All rights reserved.Given the Food and Drug Administration's (FDA's) acceptance of master protocol designs in recent guidance documents, the oncology field is rapidly moving to address the paradigm shift to molecular subtype focused studies. Identifying new "marker-based" treatments requires new methodologies to address the growing demand to conduct clinical trials in smaller molecular subpopulations, identify effective treatment and marker interactions, and control for false positives. We introduce our methodology, Hierarchical Bayesian Clustering Design of Multiple Biomarker Subgroups (HCOMBS), a two-stage umbrella Phase II design with effect size clustering and information borrowing across multiple biomarker-treatment pairs. HCOMBS was designed to reduce required sample size, differentiate between varying effect sizes, and control for operating characteristics in the multi-arm setting. When compared to independently applied Simon's Optimal two-stage design, we showed through simulations that HCOMBS required less participants per treatment arm with a well-controlled family-wise error rate and desirable marginal power. Additionally, HCOMBS features a statistical approach that simultaneously conducts clustering and hypothesis testing in one step. We also applied the proposed design on the alliance brain metastases umbrella trial.
  To evaluate the association between antipsychotic use in pregnancy and the risk of congenital malformations in children.
 
  Searches of PubMed, EMBASE, PsycINFO and Cochrane Library were conducted from inception to 06 January 2020 using keywords antipsychotics, pregnancy, pregnancy complication and congenital abnormalities.
 
  Of 38 reports initially identified as being of potential interest, 13 studies met our inclusion criteria English observational studies that examined the association between gestational antipsychotic use and congenital malformations in children.
 
  Data were extracted independently by 2 investigators including the publication year, study site, study period, data source, study design, sample size, medication exposure, exposure period and pregnancy definition, exposure as well as outcome ascertainment, selection of study and comparison group, confounding adjustment, statistical analysis, and method of linkage between mother and children. Risk estimates were pooled using a random-effect modedication classes and dose responses, which would help clinicians decide whether to prescribe certain antipsychotics during pregnancy.Research has shown that taking 'timeouts' in medical practice improves performance and patient safety. However, the benefits of taking timeouts, or pausing, are not sufficiently acknowledged in workplaces and training programmes. To promote this acknowledgement, we suggest a systematic conceptualisation of the medical pause, focusing on its importance, processes and implementation in training programmes. By employing insights from educational and cognitive psychology, we first identified pausing as an important skill to interrupt negative momentum and bolster learning. Subsequently, we categorised constituent cognitive processes for pausing skills into two phases the decision-making phase (determining when and how to take pauses) and the executive phase (applying relaxation or reflection during pauses). We present a model that describes how relaxation and reflection during pauses can optimise cognitive load in performance. Several strategies to implement pause training in medical curricula are proposed intertwining pause training with training of primary skills, providing second-order scaffolding through shared control and employing auxiliary tools such as computer-based simulations with a pause function.Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high-performance LC/electrospray ionization-tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR-ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000-fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in-source collision-induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment.  https://www.selleckchem.com/products/sitagliptin.html  The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high-throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice.An accurate diagnosis of melanocytic lesions requires a thorough histopathological evaluation accompanied by appropriate correlation with clinical examination findings. Although most melanocytic lesions can readily be classified as one of the defined diagnostic entities according to well-established diagnostic criteria, a subset of melanocytic lesions, particularly those with blue naevus-like (pigmented dendritic) morphology, have notoriously constituted an enduring challenge for pathologists. These lesions are rare and often show histological ambiguities, with features of both benignity and malignancy, thereby making accurate risk assessment and prediction of their biological behaviours difficult on histological grounds alone. Herein, we outline a practical and systematic approach for the diagnosis of melanocytic lesions with dendritic morphology, with a particular focus on histological and immunophenotypic features that help to distinguish one entity from another. In this review, we provide the most current knowledge on these melanocytic lesions in the literature and our experience with these rare entities, and we discuss the utility of molecular techniques as an ancillary tool, especially in histologically ambiguous and/or borderline lesions.