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Background. Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are likely to use both HIV and HCV treatment. Drug—drug interactions have been demonstrated between boceprevir, an HCV protease inhibitor, and frequently prescribed antiretroviral drugs, such as efavirenz and boosted HIV protease inhibitors. Concomitant administration of boceprevir with these drugs should be avoided. This study was designed to investigate the absence of a drug-drug interaction between boceprevir and raltegravir, an HIV integrase inhibitor. Methods. This was an open-label, randomized, 2-period, crossover phase 1 trial in 24 healthy volunteers. All subjects were randomly assigned to receive boceprevir 800 mg every 8 hours for 9 days plus a single dose of raltegravir 400 mg on day 10 followed by a washout period and a single dose of raltegravir 400 mg on day 38, or the same medication in reverse order. Blood samples for pharmacokinetics were collected and pharmacokinetic parameters were calculated. Results. The geometric mean (GM) of raltegravir area under the concentration-time curve (AUC) 0–12h and maximum plasma concentration (C max ) for raltegravir + boceprevir vs raltegravir alone were 4.27 (95% confidence interval [CI], 3.22–5.66) vs 4.04 (95% CI, 3.09–5.28) mg * hour/L and 1.06 (95% CI, .76–1.49) vs 0.93 (95% CI, .70–1.23) mg/L, respectively. GM ratio estimates of raltegravir AUC 0–12h and Cmax for raltegravir + boceprevir vs raltegravir alone were 1.04 (90% CI, .88–1.22) and 1.11 (90% CI, .91–1.36), respectively. The GM of boceprevir AUC 0–8h , C max , and C 8h were 5.45 (95% CI, 5.11–5.81) mg * hour/L, 1.88 (95% CI, 1.72–2.06) mg/L, and 0.09 (95% CI, .07–.11) mg/L, respectively. These data are comparable to those from historical controls. Conclusions. Due to the absence of a clinically significant drug interaction, raltegravir can be recommended for combined HIV/HCV treatment including boceprevir. Clinical Trials Registration. NCT01288417.

Background To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. Methods/Design We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. Discussion The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases. Trial registration ClinicalTrials.gov Identifier: NCT02045667

Introduction Clinical reasoning is a core competency for every physician, as well as one of the most complex skills to learn. This study aims to provide insight into the perspective of learners by asking students about their own experiences with learning clinical reasoning throughout the medical Master’s curriculum. Methods We adopted a constructivist approach to organise three semi-structured focus groups within the Master’s curriculum at the medical school of the Radboud University Medical Center in Nijmegen (Netherlands) between August and December 2019. Analysis was performed through template analysis. Results The study included 18 participants who (1) defined and interpreted clinical reasoning, (2) assessed the teaching methods and (3) discussed how they used their context in order to learn and perform clinical reasoning during their clinical rotations. They referred to a variety of contexts, including the clinical environment and various actors within it (e.g. supervisors, peers and patients). Conclusion With regard to the process by which medical students learn clinical reasoning in practice, this study stresses the importance of integrating context into the clinical reasoning process and the manner in which it is learnt. The full incorporation of the benefits of dialogue with the practice of clinical reasoning will require additional attention to educational interventions that empower students to (1) start conversations with their supervisors; (2) increase their engagement in peer and patient learning; (3) recognise bias and copy patterns in their learning process; and (4) embrace and propagate their role as boundary crossers.

Aims/hypothesis Homozygosity for glycine at codon 16 (GlyGly) of the β 2 -adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on β 2 -adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the β 2 -adrenergic receptor. Methods We enrolled 16 healthy participants, who were either GlyGly ( n  = 8) or ArgArg ( n  = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the β 2 -adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC 25 ). Results The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia ( p  = 0.078), consistent with increased β 2 -adrenergic receptor sensitivity. This effect was driven by a significant increase in β 2 -adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants ( p  = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC 25 in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p  = 0.047). Conclusion/interpretation Antecedent hypoglycaemia did not affect β 2 -adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in β 2 -adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants. Trial registration ClinicalTrials.gov NCT00160056 Funding Radboud University Nijmegen Medical Centre.

Recently, a new digital clinical reasoning test (DCRT) was developed to evaluate students’ clinical-reasoning skills. Although an assessment tool may be soundly constructed, it may still prove inadequate in practice by failing to function as intended. Therefore, more insight is needed into the effects of the DCRT in practice. Individual semi-structured interviews and template analysis were used to collect and process qualitative data. The template, based on the interview guide, contained six themes: (1) DCRT itself, (2) test debriefing, (3) reflection, (4) practice/workplace, (5) DCRT versus practice and (6) ‘other’. Thirteen students were interviewed. The DCRT encourages students to engage more in formal education, self-study and workplace learning during their clerkships, particularly for those who received insufficient results. Although the faculty emphasizes the different purposes of the DCRT ( assessment of/as/for learning ), most students perceive the DCRT as an assessment of learning. This affects their motivation and the role they assign to it in their learning process. Although students appreciate the debriefing and reflection report for improvement, they struggle to fill the identified knowledge gaps due to the timing of receiving their results. Some students are supported by the DCRT in exhibiting lifelong learning behavior. This study has identified several ways in which the DCRT influences students’ learning practices in a way that can benefit their clinical-reasoning skills. Additionally, it stresses the importance of ensuring the alignment of theoretical principles with real-world practice, both in the development and utilization of assessment tools and their content. Further research is needed to investigate the long-term impact of the DCRT on young physicians’ working practice.

Homozygosity for glycine at codon 16 (GlyGly) of the β^sub 2^-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on β^sub 2^-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the β^sub 2^-adrenergic receptor. We enrolled 16 healthy participants, who were either GlyGly (n=8) or ArgArg (n=8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the β^sub 2^-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC^sup 25^). The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p=0.078), consistent with increased β^sub 2^-adrenergic receptor sensitivity. This effect was driven by a significant increase in β^sub 2^-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p=0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC^sup 25^ in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p=0.047). Antecedent hypoglycaemia did not affect β^sub 2^-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in β^sub 2^-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants. ClinicalTrials.gov NCT00160056 Radboud University Nijmegen Medical Centre.[PUBLICATION ABSTRACT]

To the Editor: In their article about the duration of dual antiplatelet therapy after implantation of drug-eluting stents, Park and colleagues (April 15 issue) 1 report that the use of extended dual antiplatelet therapy in patients who had received drug-eluting stents was not significantly more effective than aspirin monotherapy in reducing the rate of myocardial infarction or death from cardiac causes. Yet the rate of a composite of myocardial infarction, stroke, or death from any cause was nearly significantly higher in patients receiving extended dual antiplatelet therapy than in those receiving aspirin alone. These results are unpredictable and thus are difficult . . .

This report presents the activities of the `New Physics' working group for the `Physics at TeV Colliders' workshop (Les Houches, France, 10--28 June, 2019). These activities include studies of direct searches for new physics, approaches to exploit published data to constrain new physics, as well as the development of tools to further facilitate these investigations. Benefits of machine learning for both the search for new physics and the interpretation of these searches are also presented.