To describe the quality of reporting and the nature of reported harms in clinical studies on the effectiveness of supervised exercises in patients with rheumatoid arthritis (RA) or axial... Show moreTo describe the quality of reporting and the nature of reported harms in clinical studies on the effectiveness of supervised exercises in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA). We performed a systematic review, searching eight databases up to February 2023. Randomized controlled trials (RCTs) evaluating supervised exercises in adults with RA or axSpA were considered eligible. Data on harms were extracted according to the CONSORT Harms 2022 Checklist. Among others, it was recorded if harms were prespecified or non-prespecified. Moreover, the nature of reported harms was listed. Forty RCTs were included for RA and 25 for axSpA, of which 29 (73%) and 13 (52%) reported information on harms. In 13 (33%) RCTs in RA and four (16%) in axSpA, the collection of harms outcomes was described in the methods section. Prespecified outcomes were reported by eight (RA) and two (axSpA) RCTs. Non-specified harms outcomes were reported by six (RA) and four (axSpA) RCTs. Prespecified harms outcomes included measures of pain, disease activity, inflammation, and structural joint changes. The nature of non-prespecified harms outcomes varied largely, with pain being most common. A considerable proportion of trials on supervised exercise in RA or axSpA does not or inadequately report harms outcomes. Pain was the most commonly reported prespecified or non-specified harm. For a considerate interpretation of the balance between benefits and harms of supervised exercise in RA or axSpA, use of the CONSORT Harms 2022 Checklist for the design, conduct and reporting of trials is advocated. Show less
Introduction: Nanoporous microneedle arrays (npMNA) are being developed as skin patches for vaccine delivery. As alternative for needle-based immunisation, they may potentially result in higher... Show moreIntroduction: Nanoporous microneedle arrays (npMNA) are being developed as skin patches for vaccine delivery. As alternative for needle-based immunisation, they may potentially result in higher vaccine acceptance, which is important for future mass vaccination campaigns to control outbreaks, such as COVID-19, and for public vaccination in general. In this study we investigated the safety and immunogenicity of needle-free intradermal delivery of a fractional third or fourth dose of mRNA-1273 vaccine by npMNA.Methods: This study was an open-label, randomised-controlled, proof-of-concept study. Healthy adults were eligible if they had received a primary immunisation series against SARS-CoV-2 with two doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) mRNA vaccine. A history of a COVID-19 infection or booster vaccination with mRNA-1273 or BNT162b2 was allowed if it occurred at least three months before inclusion. Participants were randomised in a 1:1 ratio to receive 20 & mu;g mRNA-1273 vaccine, either through npMNA patch applied on the skin (ID-patch group), or through intramuscular (IM) injection (IM-control group). Primary outcomes were reactogenicity up to two weeks after vaccination, and fold-increase of SARS-CoV-2 spike S1specific IgG antibodies 14 days post-vaccination.Results: In April 2022, 20 participants were enroled. The geometric mean concentration (GMC) did not increase in the ID-patch group after vaccination, in contrast to the IM-control group (GMC was 1,006 BAU/mL (95% CI 599-1,689), 3,855 (2,800-5,306), and 3,513 (2,554-4,833) at day 1, 15 and 29, respectively). In addition, SARSCoV-2-specific T cell responses were lower after ID vaccination through npMNA.Conclusion: Needle-free delivery of 20 & mu;g mRNA-1273 vaccine by npMNA failed to induce antibody and T cell responses. As this is a potentially very useful vaccination method, it is important to determine which adjustments are needed to make this npMNA successful. Clinical trial registry (on ClinicalTrial.gov): NCT05315362. Show less
BackgroundAdequate real-world safety and efficacy of leadless pacemakers (LPs) have been demonstrated up to 3 years after implantation. Longer-term data are warranted to assess the net clinical... Show moreBackgroundAdequate real-world safety and efficacy of leadless pacemakers (LPs) have been demonstrated up to 3 years after implantation. Longer-term data are warranted to assess the net clinical benefit of leadless pacing.ObjectiveThe purpose of this study was to evaluate the long-term safety and efficacy of LP therapy in a real-world cohort.MethodsIn this retrospective cohort study, all consecutive patients with a first LP implantation from December 21, 2012, to December 13, 2016, in 6 Dutch high-volume centers were included. The primary safety endpoint was the rate of major procedure- or device-related complications (ie, requiring surgery) at 5-year follow-up. Analyses were performed with and without Nanostim battery advisory-related complications. The primary efficacy endpoint was the percentage of patients with a pacing capture threshold ≤2.0 V at implantation and without ≥1.5-V increase at the last follow-up visit.ResultsA total of 179 patients were included (mean age 79 ± 9 years), 93 (52%) with a Nanostim and 86 (48%) with a Micra VR LP. Mean follow-up duration was 44 ± 26 months. Forty-one major complications occurred, of which 7 were not advisory related. The 5-year major complication rate was 4% without advisory-related complications and 27% including advisory-related complications. No advisory-related major complications occurred a median 10 days (range 0–88 days) postimplantation. The pacing capture threshold was low in 163 of 167 patients (98%) and stable in 157 of 160 (98%).ConclusionThe long-term major complication rate without advisory-related complications was low with LPs. No complications occurred after the acute phase and no infections occurred, which may be a specific benefit of LPs. The performance was adequate with a stable pacing capture threshold. Show less
IntroductionNanoporous microneedle arrays (npMNA) are being developed as skin patches for vaccine delivery. As alternative for needle-based immunisation, they may potentially result in higher... Show moreIntroductionNanoporous microneedle arrays (npMNA) are being developed as skin patches for vaccine delivery. As alternative for needle-based immunisation, they may potentially result in higher vaccine acceptance, which is important for future mass vaccination campaigns to control outbreaks, such as COVID-19, and for public vaccination in general. In this study we investigated the safety and immunogenicity of needle-free intradermal delivery of a fractional third or fourth dose of mRNA-1273 vaccine by npMNA.MethodsThis study was an open-label, randomised-controlled, proof-of-concept study. Healthy adults were eligible if they had received a primary immunisation series against SARS-CoV-2 with two doses of mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) mRNA vaccine. A history of a COVID-19 infection or booster vaccination with mRNA-1273 or BNT162b2 was allowed if it occurred at least three months before inclusion. Participants were randomised in a 1:1 ratio to receive 20 µg mRNA-1273 vaccine, either through npMNA patch applied on the skin (ID-patch group), or through intramuscular (IM) injection (IM-control group). Primary outcomes were reactogenicity up to two weeks after vaccination, and fold-increase of SARS-CoV-2 spike S1-specific IgG antibodies 14 days post-vaccination.ResultsIn April 2022, 20 participants were enroled. The geometric mean concentration (GMC) did not increase in the ID-patch group after vaccination, in contrast to the IM-control group (GMC was 1,006 BAU/mL (95% CI 599–1,689), 3,855 (2,800–5,306), and 3,513 (2,554–4,833) at day 1, 15 and 29, respectively). In addition, SARS-CoV-2-specific T cell responses were lower after ID vaccination through npMNA.ConclusionNeedle-free delivery of 20 µg mRNA-1273 vaccine by npMNA failed to induce antibody and T cell responses. As this is a potentially very useful vaccination method, it is important to determine which adjustments are needed to make this npMNA successful. Show less
Hany, M.; Aboudeeb, M.F.; Shapiro-Koss, C.; Agayby, A.S.S.; Torensma, B. 2023
Introduction Patients living with psychiatric illnesses (PIs) have a high prevalence of obesity. In a 2006 survey, 91.2% of professionals in the bariatric field identified "psychiatric issues" as... Show moreIntroduction Patients living with psychiatric illnesses (PIs) have a high prevalence of obesity. In a 2006 survey, 91.2% of professionals in the bariatric field identified "psychiatric issues" as clear contraindications to weight-loss surgery. Methods This retrospective matched case-control study investigated the impact, safety, and possible relapse after bariatric metabolic surgery (BMS) in patients with PIs. Also, we tested the incidence of patients who developed PI after BMS and compared the post-procedural weight loss with that in a matched control group without PIs. The cases were matched in a ratio of 1:4 to the control patients standardized for age, sex, preoperative BMI, and type of BMS. Results Of 5987 patients, 2.82% had a preoperative PI; postoperative de novo PI was present in 0.45%. Postoperative BMI was significantly different between the groups when compared to preoperative BMI (p < 0.001). Percentage of total weight loss (%TWL) after six months was not significantly different between the case (24.6% +/- 8.9) and control groups (24.0% +/- 8.4, p = 1.000). Early and late complications were not significantly different between the groups. The psychiatric drug use and dosage changes did not differ significantly pre- and postoperatively. Of the psychiatric patients, 5.1% were postoperatively admitted to a psychiatric hospital (p = 0.06) unrelated to BMS, and 3.4% had a prolonged absence from work after surgery. Conclusion BMS is an effective weight loss treatment and a safe procedure for patients with psychiatric disorders. We found no change in the patients' psychiatric status outside the usual disease course. Postoperative de novo PI was rare in the present study. Furthermore, patients with severe psychiatric illness were excluded from undergoing surgery and, therefore, from the study. Careful follow-up is necessary to guide and protect patients with PI. Show less
Platelet transfusions are used to provide hemostatic capacity to patients with decreased number or functionality of platelets. The aim of this thesis was to expand knowledge about the safety and... Show morePlatelet transfusions are used to provide hemostatic capacity to patients with decreased number or functionality of platelets. The aim of this thesis was to expand knowledge about the safety and efficacy of platelet transfusions in general and in particular in cardiac surgery patients. In this thesis we found that cardiac surgery patients receiving an platelet transfusion shortly after cardiopulmonary bypass experienced less blood loss than patients who did not receive an early platelet transfusion. However, early platelet transfusion was not associated with more reinterventions, thromboembolic complications, infections, multi-organ failure, or mortality. Furthermore, we discovered that PAS-C as storage medium for platelets is associated with more favorable outcomes than plasma with regard to transfusions reactions, but not with regard to in vitro hemostatic measurements. Furthermore, we observed that fresh platelet concentrates are associated with more favorable outcomes than older platelet concentrates: less transfusions reactions in the whole transfused population, better hemostatic measurements in vitro, and less blood loss and mortality in cardiac surgery patients. Show less
Introduction: To compare the real-world safety profile of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors between younger and older patients.Materials and... Show moreIntroduction: To compare the real-world safety profile of programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) inhibitors between younger and older patients.Materials and Methods: All patients receiving pembrolizumab, nivolumab, atezolizumab or durvalumab between September 2016 and September 2019 at Haga Teaching Hospital, The Hague, The Netherlands were included in this retrospective study. Immune-related adverse drug reactions (irADRs) were manually retrieved from the electronic patient files. The cumulative incidence of irADRs were compared between younger (<65 years) and older (>= 65 years) patients using a Pearsons Chi-square test.Results: We identified 217 patients who were treated with at least one dose of PD-(L)1 inhibitor. 58% were 65 years or older at the start of immunotherapy. 183 patients (84.3%) received monotherapy PD-(L)1 inhibitors and 34 (15.7%) received chemo-immunotherapy. A total of 278 irADRs were registered. Cutaneous irADRs (53.9%), thyroid gland disorders (20.3%), and non-infectious diarrhoea/colitis (17.5%) were the most frequently reported irADRs. The majority of the irADRs were mild to moderate and no fatal irADRs were observed. 61 (21.9%) of the irADRs needed systemic treatment, of which 19 (6.8%) required treatment with corticosteroids. 18 irADRs (6.5%) were severe and resulted in hospitalisation.The cumulative incidence of cutaneous irADRs was different between the age groups: 45.7% of the patients <65 years and in 60.0% of the patients >= 65 years (p = 0.036). No statistical difference was found in the cumulative incidence of other irADRs between the two age groups.Discussion: Advanced age is not associated with immune-related adverse drug reactions of PD-1 and PD-L1 inhibitors. Show less
Ngongo, C.J.; Raassen, T.J.I.P.; Mahendeka, M.; Lombard, L.; Roosmalen, J. van 2022
Background Genito-urinary fistulas may occur as complications of obstetric surgery. Location and circumstances can indicate iatrogenic origin as opposed to pressure necrosis following prolonged,... Show moreBackground Genito-urinary fistulas may occur as complications of obstetric surgery. Location and circumstances can indicate iatrogenic origin as opposed to pressure necrosis following prolonged, obstructed labor. Methods This retrospective review focuses on 787 women with iatrogenic genito-urinary fistulas among 2942 women who developed fistulas after cesarean birth between 1994 and 2017. They are a subset of 5469 women who sought obstetric fistula repair between 1994 and 2017 in Tanzania, Uganda, Kenya, Malawi, Rwanda, Somalia, South Sudan, Zambia, and Ethiopia. We compared genito-urinary fistula classifications following vaginal birth to classifications following cesarean birth. We assessed whether and how the proportion of iatrogenic genito-urinary fistula was changing over time among women with fistula, comparing women with iatrogenic fistulas to women with fistulas attributable to pressure necrosis. We used mixed effects logistic regression to model the rise in iatrogenic fistula among births resulting in fistula and specifically among cesarean births resulting in fistula. Results Over one-quarter of women with fistula following cesarean birth (26.8%, 787/2942) had an injury caused by surgery rather than pressure necrosis due to prolonged, obstructed labor. Controlling for age, parity, and previous abdominal surgery, the odds of iatrogenic origin nearly doubled over time among all births resulting in fistula (aOR 1.94; 95% CI 1.48-2.54) and rose by 37% among cesarean births resulting in fistula (aOR 1.37; 95% CI 1.02-1.83). In Kenya and Rwanda the rise of iatrogenic injury outpaced the increasing frequency of cesarean birth. Conclusions Despite the strong association between obstetric fistula and prolonged, obstructed labor, more than a quarter of women with fistula after cesarean birth had injuries due to surgical complications rather than pressure necrosis. Risks of iatrogenic fistula during cesarean birth reinforce the importance of appropriate labor management and cesarean decision-making. Rising numbers of iatrogenic fistulas signal a quality crisis in emergency obstetric care. Unaddressed, the impact of this problem will grow as cesarean births become more common. Show less
This research revealed the role of leaders in relation to incident prevention in organisations. The acquired data showed that Dominance-oriented leaders have a negative influence on safety.... Show moreThis research revealed the role of leaders in relation to incident prevention in organisations. The acquired data showed that Dominance-oriented leaders have a negative influence on safety. Relation-oriented leaders appeared to be friendly people with no real influence on safety. Production-oriented leaders are real achievers, committed to meeting production targets. A new character emerged during our research: the Process-oriented leader. This leader proved a dedicated safety minded leader, who fulfils his production duties in a responsible way, taking care of the reliability of production without compromising the safety of his team members. Also, we developed a Risk Reduction Cycle, showing the risk reduction process. This model revealed that the recognition of risks and implementation of remedial actions are the weakest links. In conclusion, we argue that this research revealed that the effectiveness of incident prevention depends predominantly on the individual behaviour of their leaders. Consequently, in order to foster Process-oriented Safety Leadership, we recommend not to focus on operational safety practices to be carried out by the workforce. Instead, we deliberately emphasise the influential power of their leaders, and propose a set of Process-oriented Safety Leadership Principles, directed at the board room level of organisations and three external parties. Show less
Hany, M.; Sabry, A.; Torensma, B.; Ahmed, K.; Refaie, M.; Zidan, A.; ... ; Mourad, M. 2022
Background: Long-term weight regain (WR) after sleeve gastrectomy (SG) is a major challenge. Laparoscopic banded SG (BSG) was introduced to overcome pouch dilation and, consequently, WR; however,... Show moreBackground: Long-term weight regain (WR) after sleeve gastrectomy (SG) is a major challenge. Laparoscopic banded SG (BSG) was introduced to overcome pouch dilation and, consequently, WR; however, its mid-and long-term outcomes have not been sufficiently demonstrated. Objective: This study retrospectively evaluated the mid-term weight loss efficacy and morbidity over at least a 4-year follow-up after laparoscopic banded SG using a MiniMizer Gastric Ring (R) and laparoscopic non-banded SG. Method: The data of 1586 bariatric surgeries were retrospectively evaluated. To ensure homogeneity in our study cohort, propensity score matching (PSM) was performed. Results: The final cohort comprised 1392 patients: the non-banded SG (n = 1260) and BSG (n = 132) groups. In our matched cohort (SG, n = 655 and BSG, n = 132), WR was noted in 4 (3.0%) and 71 (10.8%) patients in the BSG and SG groups, respectively. Gastric band erosion or slippage was not noted in the BSG cohort. The levels of cholesterol and triglyceride were similar in the two groups. Postoperative glycemic control was significantly reduced in the BSG group. Conclusion: Although the percentage of weight loss achieved in the BSG group was low in the first year postoperatively, the mid-term (sustained) weight loss associated with BSG was superior to that associated with non-banded SG. BSG is a safe procedure with no significant mid-term band-related morbidity; its impact on the resolution of comorbidities is equivalent and perhaps superior to SG. Show less
Background: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement... Show moreBackground: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. Methods: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. Results: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. Conclusion: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. Current knowledge about this subject. COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation.. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups.. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study. Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a twoyear follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5.. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group.. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy. Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19.. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy. Show less
Background: The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma.... Show moreBackground: The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma. However, patients aged >_75 years are often under-represented in clinical trials, therefore raising questions on safety and efficacy of treatment. Patients and methods: We analyzed a real-world cohort of 3054 patients with metastatic melanoma stratified for age (<_65 years, 66-74 years and >_ 75 years), and BRAF status, providing data on treatment strategies, toxicity, and survival. Kaplan Meier curves and Cox Proportional Hazard Models were used to present overall survival (OS) and Melanoma Specific Survival (MSS). Results: Overall, 52.2% of patients were <_ 65 years and 18.4% of patients >_75 years. BRAF mutated tumors were found less often in patients >_75 years: 34.5% versus 65% in patients <_65 years. Patients >_75 years received systemic therapy less frequently compared to their younger counterparts independent of the BRAF status. When receiving treatment, no statistical significant difference in grade 3 or 4 toxicity was observed. Three year Overall Survival rate was 13.7% (9.1-19.3) in patients >_75 years versus 26.7% (23.1-30.4) in patients <_65 years, with a Hazard Ratio (HR) of 1.71 (95%CI 1.50-1.95), p < 0.001. Three year Melanoma Specific Survival was 30.4% (22.0-39.2) versus 34.0% (29.7-38.2), HR 1.26 (95% CI 1.07-1.49), p = 0.005 with an adjusted HR of 1.21 (1.00-1.47), p = 0.049 Conclusion: Patients with metastatic melanoma >_75 years are less frequently treated, but when treated there is no statistical significant increase in toxicity and only a borderline statistical significant difference in Melanoma Specific Survival was seen, compared to younger patients. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Slingerland-Boot, R.; Bouw-Ruiter, M.; Manen, C. van; Arbous, S.; Zanten, A. van 2021
Introduction: In critically ill patients, nasogastric (NG) and nasojejunal (NJ) feeding tube placements are standard procedures. However, about 1.9% of blind tube insertions are malpositioned in... Show moreIntroduction: In critically ill patients, nasogastric (NG) and nasojejunal (NJ) feeding tube placements are standard procedures. However, about 1.9% of blind tube insertions are malpositioned in the tracheopulmonary system, whereas guided procedures may result in a significant delay in nutritional delivery. Guided methods, such as Cortrak and fluoroscopy, have success rates of 82.6-85% and 93% respectively. The current study aims to investigate the performance of video-assisted feeding tube placement in the post-pyloric position using Integrated Real Time Imaging System (IRIS-) technology. Methods: A prospective cohort study in patients requiring enteral feeding was conducted in a mixed medical-surgical intensive care unit (ICU). The primary outcome was the post-pyloric placement of IRIS feeding tubes, as confirmed by X-ray. Secondary study objectives included gastric placement, ease of use and adverse events. Results: Thirty-one feeding tubes were placed using IRIS-technology; one patient was excluded for analysis due to protocol violation. One procedure was terminated due to significant bleeding (epistaxis) and desaturation. Only eighteen (58%) feeding tubes were placed in post-pyloric position (including two past the ligament of Treitz). In subjects who needed post-pyloric placement due gastroparesis, IRIS was mostly unsuccessful (success rate of 25%). However, when gastric placement was the primary objective, 96.8% of tubes were correctly placed. During insertion, tracheal visualization occurred in 27% of cases, and the IRIS feeding tube was repositioned early in the procedure without causing patient harm. Conclusions: Real-time video-assisted post-pyloric feeding tube placement in critically ill ICU patients was only successful in 58% of cases and therefore currently cannot be recommended for this indication. However, a high success rate (96.8%) for gastric placement was achieved. IRIS tube placement detected tracheal misplacement immediately and had few adverse events. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Background European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially... Show moreBackground European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim(R) during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap. Methods Participants were recruited through Health Care Provider's safety registry in 15 centres across 6 European countries in the period 2013-2016. Adverse events (AE) were collected, with a special focus on cardiovascular safety by including electrocardiogram QT intervals evaluated after correction with either Bazett's (QTcB) or Fridericia's (QTcF) methods, at baseline and after treatment. QTcB and/or QTcF prolongation were defined by a value > 450 ms for males and children and > 470 ms for females. Results Among 294 participants, 30.3% were women, 13.7% of Caucasian origin, 13.5% were current smoker, 13.6% current alcohol consumer and 42.2% declared at least one illness history. The mean (SD) age and body mass index were 39.8 years old (13.2) and 25.9 kg/m(2) (4.7). Among them, 75 reported a total of 129 AE (27 serious), 46 being suspected to be related to APQ (11 serious) and mostly labelled as due to haematological, gastrointestinal, or infection. Women and Non-African participants had significantly (p < 0.05) more AEs. Among AEs, 21 were due to cardiotoxicity (7.1%), mostly QT prolongation, while 6 were due to neurotoxicity (2.0%), mostly dizziness. Using QTcF correction, QT prolongation was observed in 17/143 participants (11.9%), only 2 of them reporting QTcF > 500 ms (milliseconds) but no clinical symptoms. Using QTcB correction increases of > 60 ms were present in 9 participants (6.3%). A trend towards increased prolongation was observed in those over 65 years of age but only a few subjects were in this group. No new safety signal was reported. The overall efficacy rate was 255/257 (99.2%). Conclusions APQ appears as an effective and well-tolerated drug for treatment of malaria in patients recruited in European countries. AEs and QT prolongation were in the range of those obtained in larger cohorts from endemic countries. Trial registration This study has been registered in EU Post-Authorization Studies Register as EUPAS6942 Show less
OBJECTIVESleep deprivation is known to affect driving behavior and may lead to serious car accidents similar to the effects from e.g., alcohol. In a previous study, we have demonstrated that the... Show moreOBJECTIVESleep deprivation is known to affect driving behavior and may lead to serious car accidents similar to the effects from e.g., alcohol. In a previous study, we have demonstrated that the use of machine learning techniques allows adequate characterization of abnormal driving behavior after alprazolam and/or alcohol intake. In the present study, we extend this approach to sleep deprivation and test the model for characterization of new interventions. We aimed to classify abnormal driving behavior after sleep deprivation, and, by using a machine learning model, we tested if this model could also pick up abnormal driving behavior resulting from other interventions.METHODSData were collected during a previous study, in which 24 subjects were tested after being sleep-deprived and after a well-rested night. Features were calculated from several driving parameters, such as the lateral position, speed of the car, and steering speed. In the present study, we used a gradient boosting model to classify sleep deprivation. The model was validated using a 5-fold cross validation technique. Next, probability scores were used to identify the overlap of driving behavior after sleep deprivation and driving behavior affected by other interventions. In the current study alprazolam, alcohol, and placebo are used to test/validate the approach.RESULTSThe sleep deprivation model detected abnormal driving behavior in the simulator with an accuracy of 77 ± 9%. Abnormal driving behavior after alprazolam, and to a lesser extent also after alcohol intake, showed remarkably similar characteristics to sleep deprivation. The average probability score for alprazolam and alcohol measurements was 0.79, for alcohol 0.63, and for placebo only 0.27 and 0.30, matching the expected relative drowsiness.CONCLUSIONWe developed a model detecting abnormal driving induced by sleep deprivation. The model shows the similarities in driving characteristics between sleep deprivation and other interventions, i.e., alcohol and alprazolam. Consequently, our model for sleep deprivation may serve as a next reference point for a driving test battery of newly developed drugs. Show less
Background: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under... Show moreBackground: The cholinergic system and M-1 receptor remain an important target for symptomatic treatment of cognitive dysfunction. The selective M-1 receptor partial agonist HTL0018318 is under development for the symptomatic treatment of Dementia's including Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We investigated the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of multiple doses of HTL0018318 in healthy younger adults and elderly subjects.Methods: This randomised, double blind, placebo-controlled study was performed, investigating oral doses of 15-35 mg/day HTL0018318 or placebo in 7 cohorts of healthy younger adult (n = 36; 3 cohorts) and elderly (n = 50; 4 cohorts) subjects. Safety, tolerability and pharmacokinetic measurements were performed. Pharmacodynamics were assessed using a battery of neurocognitive tasks and electrophysiological biomarkers of synaptic and cognitive functions.Results: HTL0018318 was generally well-tolerated in multiple doses up to 35 mg/day and were associated with mild or moderate cholinergic adverse events. There were modest increases in blood pressure and pulse rate when compared to placebo-treated subjects, with tendency for the blood pressure increase to attenuate with repeated dosing. There were no clinically significant observations or changes in blood and urine laboratory measures of safety or abnormalities in the ECGs and 24-h Holter assessments. HTL0018318 plasma exposure was dose-proportional over the range 15-35 mg. Maximum plasma concentrations were achieved after 1-2 h. The apparent terminal half-life of HTL0018318 was 16.1 h (+/- 4.61) in younger adult subjects and 14.3 h (+/- 2.78) in elderly subjects at steady state. HTL0018318 over the 10 days of treatment had significant effects on tests of short-term (working) memory (n-back) and learning (Milner maze) with moderate to large effect sizes.Conclusion: Multiple doses of HTL0018138 showed well-characterised pharmacokinetics and were safe and generally well-tolerated in the dose range studied. Pro-cognitive effects on short-term memory and learning were demonstrated across the dose range. These data provide encouraging data in support of the development of HTL0018138 for cognitive dysfunction in AD and DLB. Show less
Aims Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. Recent randomized clinical trials have demonstrated that... Show moreAims Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. Recent randomized clinical trials have demonstrated that novel antithrombotic therapies improve in-hospital outcomes in STEMI patients. We aimed to describe the effectiveness and safety of P2Y12 receptor inhibitors in clinical practice in patients with STEMI based on data from contemporary European ACS registries.Methods and results Five registries from the PIRAEUS initiative (AAPCI/ADPAT, ALKK-PIC, AMIS Plus, Belgium STEMI, and EYESHOT) provided data for the assessment of P2Y12 receptor inhibitor-based dual antiplatelet therapy. Registries were heterogeneous in terms of setting, patient characteristics, and treatment selection. Matched pair analysis and propensity score matching were used to assess all-cause in-hospital death rates based on data from 25 250 patients (8577 patients on prasugrel, 5995 on ticagrelor, and 10 678 on clopidogrel). The odds ratio (OR) for the death of any cause when compared with clopidogrel was 0.72 [95% confidence interval (CI) 0.62-0.84, P < 0.001] in favour of the new P2Y12 receptor inhibitors (prasugrel and ticagrelor combined). In the comparison between prasugrel and ticagrelor, there were no relevant differences (OR 0.97, 95% CI 0.77-1.23; P= 0.81). Event rates of cardiovascular death and stroke were also substantially lower for the new P2Y12 receptor inhibitors. The differences between clopidogrel and prasugrel or ticagrelor on major bleeding were numerically in the same order as for death of any cause but were not statistically significant. No differences in ischaemic and bleeding outcomes were observed between prasugrel and ticagrelor.Conclusion This analysis suggests that the prasugrel or ticagrelor compared with clopidogrel have favourable outcomes in clinical practice while not being inferior in terms of safety. Show less
Background: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent... Show moreBackground: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent morbidity and mortality amongst infants and young children but could also reduce transmission to elderly. The RSVDG vaccine consists of a live-attenuated RSV that lacks the G attachment protein. RSVDG is severely impaired in binding to host cells and exhibits reduced infectivity in preclinical studies. Intranasal immunization of cotton rats with RSVDG vaccine protected against replication of wildtype RSV, without inducing enhanced disease.Methods: We performed a first-in-human trial with primary objective to evaluate safety and shedding of RSV Delta G (6.5 log(10) CCID50) after intranasal administration. Healthy adults aged between 18 and 50, with RSV neutralizing serum titers below 9.6 log(2), received a single dose of either vaccine or placebo (n = 48, ratio 3:1). In addition to safety and tolerability, nasal viral load, and systemic and humoral immune responses were assessed at selected time points until 4 weeks after immunization.Results: Intranasal administration of RSV Delta G was well tolerated with no findings of clinical concern. No infectious virus was detected in nasal wash samples. Similar to other live-attenuated RSV vaccines, neutralizing antibody response following inoculation was limited in seropositive adults.Conclusions: A single dose of 6.5 log(10) CCID50 of RSV Delta G was safe and well-tolerated in seropositive healthy adults. RSV Delta G was sufficiently attenuated but there were no signs of induction of antibodies. Safety and immunogenicity can now be explored in children and eventually in seronegative infants. (C) 2020 The Author(s). Published by Elsevier Ltd. Show less
Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1... Show moreRimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies. Show less
Het Europese non-foodproductveiligheidsrecht bevat productnormen die veelal als publiekrechtelijk worden bestempeld. Bij de harmonisatie gebruikt de Europese wetgever verschillende soorten... Show moreHet Europese non-foodproductveiligheidsrecht bevat productnormen die veelal als publiekrechtelijk worden bestempeld. Bij de harmonisatie gebruikt de Europese wetgever verschillende soorten productnormen, namelijk bindende eisen in richtlijnen en verordeningen en niet-bindende Europese normalisatienormen. De literatuur neemt aan dat Europese productnormen ook invloed kunnen hebben op de privaatrechtelijke normen die gelden in rechtsverhoudingen tussen bijvoorbeeld de eindgebruiker van het product en andere partijen in de handelsketen, alsmede tussen concurrenten. Dit onderzoek beantwoordt de vraag wat de exacte betekenis is van Europese productnormen voor privaatrechtelijke normstelling. Wanneer is een productnorm slechts een van de relevante omstandigheden van het geval bij de formulering van een privaatrechtelijke norm? Wanneer vult een productnorm een privaatrechtelijke norm grotendeels in, in de zin dat de productnorm het uitgangspunt vormt? Van welke omstandigheden en factoren is deze betekenis afhankelijk?Het onderzoek biedt de lezer een nadere introductie in het wat onderbelichte Europese productveiligheidsrecht en beantwoordt de hoofdvraag aan de hand van een Europeesrechtelijk, institutioneel en privaatrechtelijk perspectief. De privaatrechtelijke analyse ziet op de belangrijkste Nederlandse rechtsgronden voor doorwerking van productnormen en bevat rechtsvergelijking met het Engelse en Duitse recht. Bovendien vindt een uitvoerige analyse van Nederlandse feitenrechtspraak plaats om te zien hoe feitenrechters in de praktijk met productnormen bij de invulling van privaatrechtelijke normen omgaan. Het onderzoek besluit met een overzicht van gezichtspunten die behulpzaam kunnen zijn bij het beoordelen van de betekenis van productnormen voor privaatrechtelijke normstelling in concrete gevallen. Show less
