Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands

Purpose: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. Methods: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. Results: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be amore limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (−0.42%, 95% CI, −0.66% to −0.18%), England (−0.09%, 95% CI, −0.11% to −0.08%), and Scotland (−0.67%, 95% CI, −0.79% to −0.55%); and falling trends in diclofenac initiation in the Netherlands (−0.03%, 95% CI, −0.06% to −0.01% per quarter) and Scotland (−0.04%, 95% CI, −0.05% to −0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. Conclusions: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching

When is impairment in development of motor coordination not solely explicable in terms of intelligence?

Objective: In both clinical practice and research, motor delay is understood to be explained, at least in part, by intellectual abilities. However, no data are available in order to operationalise these criteria to guide clinical decision making. This study provides data on IQ and motor skill in children to answer three research questions concerning the relationship between IQ and motor skill: (1) Can motor coordination impairment be explained in terms of general intellectual retardation? (2) What level of motor performance is to be expected given the person's measured intelligence? (3) At what point are motor difficulties considered to be in excess of those usually associated with mental retardation? Participants & Methods: IQ and motor skill data were analysed from a group of 460 children identified with/without motor difficulties from both clinical and educational settings. Results: Typical and atypical motor skill was seen at all IQ levels, 19% of the variance in motor outcomes was explained by IQ scores, and for each standard deviation lower IQ, a mean loss of 10 percentile motor points should be expected. Conclusions: Although individuals with a lower measured IQ more often showed poorer motor performance than those with a higher measured IQ, motor skill at all levels of proficiency was seen in all IQ categories. These findings have important implications for clinical judgements and decision-making as well as for future research directions to further operationalise the criteria relating to motor disorders in both DSM-IV and ICD-10

HANDS-ON EXPERIMENTATION IN THE FLUID MECHANICS CLASSROOM AS HOMEWORK WITH EFLUIDS.COM

ABSTRACT In an introductory fluid mechanics course, it is important for students to realize that the mathematical models they are deriving in class sometimes model the real world well and sometimes not so well. One way to demonstrate this is to have the students model a simple experiment and compare the results of the model to those of the experiment. This exercise teaches the importance of the model assumptions and the applicability of the model. It would be even more effective if the experiments were simple enough so that students could do them at home as a homework assignment, rather than restricting their experience to a "canned" two hour lab course. At eFluids.com, we are building a library of such experiments in an effort to build a community of educators that moves beyond the traditional mathematical exercises for homework. Here, we describe a number of these experiments and how they can be used in classes

Validation of safety outcomes in routinely collected data:Lessons learned from a multinational postapproval safety study

Key Points- Trial-based case definitions assume close patient monitoring that captures both clinical and subclinical disease manifestations. Adapting such definitions as reference standards to validate cases in observational studies of routinely collected data is therefore challenging.- In validation studies, trial-based case definitions should be calibrated to reflect routine medical care.- When multiple databases are involved in a validation study, database- and country-specific differences in the availability and completeness of the required information should be taken into account.- Researchers should also consider more than one validation approach to ensure cases are accurately captured; additionally, procedures for quantifying uncertainty should be explored.- Results from validations of case definitions in routinely collected data should be appropriately interpreted in light of how the case definitions were derived

Impact of EMA regulatory label changes on hydroxyzine initiation, discontinuation and switching to other medicines in Denmark, Scotland, England and the Netherlands:an interrupted time series regression analysis

Background: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands. Method: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression. Results: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (−12.05, 95%CI −18.47 to −5.63) and Scotland (−19.01, 95%CI −26.99 to −11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (−1.72, 95%CI −2.69 to −0.75) and Scotland (−2.38, 95%CI −3.32 to −1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country. Conclusion: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants

The presence of <i>Clostridioides difficile</i> in faeces before and after faecal microbiota transplantation and its relation with recurrent <i>C. difficile</i> infection and the gut microbiota in a Dutch cohort

Objectives: The objectives of this study are to investigate the presence of Clostridioides difficile in faeces of patients with recurrent C. difficile infection (rCDI) before and after faecal microbiota transplantation (FMT) and to identify risk factors for faecal C. difficile and C. difficile infection (CDI) recurrence. Methods: n = 83 faecal sample triads (pre-FMT [∼1 day], post-FMT [∼3 weeks], and a corresponding FMT donor sample), and n = 22 long-term (∼1–3 years) follow-up faecal samples were collected from FMT-treated patients. The presence of C. difficile in faeces was assessed by enrichment broth culture and PCR (tcdB gene) and associated with patient characteristics, FMT outcome, duration of pre-FMT vancomycin, FMT donor, post-FMT antibiotic use, and faecal microbiota composition (shotgun metagenomics). Results: The FMT cure rate for rCDI was 92.8% (77/83), with six early CDI recurrences (&lt;2 months post-FMT). Toxigenic C. difficile was cultured in 27.7% (23/83) of all patients post-FMT, 23.4% (18/77) of patients cured 2 months post-FMT, and 13.6% (3/22) at long-term follow-up. Early CDI recurrence (n = 6) was associated with positive C. difficile culture post-FMT (21.7% [5/23] vs. 1.7% [1/60], p 0.01), post-FMT antibiotics (30.0% [3/10] vs. 4.6% [3/65], p 0.03), and a short course of pre-FMT vancomycin (median 6.0 days, IQR [5–12] vs. 18 days, IQR [10.8–29], p &lt; 0.05). Additionally, positive C. difficile culture directly pre-FMT was associated with a short course of pre-FMT vancomycin (median 9 days IQR [5–18] vs. 17 days, IQR [10–29.2], p 0.04). Gut microbiota analyses did not reveal signatures associated with C. difficile culture result, despite statistically non-significant trends in relative abundances of the Enterobacteriaceae family, and Dorea, Roseburia, and Clostridiales species. Discussion: Although eradication of C. difficile is not required for clinical cure of rCDI by FMT, it is associated with reduced prevalence of early CDI recurrence, as are the full completion of pre-FMT vancomycin (at least 10 days) and avoiding post-FMT antibiotics.</p

The Results of ADVANCE-CIDP IVIG Trial: Intravenous Immunoglobulin 10% Therapy With GAMMAGARD LIQUID Kiovig for Treatment of Relapse in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

BackgroundADVANCE-CIDP IVIG evaluated the efficacy and safety of immune globulin infusion (human) 10% solution (IVIG 10%; GAMMAGARD LIQUID, also known as Kiovig) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as a rescue treatment for patients relapsing during the ADVANCE-CIDP 1 trial.MethodsOpen-label ADVANCE-CIDP IVIG included adult patients with confirmed CIDP relapse (>= 1-point increase in adjusted Inflammatory Neuropathy Cause and Treatment [INCAT] disability scores from pre-treatment baseline) during ADVANCE-CIDP 1, which assessed the efficacy and safety of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10%. Patients received an induction IVIG 10% dose (2 g/kg) followed by maintenance infusions at the same monthly equivalent dose of pre-randomization IVIG, 3-weekly for 6 months. The primary outcome was the responder rate (>= 1-point decrease in adjusted INCAT scores at treatment cessation vs. pre-IVIG 10% baseline, in patients receiving placebo in ADVANCE-CIDP 1). Other outcomes included the responder rate across all patients relapsing on fSCIG 10% or placebo in ADVANCE-CIDP 1, time to functional improvement (>= 1-point decrease in adjusted INCAT score), and change in adjusted INCAT scores and Rasch-built Overall Disability Scale (R-ODS) centile scores from pre-IVIG 10% baseline.ResultsOverall, 20 patients received IVIG 10% (n = 4 [fSCIG 10%-relapse group]; n = 16 [placebo-relapse group]). Responder rate (95% confidence interval) was 100.0% (80.6%-100.0%) in the placebo-relapse group and 95.0% (76.4%-99.1%) in the overall-relapse population. Across all patients, median time to functional improvement was 25 days. At treatment cessation, mean changes from pre-IVIG 10% baseline in adjusted INCAT and R-ODS centile scores were -1.9 and 12.9, respectively.ConclusionsIVIG 10% effectively treated CIDP relapse and improved functional abilities

Kerkenbos in Muizen (Mechelen). Een grafveld en andere sporen uit de metaaltijden en Romeinse periode

De interpretatie van de structuren uit de metaaltijden is in dit rapport gebaseerd op de vormelijke kenmerken van de verschillende structuren, het aanwezige aardewerk en de uitgevoerde radiokoolstofdateringen. Het grote cirkelvormige monument omgeven door een dens gespatieerde dubbele palenrij is wellicht te interpreteren als een type grafmonument dat in de Lage Landen hoofdzakelijk gedateerd wordt in de periode tussen 1700 en 1300 vóór Christus, dus de midden bronstijd. Het is duidelijk dat dit monument lange tijd zichtbaar bleef in het landschap. Alle andere latere funeraire structuren en graven op de site zijn immers duidelijk buiten deze structuur aangelegd. De kringgreppels en overige graven op de site zijn te situeren in de periode van de late brons- vroege ijzertijd. Ook de aangetroffen grafstructuren, met zowel urnengraven als zgn. brandrestengraven, strookt met deze periode. Wat betreft de uitgestrektheid van de site weten we met zekerheid dat de begraafplaats nog verder doorloopt in het zuidwestelijke gedeelte van het perceel. De combinatie van deze types van monumenten en graven wijst op de aanwezigheid van een zone die gedurende lange periode, zelfs verschillende eeuwen, een rituele en funeraire functie had in het landschap. We kunnen dan ook stellen dat er in deze micro-regio, op de dekzandrug direct ten zuiden van het alluviaal terras van de Dijlevallei, sprake is van een georganiseerd en intensief gebruikt landschap van de midden/ late bronstijd tot de late ijzertijd

Atypical presentation of COVID-19 in older patients is associated with frailty but not with adverse outcomes

Purpose: Older patients with COVID-19 can present with atypical complaints, such as falls or delirium. In other diseases, such an atypical presentation is associated with worse clinical outcomes. However, it is not known whether this extends to COVID-19. We aimed to study the association between atypical presentation of COVID-19, frailty and adverse outcomes, as well as the incidence of atypical presentation. Methods: We conducted a retrospective observational multi-center cohort study in eight hospitals in the Netherlands. We included patients aged ≥ 70 years hospitalized with COVID-19 between February 2020 until May 2020. Atypical presentation of COVID-19 was defined as presentation without fever, cough and/or dyspnea. We collected data concerning symptoms on admission, demographics and frailty parameters [e.g., Charlson Comorbidity Index (CCI) and Clinical Frailty Scale (CFS)]. Outcome data included Intensive Care Unit (ICU) admission, discharge destination and 30-day mortality. Results: We included 780 patients, 9.5% (n = 74) of those patients had an atypical presentation. Patients with an atypical presentation were older (80 years, IQR 76–86 years; versus 79 years, IQR 74–84, p = 0.044) and were more often classified as severely frail (CFS 6–9) compared to patients with a typical presentation (47.6% vs 28.7%, p = 0.004). Overall, there was no significant difference in 30-day mortality between the two groups in univariate analysis (32.4% vs 41.5%; p = 0.173) or in multivariate analysis [OR 0.59 (95% CI 0.34–1.0); p = 0.058]. Conclusions: In this study, patients with an atypical presentation of COVID-19 were more frail compared to patients with a typical presentation. Contrary to our expectations, an atypical presentation was not associated with worse outcomes.</p

Economic evaluation of multiplex ligation-dependent probe amplification and karyotyping in prenatal diagnosis: a cost-minimization analysis

textabstractPurpose: To assess the cost-effectiveness of Multiplex Ligation-dependent Probe Amplification (MLPA, P095 kit) compared to karyotyping. Methods: A cost-minimization analysis alongside a nationwide prospective clinical study of 4,585 women undergoing amniocentesis on behalf of their age (≥36 years), an increased risk following first trimester prenatal screening or parental anxiety. Results: Diagnostic accuracy of MLPA (P095 kit) was comparable to karyotyping (1.0 95% CI 0.999-1.0). Health-related quality of life did not differ between the strategies (summary physical health: mean difference 0.31, p = 0.82; summary mental health: mean difference 1.91, p = 0.22). Short-term costs were lower for MLPA: mean difference €315.68 (bootstrap 95% CI €315.63-315.74; -44.4%). The long-term costs were slightly higher for MLPA: mean difference €76.42 (bootstrap 95% CI €71.32-81.52; +8.6%). Total costs were on average €240.13 (bootstrap 95% CI €235.02-245.23; -14.9%) lower in favor of MLPA. Cost differences were sensitive to proportion of terminated pregnancies, sample throughput, individual choice and performance of tests in one laboratory, but not to failure rate or the exclusion of polluted samples. Conclusion: From an economic perspective, MLPA is the preferred prenatal diagnostic strategy in women who undergo amniocentesis on behalf of their age, following prenatal screening or parental anxiety