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Sustainable intensification of agriculture requires understanding of the effect of soil characteristics and nutrient supply on crop growth. As farms are increasing in size by acquiring small fields from various farmers, the soil characteristics and nutrient supply might be very different from field to field, while at the same time specific soil properties might limit the nutrient uptake. As a result, there might be a large number of heterogeneous reasons why crop growth varies significantly. New data analysis techniques can help to explain variability in crop growth among fields. This paper introduces Exceptional Growth Mining (EGM) as a first contribution. EGM instantiates the data mining framework Exceptional Model Mining (EMM) such that subgroups of fields can be found that grow exceptionally in terms of three growth parameters (high/low maximum growth, steep/flat linear growth and early/late midpoint of maximum growth). As second contribution, we apply EGM to a case study by analyzing the dataset of a potato farm in the south of the Netherlands. EGM consists of (i) estimating growth curves by applying nonlinear mixed models, (ii) investigating the correlation between the estimated growth parameters, and (iii) applying EMM on these growth curve parameters using a growth curve-specific quality measure. By applying EGM on the data of the potato farm, we obtain the following results: 1) the estimated growth curves represent the variability in potato tuber growth very well (R2 of 0.92), 2) the steepness of the growth curve has a strong correlation with the maximum growth and the midpoint of maximum growth, and the correlation between the midpoint of maximum growth and maximum growth is weak, 3) the subgroup analyses indicate that: high values of K correspond to high maxima; low values of K correspond to low maxima, steep growth curves', and a late midpoint of halfway growth; Mg influences the midpoint of the growth curve; values of B are higher on dry soils with high tuber growth, while low values of B are found on wet soils with high tuber growth; high values of Zn, Mn, and Fe are found in subgroups with low tuber weight, probably related to the soil's low pH. In summary, this paper introduces EGM to obtain understanding in crop response to soil properties and nutrient supply. In addition, EGM provides a way to analyze only small parts of a large dataset, such that the impact of soil factors on growth can be analyzed on a more detailed level than existing methods. [ABSTRACT FROM AUTHOR]

Purpose: For wheelchair users with a spinal cord injury, the lower body may be a more convenient cooling site than the upper body. However, it remains unknown if leg cooling reduces thermal strain in these individuals. We compared the impact of upper-body versus lower-body cooling on physiological and perceptual outcomes during submaximal arm-crank exercise under heat stress in individuals with paraplegia. Methods: Twelve male participants with paraplegia (T4-L2, 50% complete lesion) performed a maximal exercise test in temperate conditions, and three heat stress tests (32°C, 40% relative humidity) in which they received upper-body cooling (COOL-UB), lower-body cooling (COOL-LB), or no cooling (CON) in a randomized counterbalanced order. Each heat stress test consisted of four exercise blocks of 15 min at 50% of peak power output, with 3 min of rest in between. Cooling was applied using water-perfused pads, with 14.8-m tubing in both COOL-UB and COOL-LB. Results: Gastrointestinal temperature was 0.2°C (95% confidence interval (CI), 0.1°C to 0.3°C) lower during exercise in COOL-UB versus CON (37.5°C ± 0.4°C vs 37.7°C ± 0.3°C, P = 0.009), with no difference between COOL-LB and CON (P = 1.0). Heart rate was lower in both COOL-UB (-7 bpm; 95% CI, -11 to -3 bpm; P = 0.01) and COOL-LB (-5 bpm; 95% CI, -9 to -1 bpm; P = 0.049) compared with CON. The skin temperature reduction at the cooled skin sites was larger in COOL-LB (-10.8°C ± 1.1°C) than in COOL-UB (-6.7°C ± 1.4°C, P < 0.001), which limited the cooling capacity in COOL-LB. Thermal sensation of the cooled skin sites was improved and overall thermal discomfort was lower in COOL-UB (P = 0.01 and P = 0.04) but not in COOL-LB (P = 0.17 and P = 0.59) compared with CON. Conclusions: Upper-body cooling more effectively reduced thermal strain than lower-body cooling in individuals with paraplegia, as it induced greater thermophysiological and perceptual benefits. [ABSTRACT FROM AUTHOR]

Introduction: Endovascular treatment (EVT) has been proven to be both effective and cost-effective for patients with acute ischaemic stroke. We investigated the budget impact of large-scale implementation of EVT for acute ischaemic stroke patients in the Netherlands for 2015–2021. Methods: An analysis was performed from a healthcare perspective as a preplanned substudy of the Multicenter Randomized Clinical trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). Estimated yearly costs during follow-up after stroke for patients who had or had not been treated with EVT as add-on to usual care were linked to numbers of new patients retrieved from 2 Dutch registries of EVT that started after the last inclusion in MR CLEAN (2014). Aggregated costs and costs per care sector were calculated based on prevalence using a population dynamic tool. Results: From 2015, the yearly number of new acute ischaemic stroke patients receiving EVT increased almost threefold, from 812 in 2015 to 2,370 in 2021. The introduction of EVT plus usual care resulted in estimated net annual savings that increased from € 2.9 million in 2015 to € 58 million in 2021. Conclusion: Offering EVT as add-on to usual care for acute ischaemic stroke patients was increasingly cost saving from a national healthcare perspective but affected distinct healthcare sectors differently. [ABSTRACT FROM AUTHOR]

Tick-borne encephalitis virus (TBEV) may cause tick-borne encephalitis (TBE), a potential life-threatening infection of the central nervous system in humans. Phylogenetically, TBEVs can be subdivided into three main subtypes, which differ in endemic region and pathogenic potential. In 2016, TBEV was first detected in the Netherlands. One of two detected strains, referred to as Salland, belonged to the TBEV-Eu subtype, yet diverged ≥ 2% on amino acid level from other members of this subtype. Here, we report the successful rescue of this strain using infectious subgenomic amplicons and its subsequent in vitro characterization by comparison to two well-characterized TBEV-Eu strains; Neudoerfl and Hypr. In the human alveolar epithelial cell line A549, growth kinetics of Salland were comparable to the high pathogenicity TBEV-Eu strain Hypr, and both strains grew considerably faster than the mildly pathogenic strain Neudoerfl. In the human neuroblastoma cell line SK-N-SH, Salland replicated faster and to higher infectious titers than both reference strains. All three TBEV strains infected primary human monocyte-derived dendritic cells to a similar extent and interacted with the type I interferon system in a similar manner. The current study serves as the first in vitro characterization of the novel, divergent TBEV-Eu strain Salland. [ABSTRACT FROM AUTHOR]

The spread of deceiving content on social media platforms is a growing concern amongst scholars, policymakers, and the public at large. We examine the extent to which influential users (i.e., "deceitful opinion leaders") on Twitter engage in the spread of different types of deceiving content, thereby overcoming the compartmentalized state of the field. We introduce a theoretical concept and approach that puts these deceitful opinion leaders at the center, instead of the content they spread. Moreover, our study contributes to the understanding of the effects that these deceiving messages have on other Twitter users. For 5,574 users and 731,371 unique messages, we apply computational methods to study changes in messaging behavior after they started following a set of eight Dutch deceitful opinion leaders on Twitter during the Dutch 2021 election campaign. The results show that users apply more uncivil language, become more affectively polarized, and talk more about politics after following a deceitful opinion leader. Our results thereby underline that this small group of deceitful opinion leaders change the norms of conversation on these platforms. Hence, this accentuates the need for future research to study the literary concept of deceitful opinion leaders. [ABSTRACT FROM AUTHOR]

Aim: The sigmoid take‐off (STO), the point on imaging where the sigmoid sweeps ventral from the sacrum, was chosen as the definition of the rectum during an international Delphi consensus meeting and has been incorporated into the Dutch guidelines since October 2019. The aim of this study was to evaluate the implementation of this landmark 1 year after the guideline implementation and to perform a quality assessment of the STO training. Method: Dutch radiologists, surgeons, surgical residents, interns, PhD students and physician assistants were asked to complete a survey and classify 20 tumours on MRI as 'below', 'on' or 'above' the STO. Outcomes were agreement with the expert reference, inter‐rater variability and accuracy before and after the training. Results: Eighty‐six collaborators participated. Six radiologists (32%) and 11 surgeons (73%) used the STO as the standard landmark to distinguish between rectal and sigmoidal tumours during multidisciplinary meetings. Overall agreement with the expert reference improved from 53% to 70% (p < 0.001) after the training. The positive predictive value for diagnosing rectal tumours was high before and after the training (92% vs. 90%); the negative predictive value for diagnosing sigmoidal tumours improved from 39% to 63%. Conclusion: Approximately half of the represented hospitals have implemented the new definition of rectal cancer 1 year after the implementation of the Dutch national guidelines. Overall baseline agreement with the expert reference and accuracy for the tumours around the STO was low, but improved significantly after training. These results highlight the added value of training in implementation of radiological landmarks to ensure unambiguous assessment. [ABSTRACT FROM AUTHOR]

Context: A research agenda for oral health care was established in the Netherlands using the Dialogue Model. This project served as a case study in which we applied boundary‐work theory as a framework to understand boundaries (ie demarcations) between and within groups, and how these boundaries can be overcome. Objective: To gain insights into the boundaries encountered when setting a research agenda, we analysed how this agenda served as a boundary object (ie circumstances, situations or material that connect actor groups and allow boundary crossing) that facilitated crossing boundaries and uniting the perspectives of patients and practitioners. Methods: We used a thematic approach to analyse researchers' observations, meeting materials, emails, interviews with patients (n = 11) and a survey among patients and practitioners (n = 18). Results: Setting the research agenda helped to cross boundaries in oral health care, which demonstrates its role as a boundary object. First, this made it possible to integrate research topics representing the perspectives and priorities of all patients and also to unite those perspectives. It was essential to involve practitioners at an early stage of the project so that they could better accept the patients' perspectives. This resulted in support for an integrated research agenda, which facilitated the crossing of boundaries. Conclusions: The research agenda‐setting project was found to serve as a boundary object in uniting the perspectives and priorities of patients and practitioners. Patient contribution: Patient involvement in this case study was structured in the process of research agenda setting using the Dialogue Model. [ABSTRACT FROM AUTHOR]

Objective: To analyze the incidence of submucous cleft palate (SMCP) in a large national database and raise awareness among referring providers: pediatricians, speech pathologists, and dentists to minimize delay in diagnosis. Design: Retrospective cohort study. Setting: Tertiary setting. Patients: Patients were extracted from the "Dutch Association for Cleft and Craniofacial Anomalies" database. A total of 6916 patients were included from 1997 until 2018 and divided into 2 groups (ie, SMCP versus cleft palate [CP]). Patients born before 1997 and adopted patients were excluded. Interventions: Clefts were classified as either hard of soft palatal involvement based on anatomical landmarks at first consultation. Main Outcome Measures: Primary outcomes were the patient characteristics in both groups (ie, gender, birth weight, gestational age, and additional anomalies). Secondary outcome was the time of diagnosis among subgroups. Results: In total, 532 patients were diagnosed with SMCP (7.7%). Birth weight, gestational age, and additional anomalies did not differ between subgroups, but there were more males in the SMCP group (P <.001). The median age of diagnosis of the SMCP group was significantly higher than of the CP group (987 vs 27 days; P <.001). Over the course of 22 years, the time of diagnosis for SMCP did not decrease. Conclusion: Submucous cleft palate represents <10% of the Dutch cleft population and 19.4% of all CP. Time of diagnosis for SMCP is significantly longer when compared with time of diagnosis of CP, and this has not changed over the study period of 22 years. [ABSTRACT FROM AUTHOR]

African migrants are underrepresented as blood donors in many Western countries, which can lead to shortages of specific blood types for transfusion. More insight in the reasons for this underrepresentation is required to improve blood donor recruitment and retention strategies. The aim of this qualitative study was to explore barriers and motivators for donating blood among migrants of African background. The research population consisted of first and second generation African‐Surinamese (n = 20) and Ghanaian (n = 16) migrants living in the Netherlands. In semi‐structured personal interviews performed in 2016 and 2017, their experiences and opinions regarding blood donation, barriers, and motivators to (not) become a blood donor and their suggestions to improve recruitment were explored. Data collection was continued until data saturation was achieved. The interviews revealed that although all participants knew about blood donation in general, only four had previously heard of the Dutch national blood bank organisation. Participants expected that if blood was needed, the blood bank would directly approach them, as in their country of origin. Other main blood donation barriers were fear (e.g., of needles, losing too much blood) and issues related to health and non‐eligibility to donate. Main motivators were mainly of altruistic nature (e.g., saving a life) and an increased awareness of the need via personal recruitment appeals. It is concluded that expectations regarding donor recruitment—derived from the country of origin—and unawareness of the need for blood can act as important barriers in blood donation among African migrants. Contrary to studies in the United States and Australia, perceived discrimination and social exclusion did not seem to be a donation deterrent among migrants in the Netherlands. Creating awareness of the need of blood by actively approaching, and informing migrants about the donation procedure in the host country, should be considered by blood banks. [ABSTRACT FROM AUTHOR]

In the Dutch health care system, hospitals are expected to compete. A necessary condition for competition among hospitals is that patients do not automatically choose the nearest hospital, but are-at least to some extent-sensitive to differences in hospital quality. In this study, an analysis is performed on the underlying features of patient hospital choice in a setting where prices do not matter for patients as a result of health insurance coverage. Using claims data from all Dutch hospitals over the years 2008-2010, a conditional logit model examines the relationship between patient characteristics (age, gender and reoperations) and hospital attributes (hospital quality information, waiting times on treatments and travel time for patients to the hospitals) in the market for general non-emergency hip replacement treatments. The results show that travel time is the most important determinant in patient hospital choice. From our analysis, however, it follows that publicly available hospital quality ratings and waiting times also have a significant impact on patient hospital choice. The panel data used for this study (2008-2010) is rather short, which may explain why no coherent and persistent changes in patient hospital choice behaviour over time are found. [ABSTRACT FROM AUTHOR]

Objective: To assess a scoring system for predicting recurrence of fulminant bacterial peritonitis after discontinuation of antimicrobial treatment in patients being treated by open management of the abdomen for persistent bacterial peritonitis after perforation of the digestive tract, anastomotic disruption, or necrotising pancreatitis. Design: Retrospective study. Setting: University Hospital, The Netherlands. Subjects: 58 consecutive patients. Main outcome measurements: Recurrence of fulminant bacterial peritonitis and survival. Results: 13 of the 58 patients (22%) died during the initial course of antimicrobial drugs. 14 of the remaining 45 patients had a recurrence of fulminant bacterial peritonitis after discontinuation of antimicrobial drugs, 4 of whom died. Predictive criteria included raised white cell count (WCC) (p = 0.02), duration of initial antibiotic treatment (p = 0.05), and deterioration in Simplified Acute Physiology Score (p = 0.05). Using the WCC and the duration of initial antimicrobial treatment together with other variables that showed a predictive trend (body temperature, percentage band cells, underlying disease, and use of inotropic agents), in a new scoring system (0–12), fulminant bacterial peritonitis did not recur when the score was 0-3, but in 9 of 11 patients with a score of 6 or more it did (p < 0.001). Conclusion: Patients at increased risk of recurrence of fulminant bacterial peritonitis during open management of the abdomen can be identified at the time of discontinuation of antimicrobial treatment by a new scoring system; antimicrobial treatment should not be discontinued in patients with a score of 6 or more. [ABSTRACT FROM AUTHOR]

• A method is provided to analyze within-farm variability. • Determined factors influencing growth are year-independent. • Stem length growth has a strong positive relation with yield. • Fields with a deep groundwater level have a high yield potential. • Fertilization should be adapted based on the field-specific conditions. The growth and yield of crops within a farm largely vary among fields. Farms are increasing in size by acquiring smaller land parcels from different farmers who have different management strategies. As a result, between-field variability increases and understanding such variability is a necessity for precision farming. New data analysis techniques are needed in this context, especially given the trend that more farms are collecting more data. Therefore, this study has the objective to provide a data analysis methodology to analyze within-year variability and identify year-independent factors that influence growth. As a second objective, we applied this novel methodology to a case study, where we analyzed potato growth data of four successive years of a farm in the south of the Netherlands. The methodology consists of three main steps: (1) describing growth using mixed models, (2) clustering and explaining growth by correlating the clusters to (a) yield, (b) other plant characteristics and (c) to defining, limiting and reducing variables, and (3) predicting growth by automatically selecting a regression model. By applying our method on the potato growth data, we obtained the following results. The main results of the work are: (1) the estimated growth curves of the stems, haulm and tubers explain the between-field variability in growth well very well (R 2 of 0.85 , 0.74 and 0.89 , respectively), (2) clusters with a stem length between 110 and 130 cm have the highest average yield, (3) deeper groundwater level and sugar beet or grass as previously cultivated crop positively influence growth, and (4) N and K fertilization must be adjusted for optimal growth. Concluding, this study responds to the quest for new data-based methods for sustainable intensification, and is the first to explicitly analyze and explain differences in crop growth between fields in practice. In addition, clear management advice could be provided, showing the scientific and practical potential of our methodology. [ABSTRACT FROM AUTHOR]

Background: Some studies have suggested that transdermal administration of glyceryl trinitrate (GTN; nitroglycerin) in the first few hours after symptom onset increases the chance of a favourable outcome after ischaemic stroke or intracerebral haemorrhage, possibly through an increase in intracranial collateral blood flow and a reduction in blood pressure. The Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch (MR ASAP) aims to assess the effect of transdermal GTN, started within 3 h after stroke onset in the prehospital setting, on functional outcome at 90 days in patients with acute ischaemic stroke or intracerebral haemorrhage.Methods: MR ASAP is a phase III, multicentre, randomised, open-label clinical trial with a blinded outcome assessment. A total of 1400 adult patients with suspected stroke and a systolic blood pressure ≥ 140 mmHg will be randomised to transdermal GTN (5 mg/day), administered as a transdermal patch by paramedics in the prehospital setting within 3 h of stroke onset and continued for 24 h or to standard care. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days, analysed with ordinal logistic regression. Secondary outcomes include blood pressure and collateral circulation at hospital admission, neurological deficit measured with the National Institutes of Health Stroke Scale at 24 h, and mortality and poor outcome (mRS score 3 to 6) at 90 days. This trial will be conducted in the Netherlands and will use a deferred consent procedure. The trial is part of the Collaboration for New Treatments of Acute Stroke (CONTRAST) programme.Discussion: MR ASAP will assess whether very early administration of GTN improves outcome after stroke in a setting where rates of intravenous thrombolysis and endovascular treatment for acute ischaemic stroke are high. The deferred consent procedure facilitates prompt GTN treatment and will prevent delay to revascularisation therapies. If early transdermal GTN treatment proves to be effective, this low-cost treatment can be readily implemented into daily clinical practice.Trial Registration: ISRCTN Registry, ISRCTN99503308 . Registered on 2 January 2018. [ABSTRACT FROM AUTHOR]

Background: Phobic anxiety disorders are among the most prevalent psychiatric disorders and are burdensome in terms of loss of quality of life and work productivity. Evidence-based treatments are relatively successful in the majority of patients, especially exposure therapy. However, a substantial subset of patients fails to achieve or stay in remission. Preclinical and genetic research have yielded evidence that the cannabinoid system is involved in the extinction of fear, presumed to underlie the beneficial effects of exposure therapy in phobic disorders. A cannabinoid constituent that may enhance endocannabinoid signaling is cannabidiol (CBD), a non-psychoactive component of cannabis. Hence, the addition of CBD to exposure therapy is expected to strengthen effects of treatment. To determine the added benefit of CBD on exposure therapy, we conduct a randomized controlled trial, in which patients in whom previous treatment as usual has not yielded sufficient response receive either CBD or placebo preceding 8 exposure sessions in a double-blind fashion. A subsidiary aim is to explore which (combination of) clinical, behavioral and genetic profiles of patients are related to treatment response. Methods/design: This is an 8-week multicenter, randomized, double-blind, placebo-controlled trial. Seventy-two patients with social phobia or panic disorder with agoraphobia with incomplete response to earlier treatment will be included from outpatient clinics in the Netherlands. Patients are randomized to augmentation of exposure therapy with 300 mg CBD or placebo. The study medication is administered orally, 2 h preceding each of the eight 90 min exposure sessions. Measurements will take place at baseline, first administration of medication, every session, mid-treatment, last administration of medication, post-treatment and at 3 and 6 months' follow-up. The primary outcome measure is the score on the Fear Questionnaire (FQ). In addition, determinants of the expected treatment enhancing effect of CBD will be explored. Discussion: This is the first trial to investigate whether the addition of CBD to exposure therapy is effective in reducing phobic symptoms in treatment refractory patients with social phobia or panic disorder with agoraphobia. Trial registration: Netherlands Trial Register NTR5100. Registered 13 March 2015. Protocol version: issue date 17 Jan 2018, protocol amendment number 7. [ABSTRACT FROM AUTHOR]

Background: MR CLEAN was the first randomized trial to demonstrate the short-term clinical effectiveness of endovascular treatment in patients with acute ischemic stroke caused by large vessel occlusion in the anterior circulation. Several other trials confirmed that endovascular treatment improves clinical outcome at three months. However, limited data are available on long-term clinical outcome. We aimed to estimate the effect of endovascular treatment on functional outcome at two-year follow-up in patients with acute ischemic stroke. Secondly, we aimed to assess the effect of endovascular treatment on major vascular events and mortality during two years of follow-up.Methods: MR CLEAN is a multicenter clinical trial with randomized treatment allocation, open-label treatment, and blinded endpoint evaluation. Patients included were 18 years or older with acute ischemic stroke caused by a proven anterior proximal artery occlusion who could be treated within six hours after stroke onset. The intervention contrast was endovascular treatment and usual care versus no endovascular treatment and usual care. The current study extended the follow-up duration from three months to two years. The primary outcome is the score on the modified Rankin scale at two years. Secondary outcomes include all-cause mortality and the occurrence of major vascular events within two years of follow-up.Discussion: The results of our study provide information on the long-term clinical effectiveness of endovascular treatment, which may have implications for individual treatment decisions and estimates of cost-effectiveness.Trial Registration: NTR1804 . Registered on 7 May 2009; ISRCTN10888758 . Registered on 24 July 2012 (main MR CLEAN trial); NTR5073 . Registered on 26 February 2015 (extended follow-up study). [ABSTRACT FROM AUTHOR]

Background: Whether infarct size modifies intra-arterial treatment effect is not certain, particularly in patients with large infarcts. We examined the effect of the baseline Alberta Stroke Program Early CT Score (ASPECTS) on the safety and efficacy of intra-arterial treatment in a subgroup analysis of the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN).Methods: MR CLEAN was a randomised, controlled, open-label, phase 3 trial of intra-arterial treatment in patients (aged ≥18 years from the Netherlands) with proximal arterial occlusion of the anterior circulation, given intra-arterial treatment within 6 h of stroke onset. The primary outcome was 90 day modified Rankin Scale (mRS) score. We estimated the intra-arterial treatment effect for all patients in MR CLEAN who had ASPECTS graded by using multivariable ordinal logistic regression analysis (a proportional odds model) to calculate the adjusted common odds ratio for a shift towards a better functional outcome according to the mRS for intra-arterial treatment and usual care than for usual care alone. We entered an interaction term into the model to test for interaction with prespecified ASPECTS subgroups: 0-4 (large infarct) versus 5-7 (moderate infarct) versus 8-10 (small infarct). MR CLEAN is registered with the Netherlands Trial Registry, number NTR1804, and the ISRCTN Registry, number ISRCTN10888758.Findings: 496 patients-232 (47%) in the intra-arterial treatment and usual care group and 264 (53%) in the usual care alone group-were included in the analysis. We noted no significant difference in intra-arterial treatment effect between the ASPECTS subgroups according to 90 day ordinal mRS (adjusted common odds ratio interaction term relative to ASPECTS 8-10: ASPECTS 0-4: 0·79 [95% CI 0·20-3·19], p=0·740; and ASPECTS 5-7: 1·02 [0·44-2·35], p=0·966). Intra-arterial treatment did not cause a significant increase in the proportion of patients with at least one serious adverse event in any of the ASPECTS subgroups (ASPECTS 0-4: eight [73%] of 11 patients in treatment and usual care group vs 11 [58%] of 19 in usual care alone group, p=0·42; ASPECTS 5-7: 32 [59%] of 54 vs 19 [49%] of 39, p=0·31; ASPECTS 8-10: 70 [42%] of 167 vs 82 [40%] of 206; p=0·68). For death within 7 days or within 30 days and hemicraniectomy, the differences between the intra-arterial treatment and usual care versus usual care alone groups were not significant by ASPECTS subgroups. A significantly higher proportion of patients had recurrent ischaemic stroke in the intra-arterial treatment plus usual care group than in the usual care alone group in the ASPECTS 8-10 subgroup (eight [5%] vs one [<1%]; p=0·007).Interpretation: Contrary to findings from previous studies suggesting that only patients with non-contrast CT ASPECTS of more than 7 benefit from intra-arterial treatment, data from this study suggest that patients with ASPECTS 5-7 should be treated. Further evidence is needed for patients with ASPECTS 0-4, for whom treatment might yield only marginal absolute benefit.Funding: Dutch Heart Foundation, AngioCare, Medtronic/Covidien/EV3, Medac/Lamepro, Penumbra, Stryker, and Top Medical. [ABSTRACT FROM AUTHOR]

Background: Pooled analyses of previous randomised studies have suggested that very early treatment with glyceryl trinitrate (also known as nitroglycerin) improves functional outcome in patients with acute ischaemic stroke or intracerebral haemorrhage, but this finding was not confirmed in a more recent trial (RIGHT-2). We aimed to assess whether patients with presumed acute stroke benefit from glyceryl tr initrate started within 3 h after symptom onset.Methods: MR ASAP was a phase 3, randomised, open-label, blinded endpoint trial done at six ambulance services serving 18 hospitals in the Netherlands. Eligible participants (aged ≥18 years) had a probable diagnosis of acute stroke (as assessed by a paramedic), a face-arm-speech-time test score of 2 or 3, systolic blood pressure of at least 140 mm Hg, and could start treatment within 3 h of symptom onset. Participants were randomly assigned (1:1) by ambulance personnel, using a secure web-based electronic application with random block sizes stratified by ambulance service, to receive either transdermal glyceryl trinitrate 5 mg/day for 24 h plus standard care (glyceryl trinitrate group) or to standard care alone (control group) in the prehospital setting. Informed consent was deferred until after arrival at the hospital. The primary outcome was functional outcome assessed with the modified Rankin Scale (mRS) at 90 days. Safety outcomes included death within 7 days, death within 90 days, and serious adverse events. Analyses were based on modified intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. We separately analysed the total population and the target population (ie, patients with intracerebral haemorrhage, ischaemic stroke, or transient ischaemic attack). The target sample size was 1400 patients. The trial is registered as ISRCTN99503308.Findings: On June 24, 2021, the MR ASAP trial was prematurely terminated on the advice of the data and safety monitoring board, with recruitment stopped because of safety concerns in patients with intracerebral haemorrhage. Between April 4, 2018, and Feb 12, 2021, 380 patients were randomly allocated to a study group. 325 provided informed consent or died before consent could be obtained, of whom 170 were assigned to the glyceryl trinitrate group and 155 to the control group. These patients were included in the total population. 201 patients (62%) had ischaemic stroke, 34 (10%) transient ischaemic attack, 56 (17%) intracerebral haemorrhage, and 34 (10%) a stroke-mimicking condition. In the total population (n=325), the median mRS score at 90 days was 2 (IQR 1-4) in both the glyceryl trinitrate and control groups (adjusted common OR 0·97 [95% CI 0·65-1·47]). In the target population (n=291), the 90-day mRS score was 2 (2-4) in the glyceryl trinitrate group and 3 (1-4) in the control group (0·92 [0·59-1·43]). In the total population, there were no differences between the two study groups with respect to death within 90 days (adjusted OR 1·07 [0·53-2·14]) or serious adverse events (unadjusted OR 1·23 [0·76-1·99]). In patients with intracerebral haemorrhage, 12 (34%) of 35 patients allocated to glyceryl trinitrate versus two (10%) of 21 allocated to the control group died within 7 days (adjusted OR 5·91 [0·78-44·81]); death within 90 days occurred in 16 (46%) of 35 in the glyceryl trinitrate group and 11 (55%) of 20 in the control group (adjusted OR 0·87 [0·18-4·17]).Interpretation: We found no sign of benefit of transdermal glyceryl trinitrate started within 3 h of symptom onset in the prehospital setting in patients with presumed acute stroke. The signal of potential early harm of glyceryl trinitrate in patients with intracerebral haemorrhage suggests that glyceryl trinitrate should be avoided in this setting.Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation. [ABSTRACT FROM AUTHOR]

Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid- and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (β = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (β = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens. [ABSTRACT FROM AUTHOR]