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This trial aimed to identify the effects of providing pharmacogenomic (PGx) results and recommendations for patients with chronic pain treated in primary care practices compared to standard care. An open‐label, prospective, largely virtual, type‐2 hybrid effectiveness trial randomized participants to PGx or standard care arms. Adults with pain ≥ 3 months who were treated with tramadol, codeine, or hydrocodone enrolled. Alternative analgesics were recommended for CYP2D6 intermediate or poor metabolizers (IM/PMs). Prescribing decisions were at providers' discretion. The trial randomized 253 participants. A modified intent‐to‐treat primary analysis assessed change in pain intensity over 3 months among IM/PMs (PGx: 49; Standard care: 57). The PGx and standard care arms showed no difference in pain intensity change (−0.10 ± 0.63 vs. −0.21 ± 0.75 standard deviation; p = 0.74) or PGx‐aligned care (69% vs. 63%; standardized difference [SD] = 0.13). In IM/PMs, secondary analyses of pain intensity change suggested improvements with PGx‐aligned (n = 70; −0.21 ± 0.70) vs. unaligned care (n = 36; −0.06 ± 0.69) (SD = −0.22), with this difference increasing when examining IM/PMs with an analgesic change (aligned: n = 31, −0.28 ± 0.76; unaligned: n = 36, −0.06 ± 0.69; SD = −0.31). This approach to PGx implementation for chronic pain was not associated with different prescribing (i.e., similar proportions of PGx‐aligned care) or clinical outcomes. Secondary analyses suggest that prescribing aligned with PGx recommendations showed a small improvement in pain intensity. However, the proportion of patients with a clinically meaningful improvement (≥ 30%) in pain intensity was similar. Future efforts should identify effective implementation methods.

Background The impact of educational strategies in the management of adverse treatment effects and drug interactions in adult patients with epilepsy with comorbidities remains undetermined. Objective The EDU-COM study is a randomised, pragmatic trial investigating the effect of a patient-tailored educational plan in patients with epilepsy with comorbidity. Methods 174 adult patients with epilepsy with chronic comorbidities, multiple-drug therapy and reporting at least one adverse treatment effect and/or drug interaction at study entry were randomly assigned to the educational plan or usual care. The primary endpoint was the number of patients becoming free from adverse treatment events and/or drug interactions after a 6-month follow-up. The number of adverse treatment events and drug interactions, health-related quality of life (HRQOL) summary score changes and the monetary costs of medical contacts and drugs were assessed as secondary outcomes. Results The primary endpoint was met by 44.0% of patients receiving the educational plan versus 28.9% of those on usual care (p=0.0399). The control group reported a significantly higher risk not to meet successfully the primary endpoint at the end of the study: OR (95% CI) of 2.29 (1.03 to 5.09). A separate analysis on drug adverse effects and drug interactions showed that the latter were more sensitive to the effect of educational treatment. Quality of life and costs were not significantly different in the two groups. Conclusions A patient-tailored educational strategy is effective in reducing drug-related problems (particularly drug interactions) in epilepsy patients with chronic comorbidities, without adding significant monetary costs. Registered at ClinicalTrials.gov, identifier NCT01804322, (http://www.clinicaltrials.gov).

BackgroundSubclinical atrial fibrillation (SCAF) may represent a cause of embolic stroke of undetermined source (ESUS) and its detection has important implications for secondary prevention with anticoagulation. Indications to implantable cardiac monitors (ICM) include SCAF detection. The aims of this study were to (1) evaluate the frequency of ICM-detected SCAF; (2) determine predictors of SCAF; and (3) identify patients who would benefit most from ICM implantation.MethodsBetween February 2017 and November 2020, all consecutive patients referred for ICM implantation after a diagnosis of ESUS and without previous history of atrial fibrillation or atrial flutter were included in this study. SCAF was diagnosed if the ICM electrogram demonstrated an episode of irregularly irregular rhythm without distinct P waves lasting > 2 min.ResultsWe enrolled 109 patients (age 66, SD = 13 years; 36% females). During a median follow-up of 19.2 (IQR 11.0–27.5) months, SCAF episodes were detected in 36 (33%) patients. Only abnormal P wave terminal force in lead V1, left atrial end-systolic indexed volume > 34 ml/m2, and BMI > 25 kg/m2 were independently associated with an increased risk of SCAF (HR 2.44, 95% CI 1.14–5.21, p = 0.021; HR 2.39, 95% CI 1.11–5.13, p = 0.026; and HR 2.64, 95% CI 1.06–6.49, p = 0.036 respectively). The ROC curve showed that the presence of all three parameters had the best accuracy (74%) to predict SCAF detection (sensitivity 39%, specificity 91%).ConclusionA multiparametric evaluation has the best accuracy to predict SCAF in ESUS patients and may help identifying those who would benefit most from ICM.

Mutations of the calcium/calmodulin-dependent serine protein kinase ( CASK ) gene have recently been associated with X-linked mental retardation (XLMR) with microcephaly, optic atrophy and brainstem and cerebellar hypoplasia, as well as with an X-linked syndrome having some FG-like features. Our group has recently identified four male probands from 358 probable XLMR families with missense mutations (p.Y268H, p.P396S, p.D710G and p.W919R) in the CASK gene. Congenital nystagmus, a rare and striking feature, was present in two of these families. We screened a further 45 probands with either nystagmus or microcephaly and mental retardation (MR), and identified two further mutations, a missense mutation (p.Y728C) and a splice mutation (c.2521-2A>T) in two small families with nystagmus and MR. Detailed clinical examinations of all six families, including an ophthalmological review in four families, were undertaken to further characterise the phenotype. We report on the clinical features of 24 individuals, mostly male, from six families with CASK mutations. The phenotype was variable, ranging from non-syndromic mild MR to severe MR associated with microcephaly and dysmorphic facial features. Carrier females were variably affected. Congenital nystagmus was found in members of four of the families. Our findings reinforce the CASK gene as a relatively frequent cause of XLMR in females and males. We further define the phenotypic spectrum and demonstrate that affected males with missense mutations or in-frame deletions in CASK are frequently associated with congenital nystagmus and XLMR, a striking feature not previously reported.

This paper presents a novel GIS-based methodological framework for multiscale digital mapping and database implementation in sediment dynamics assessments. It relies on the concept of 'Geomorphic Entities' (GEs), which are polygon objects representing complex, polygenetic geomorphic systems. GEs allow mapping 'focal landforms' as elementary mapping units, while the database stores hierarchical information on sediment sources/sinks classification, process composition, activity, and morphodynamics. We tested this approach in the upper Val d'Arda (N-Apennines, Italy), integrating pre-existing geomorphological datasets with field assessments, photointerpretation, terrain analysis, semi-automated landform classification, and manual digital mapping to produce an Inventory Map of GEs. The primary result is a WebGIS application, allowing end-users to consult and query geospatial data and associated attributes interactively. By combining geomorphological and GIS expertise, this framework addresses the limitations of classical symbol-oriented maps, supporting scientific and applied purposes. It complements traditional mapping methods by structuring complex geomorphological data for use in integrated modelling procedures.

Background Exposure to refugee and traumatic experiences in early childhood can dysregulate the stress response system and lower children’s threshold for aggression. This study examines differences in amount and patterns of aggressive play in children with and without refugee or traumatic experiences, while also assessing how other environmental factors, such as flight duration as a marker of cumulated adverse experiences, time spent in the host country, parental distress, and screen exposure, are associated with such behaviour. Methods In standardized 10 min free individual play sessions, episodes of aggressive behaviours were observed in 62 children with refugee experience and 64 children from a clinically referred comparison group without refugee experience (aged 3–6 years) and coded into four categories: physical, verbal, instrumental, and symbolic. Emotional states were documented to clarify the background mood and context of the aggressive episodes. Parents reported sociodemographic data, screen time, and filled out the Child and Adolescent Trauma Screening for children aged 3–6 (CATS 3–6), assessing potentially traumatic experiences of their children with corresponding symptoms, and the Refugee Health Screener (RHS) for information on their own mental health and distress levels. We correlated these factors with our structured observations of aggressive episodes during children’s play in a standardized situation. Results No significant difference in the distribution of aggressive behaviour episodes between the refugee and comparison groups was observed, even after accounting for gender. Symbolic aggression was more frequent among boys from the comparison group (p = 0.014), while no group or gender effects emerged for other aggression categories. Amount of aggressive behaviour was not related to parent-rated traumatic experiences or symptoms, but a significant correlation appeared, with the reported amount of screen time within the male sub-group (ρ = 0.209, p =0 .027). Conclusion Refugee and traumatic experiences showed no association with increased aggressive behaviour, whereas higher screen time was observed alongside elevated amounts of aggressive episodes among boys in our study. Children from both, refugee and clinical comparison group predominantly engaged in non-violent play in calm, low demand setting, highlighting potential protective role of safe, stimulating environments. Trial registration German clinical trials register, registration number: DRKS00025734, date: 07–23-2021.

Aims/hypothesis Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear. Methods In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers. Results We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression. Conclusions/interpretation Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity. Graphical abstract