in 3.5%. Overall, patients aged 65-74 years more often presented with symptoms than those aged ≥ 75 years (73.5% vs 60.6%; p = 0.042). In 31.5% of the patients, AF was diagnosed incidentally ('silent AF'). Silent-AF patients were on average 2 years older than symptomatic-AF patients. GPs less often diagnosed silent AF than symptomatic AF (21.0% vs 39.0%; p = 0.008), whereas physicians other than GPs or cardiologists more often diagnosed symptomatic AF than silent AF (34.6% vs 11.9%; p 0.001). Most diagnoses were based on a 12-lead electrocardiogram (93.8%).Diagnosing AF is a multidisciplinary process. The irregular heartbeat was most often detected by the GP, but cardiologists diagnosed most cases. One-third of all newly diagnosed AF was silent.

ObjectiveTo 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).DesignWe 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.Setting47 general practices participated between September 2015 and August 2018.ParticipantsIn 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.OutcomesDiagnostic accuracy of individual tests and test combinations to detect unknown AF.ResultsWe 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%.ConclusionIn detecting AF, electronic blood pressure measurement (WatchBP Home A), but especially handheld ECG (MyDiagnostick) showed better diagnostic accuracy than radial pulse palpation.Trial registration numberNetherlands Trial Register No. NL4776 (old NTR4914).

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.

Knowledge, attitudes and beliefs (KABs) toward influenza vaccination (IV) play a key role in HCWs' decisions to receive vaccination and can strongly influence patients' IV uptake. We examined the knowledge, attitudes and beliefs of GPs toward IV, exploring their opinion on IV in the elderly, mandatory HCW vaccination and the desirability of an IV trial in the elderly with hospitalization/mortality as effect measure. From November 2018 to March 2019, surveys were emailed to GPs and GP-practices (n = 1676) in three regions of the Netherlands. We assessed the self-reported IV in GPs, reasons for (not) advising IV to personnel, (not) supporting mandatory IV for personnel and (not) desiring a trial on IV in the elderly on hospitalization/mortality. Multivariable logistic regression models were used to determine predictors for GP IV. A total of 552 surveys were completed and 71.9% of the GPs reported receiving IV. Determinants for IV in GPs were male sex (aOR 1.62, 95%CI 1.06-2.49, p = .03) and age >= 60 y (aOR 5.25, 95%CI 1.51-18.32, p = .01). Seventy-nine percent of the GPs recommend IV for their practice personnel. Mandatory IV for personnel was supported by 41.2% of the GPs with GP self-reporting IV being the only determinant (aOR 10.03 (95%CI 5.69-17.70 p = .00)). An IV trial on hospitalization and/or mortality was desired by 60.5% of the GPs. We concluded that the majority of Dutch GPs receives IV and recommends IV to their personnel. These high rates along with the hesitancy of GPs toward mandatory HCW IV should be considered when policymakers decide on a mandate for IV in HCW in general.

A new method for accurately analyzing octanoate enrichment in plasma was developed and validated. Samples were derivatized directly in plasma by transesterification with isobutanol and were analyzed by gas chromatography–mass spectrometry (GC-MS). This method was developed to analyze the precursor enrichment in a stable isotope tracer protocol. Glyceryl tri[1,2,3,4-13C4] octanoate, a stable isotope-labeled medium-chain triglyceride (MCT), was orally administered in combination with (1) exclusively MCT or (2) a combination of protein, carbohydrates, and MCT to investigate the metabolic route of oral MCT under various conditions. Accurate analysis of octanoate enrichment in plasma at concentrations as low as 0.43 μM (lower limit of quantification, LLOQ) was performed. This is an improvement of about twenty times for the LLOQ for analysis of the enrichment of octanoate when compared with the gold-standard method for fatty acid analysis (methyl esterification). Moreover, we found that‚ with this gold-standard method, study samples were easily contaminated with (unlabeled) octanoate from other sources, leading to biased, incorrect results. The precision and linearity obtained using the new method were good (coefficient of variation intraday R2 of the calibration curve > 0.99). The sensitivity was sufficient for analyzing samples obtained using the stable isotope protocol. This new method is more sensitive than methyl esterification and it minimizes the risk of contamination.

'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. (c) 2021 Elsevier Inc. All rights reserved.

ObjectiveTo investigate whether opportunistic screening in primary care increases the detection of atrial fibrillation compared with usual care.DesignCluster randomised controlled trial.Setting47 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.ParticipantsIn 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.InterventionsOpportunistic 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 measuresDifference in the detection rate of newly diagnosed atrial fibrillation over one year in intention-to-screen versus usual care practices.ResultsFollow-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.ConclusionsOpportunistic 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 registrationNetherlands Trial Register No NL4776 (old NTR4914).

Background Perception by workers of their health problems as work-related is possibly associated with sickness absence (SA). The aim of this study was to to study the relationship between perceived work-relatedness of health problems and SA among workers who visit their GP, taking the influence of other potential determinants into account and to study the influence of these determinants on SA. Design and setting prospective cohort study in 32 Dutch GP practices. Methods A secondary analysis of RCT data among workers, aged 18–63 years, who visited their GP. We measured self-reported SA days in 12 months and high SA (>20 days in 12 months) and compared workers who perceived work-relatedness (WR+) with workers who did not (WR−). With multivariable linear and logistic regression models, we analyzed the influence of age, gender, experienced health, chronic illness, prior SA, number of GP consultations and perceived work ability. Results We analyzed data of 209 workers, 31% perceived work-relatedness. Geometric mean of SA days was 1.6 (95% CI: 0.9–3.0) for WR+− workers and 1.2 (95% CI: 0.8–1.8) for WR− workers (P = 0.42). Incidence of high SA was 21.5 and 13.3%, respectively (odds ratio 1.79; 95% CI: 0.84–3.84). SA was positively associated with chronic illness, prior SA, low perceived work ability and age over 50. Conclusions Perceived work-relatedness was not associated with SA. SA was associated with chronic illness, prior SA, low perceived work ability and age over 50.

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.

Dutch reforms show how an expanded role for primary care can help ensure that healthcare systems continue to meet population needs, say Chris van Weel and colleagues

Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.

The effectiveness of influenza vaccination in the elderly has long been a topic of debate, fueled by the absence of direct evidence from randomized trials on its effect on mortality and the methodological limitations of observational studies pointing this direction. It is argued that new placebo-controlled trials should be undertaken to resolve this uncertainty. However, such trials may be ethically questionable. To bring this discussion forward, we provide a comprehensive overview of the ethical challenges of an influenza vaccine efficacy trial designed to evaluate mortality in the elderly. An important condition in the justification of a trial is the existence of genuine uncertainty in regard to the answer to a research question. Therefore an extensive analysis of the existing levels of knowledge is needed to support the conclusion that an effect of vaccination on mortality is uncertain. Even if a so called "clinical equipoise" status applies, denying a control group vaccination would be problematic because vaccination is considered "competent care" and withholding vaccination could substantially increase patients' risk for influenza and its complications. Given the high burden of disease and already proven benefits of vaccination, such a trial is unlikely to meet the Declaration of Helsinki stating that the importance of a trial must outweigh the risk patients are exposed to. While a placebo-controlled trial in vaccine refusers may be considered, such a trial is unlikely to meet substantial methodological barriers regarding trial size and generalizability. We conclude that a new trial is unlikely to provide for a direct answer, let alone change current policy. At the same time, given the lack of consensus on the ethical acceptability of a placebo-controlled trial on the effect of influenza vaccination on mortality in the elderly, we invite researchers considering such trials to address the ethical challenges discussed in this manuscript. (C) 2018 Elsevier Ltd. All rights reserved.

Background: Paying attention to their patients’ work and recognizing work-related problems is challenging for many general practitioners (GPs). Objectives: To assess the effect of training designed to improve the care for patients with work-related problems in general practice. Methods: A cluster randomized controlled trial among 32 Dutch GPs. GPs in the intervention group received five-hour training. GPs in the control group were not trained. Included patients (age 18–63, working ≥12 h per week) completed baseline questionnaires and follow-up questionnaires planned after one year. Primary outcome at patient level was patients’ expectations about their ability to work, measured using the return-to-work self-efficacy scale (RTW-SE). Primary outcomes on GP level were their use of ICPC-code Z05 (‘work-related problem’) per 1000 working-age patients and percentage of the electronic medical files of working-age patients in which information about occupation had been recorded. Results: A total of 640 patients completed the baseline questionnaire and 281 the follow-up questionnaire. We found no statistically significant differences in patients’ RTW-SE scores: intervention 4.6 (95%CI: 4.2–5.0); control 4.5 (95%CI: 4.1–4.9). Twenty-nine GPs provided data about the GP-level outcomes, which showed no statistically significant differences: use of ICPC code Z05 11.6 (95%CI: 4.7–18.6) versus 6.0 (95%CI: –1.2 to 13.2) per 1000 working-age patients; recording of occupation 28.8% (95%CI: 25.8–31.7) versus 28.6% (95%CI: 25.6–31.6). Conclusion: Training GPs did not improve patients’ work-related self-efficacy or GPs’ registration of work-related problems and occupation.

On April 17th 1975 the communist party of Cambodia, the Khmer Rouge, took power and evacuated the cities forcing citizens into the countryside while killing many in an attempt to eradicate members of the previous government of the Khmer Republic, as well as former soldiers, intellectuals, and artists. The Khmer Rouge employed various tactics to increase their power during this time including the elimination of ritual practices such as dance dramas, family ceremonies, and religious activities. Drawing upon memoirs, autobiographies, and other sources as well as structural ritualisation theory these developments are analysed using the concepts of strategic deritualisation and strategic ritualisation. After the elimination of important rituals the Khmer Rouge implemented new propaganda based rituals in an attempt to instill their beliefs into the minds of peasants and youth while creating a debilitating fear in the previous city dwellers. These rituals included attending speeches, singing emotionally charged revolutionary songs, and attending dance dramas depicting the glory of the revolution and its leader “Angkar.” Implications of the study are discussed especially in regard to the role ritual dynamics can play in social control and extremist (sometimes genocidal) regimes.

The ever increasing emphasis on complex reporting guidelines is getting in the way of designing and conducting good clinical trials, sayJeremy Howick,Rebecca Webster, andJ Andre Knottnerus. ButDavid Moherargues that, while following the guidelines can be frustrating, such complexity remains necessary and is improving research, not impeding it

Objective Mucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype–phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease‐modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course.

Additional file 2. Comparison of the sample characteristics with actual population distribution in the state.

Additional file 3. Comparision of the sample population with the population of the state (census 2011).

Additional file 1. Prevalence of chronic conditions and morbidity. Prevalence of single and multimodibity among public and private primary care.