Factor VIII cross-matches to the human proteome reduce the predicted inhibitor risk in missense mutation hemophilia A.

Single missense mutations in the F8 gene encoding the coagulation protein factor VIII (FVIII) give rise predominantly to non-severe hemophilia A. Despite only a single amino acid sequence difference between the replacement, therapeutic FVIII (tFVIII) and the patient's endogenous FVIII, tFVIII may still be perceived as foreign by the recipient's immune system and trigger an immune response (inhibitor). Inhibitor formation is a life-long risk for non-severe hemophilia A patients treated with tFVIII, but remains difficult to predict. The aim of this study was to understand whether fortuitous, primary sequence cross-matches between tFVIII and proteins in the human proteome are the reason why certain F8 mutations are not associated with inhibitor formation. We predicted which tFVIII differences are potentially perceived as foreign by helper T cells a necessary precursor to inhibitor development and then scanned potentially immunogenic peptides against more than 100,000 proteins in the proteome. As there are hundreds of disease-causing F8 missense mutations and the Human Leucocyte Antigen gene complex governing peptide presentation to helper T cells is highly polymorphic, these calculations pose a huge combinatorial challenge that we addressed computationally. We identify that cross-matches between tFVIII and the human proteome are commonplace and have a profound impact on the predicted risk of inhibitor development. Our results emphasize the importance of knowing both the F8 missense mutation and the Human Leucocyte Antigen alleles of a patient with missense mutation hemophilia A if his underlying risk of inhibitor development is to be estimated

The CogBIAS longitudinal study protocol: cognitive and genetic factors influencing psychological functioning in adolescence.

BACKGROUND: Optimal psychological development is dependent upon a complex interplay between individual and situational factors. Investigating the development of these factors in adolescence will help to improve understanding of emotional vulnerability and resilience. The CogBIAS longitudinal study (CogBIAS-L-S) aims to combine cognitive and genetic approaches to investigate risk and protective factors associated with the development of mood and impulsivity-related outcomes in an adolescent sample. METHODS: CogBIAS-L-S is a three-wave longitudinal study of typically developing adolescents conducted over 4 years, with data collection at age 12, 14 and 16. At each wave participants will undergo multiple assessments including a range of selective cognitive processing tasks (e.g. attention bias, interpretation bias, memory bias) and psychological self-report measures (e.g. anxiety, depression, resilience). Saliva samples will also be collected at the baseline assessment for genetic analyses. Multilevel statistical analyses will be performed to investigate the developmental trajectory of cognitive biases on psychological functioning, as well as the influence of genetic moderation on these relationships. DISCUSSION: CogBIAS-L-S represents the first longitudinal study to assess multiple cognitive biases across adolescent development and the largest study of its kind to collect genetic data. It therefore provides a unique opportunity to understand how genes and the environment influence the development and maintenance of cognitive biases and provide insight into risk and protective factors that may be key targets for intervention.This work was supported by the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no: [324176]

A program for the comprehensive cognitive training of excess weight (TRAINEP): The study protocol for a randomized, controlled trial

This is the final version. Available on open access from MDPI via the DOI in this record. Data Availability Statement: Study data will be made available from the corresponding author upon reasonable request.Background: The available treatments for people with excess weight have shown small effects. Cognitive training has shown promising results, but most of the research focused on normal-weight university students and reported immediate results after a single training session. This parallel group, randomized, controlled trial aims to study the efficacy of a program for the comprehensive cognitive treatment of excess weight. Methods and Analysis: Participants will be 150 people with excess weight recruited through social media, who will be randomized into three groups: cognitive intervention, sham cognitive intervention, and treatment as usual. All assessment and intervention sessions will be online in groups of 5–6 participants. The three groups will attend a motivational interviewing session, and they will receive individualized diet and physical exercise guidelines throughout the program. The cognitive training will consist of four weekly sessions of approximately 60–90 min, each based on approach–avoidance bias training, inhibitory control training, implementation of intentions, and episodic future thinking, respectively. The main outcome measure will be a change in Body Mass Index (kg/m2). Secondary outcomes include changes in cognitive measures, eating and physical exercise behaviors, and anthropometric measures. Assessments will be conducted up to 6 months after the end of the program. In addition, data on the use of the health system will be collected to analyze the cost-effectiveness and the cost-utility of training. Linear mixed models will be used for statistical analysis. Findings of this study will expand the available evidence on cognitive interventions to reduce excess weight.Spanish Ministry of Science, Innovation, and UniversitiesEuropean Regional Development Fund (ERDF

Dental management before radiotherapy of the head and neck region: 4‐year single‐center experience

Abstract Objective To review our experience with a standardized dental management approach in patients with planned radiotherapy of the head and neck region based on preradiation and follow‐up data. Material and Methods Records of patients who underwent radiotherapy between June 2016 and November 2020 were reviewed. Data on dental findings and therapeutic recommendations were extracted from a prospectively managed database. Hospital records were used to obtain follow‐up data. Results Two hundred eighty‐one patient records were identified. After the exclusion of 81 patients because of incomplete data, 200 patients were included in the study. Dental findings relevant to radiotherapy were found in 144 cases (72.0%). Teeth extractions were recommended in 112 (56.0%) patients. Follow‐up data were available for 172 (86.0%) patients (mean follow‐up: 16.8 ± 10.7 months). Radiodermatitis was the most frequently observed sequela of radiotherapy (42.4%), followed by dysphagia (38.4%) and stomatitis (36.6%). Osteoradionecrosis was observed in only 2.3% of the patients. Conclusion Dental findings relevant to planned radiotherapy were frequent and in many cases resulted in recommendations for teeth extraction. Based on our standardized dental management protocol, we observed low rates of late oral complications after radiotherapy of the head and neck region

Effects of very low-carbohydrate vs. high-carbohydrate weight loss diets on psychological health in adults with obesity and type 2 diabetes: a 2-year randomized controlled trial

Published online: 20 May 2021Aims: Very low-carbohydrate (LC) diets are popular for type 2 diabetes (T2DM) management; however, long-term effects on psychological health remain largely unknown. This study reports the effects of a LC diet on mood and cognitive function after 2 years and explores the potential predictors of changes in psychological health. Methods: 115 adults (57% males; age: 58.5 ± 7.1 years) with obesity and T2DM were randomized to consume an energy reduced (~ 500 to 1000 kcal/day deficit), LC diet [14% energy as carbohydrate, 28% protein, 58% fat (< 10% saturated fat)] or an isocaloric high unrefined carbohydrate, low-fat diet [HC: 53% carbohydrate, 17% protein, 30% fat (< 10% saturated fat)] for 2 years. Both diets were combined with aerobic/resistance exercise (1 h, 3 days/week). Mood/well-being [Beck Depression Inventory (BDI), Spielberger State Anxiety Inventory (SAI), Profile of Mood States (POMS)], diabetes-related quality of life [Diabetes-39 (D-39)] and distress [Problem Areas in Diabetes (PAID) Questionnaire], and cognitive function were assessed during and post-intervention. Results: 61 (LC: 33, HC: 28) participants completed the study. Weight loss was 9.1% after 12 months and 6.7% after 2 years with no difference between diet groups. There were no differences between the groups for the changes in any psychological health outcome (smallest p ≥ 0.19 for all time x diet interactions). Overtime, improvements in BDI, POMS [Total Mood Disturbance (TMD); four subscales], PAID, and D-39 (three subscales) scores occurred (p ≤ 0.05, time). Stepwise regression analysis showed improvements in BDI, POMS (TMD; two subscales), D-39, SAI, and PAID scores were significantly (p < 0.05) correlated with reductions in body weight and glycated hemoglobin. Conclusion: In adults with obesity and T2DM, energy-restricted LC and HC diets produced comparable long-term improvements on a comprehensive range of psychological health outcomes. The findings suggest both diets can be used as a diabetes management strategy as part of a holistic lifestyle modification program without concern of negative effects on mental well-being or cognition.Naomi Kakoschke, Ian T. Zajac, Jeannie Tay, Natalie D. Luscombe-Marsh, Campbell H. Thompson, Manny Noakes, Jonathan D. Buckley, Gary Wittert, Grant D. Brinkwort