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Abstract Background In biomedicine, machine learning (ML) has proven beneficial for the prognosis and diagnosis of different diseases, including cancer and neurodegenerative disorders. For rare diseases, however, the requirement for large datasets often prevents this approach. Huntington’s disease (HD) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the huntingtin gene. The world’s largest observational study for HD, Enroll-HD, describes over 21,000 participants. As such, Enroll-HD is amenable to ML methods. In this study, we pre-processed and imputed Enroll-HD with ML methods to maximise the inclusion of participants and variables. With this dataset we developed models to improve the prediction of the age at onset (AAO) and compared it to the well-established Langbehn formula. In addition, we used recurrent neural networks (RNNs) to demonstrate the utility of ML methods for longitudinal datasets, assessing driving capabilities by learning from previous participant assessments. Results Simple pre-processing imputed around 42% of missing values in Enroll-HD. Also, 167 variables were retained as a result of imputing with ML. We found that multiple ML models were able to outperform the Langbehn formula. The best ML model (light gradient boosting machine) improved the prognosis of AAO compared to the Langbehn formula by 9.2%, based on root mean squared error in the test set. In addition, our ML model provides more accurate prognosis for a wider CAG repeat range compared to the Langbehn formula. Driving capability was predicted with an accuracy of 85.2%. The resulting pre-processing workflow and code to train the ML models are available to be used for related HD predictions at: https://github.com/JasperO98/hdml/tree/main . Conclusions Our pre-processing workflow made it possible to resolve the missing values and include most participants and variables in Enroll-HD. We show the added value of a ML approach, which improved AAO predictions and allowed for the development of an advisory model that can assist clinicians and participants in estimating future driving capability.

All practically possible hydrogen abstraction reactions for guanosine and uridine have been investigated through quantum chemical calculations of energy barriers and rate constants. This was done at the level of density functional theory (DFT) with the ωB97X-D functional and the 6-311++G(2df,2pd) Pople basis set. Transition state theory with the Eckart tunneling correction was used to calculate the rate constants. The results show that the reaction involving the hydrogen labelled C4’ in the ribofuranose part has the largest rate constant for guanosine with the value 5.097×1010 L mol−1s−1 and the largest for uridine with the value 1.62×1010 L mol−1s−1. Based on the results for these two nucleosides, there is a noticeable similarity between the rate constants in the ribofuranose part of the molecule, even though they are bound to two entirely different nucleobases.

Background: Although GPs are usually the first port of call for patients with psoriasis, there is a lack of consistent and up-to-date clinical recommendations for interventions for patients with mild-to-moderate disease. Aim: To provide practical recommendations for GPs to optimise psoriasis treatment with topical therapies in four key areas: patient identification; treatment decision making with topical theory; topical treatment outcomes; and optimising patient adherence. Design & setting: A consensus-seeking programme (modified-Delphi approach) was undertaken to assess the literature and develop recommendations for GPs, based on evidence and expert opinion. Method: Three dermatologists compiled 47 questions that were subsequently ranked and refined according to clinical relevance or importance using an online survey. Thereafter, 19 dermatologists from different European countries developed statements and clinical recommendations for the top seven ranked topical treatment and GP-relevant questions based on literature research and clinical experience. The final recommendations were based on 100% agreement among a final panel of seven experts. Results: The clinical effectiveness, fast onset of action, tolerability, cosmetic acceptability, and practicability of topical therapy, in addition to good physician—patient communication, are important for optimising patient adherence and maximising efficacy. Topical treatments combining corticosteroids and vitamin D analogues (administered as fixed combination) are well-established first-line treatments in mild-to-moderate psoriasis. Conclusion: Simple but detailed practical guidance is provided, which is formed from evidence and expert clinical recommendations, to assist GPs with the optimal use of topical agents based on efficacy, tolerability, disease severity, site of psoriasis, patient lifestyle and preferences, and intended duration of treatment.

Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders. Keywords: O-GlcNAc signaling, Type 2 diabetes, N-acetyl-d-glucosamine, Tissue cross talk, Epigenetic regulation of Il15 transcription, Insulin sensitivity

The spleen is thought to play a role in atherosclerosis-associated immunity and cardiovascular research has indicated the existence of a cardio-splenic axis. The aim of this study was to assess splenic 18F-fluorodeoxyglucose uptake as a measure of systemic inflammation in patients with untreated psoriasis compared with historical controls assessed by positron emission tomography-computed tomography. Patients with moderate-to-severe psoriasis (n = 12, age 61.4 ± 4.1 years, 83% men, mean Psoriasis Area Severity Index score of 14.5) and controls (n = 23, age 60.4 ± 4.5 years, 87% men) were included in the study. Splenic inflammation was measured using the background-corrected spleen-liver-ratio (SLR) based on mean standardized uptake values. Mean ± SD SLR was increased in patients with psoriasis compared with controls (0.94 ± 0.11 vs. 0.82 ± 0.08; p = 0.001). SLR was significantly associated with aortic inflammation. These results support the existence of systemic inflammation in patients with psoriasis, and provide the rationale for a mechanistic link between psoriasis-driven inflammation and cardiovascular comorbidity through a spleen-atherosclerotic axis.

Objective: To determine the effect of common beverages and accelerated aging on the colour stability of filled resins, which could potentially be used for fabrication of 3D‐printed orthodontic brackets. Materials and Methods: GR‐17.1 (shades A1, A2, and A3), and GR‐10 Guide resins (pro3dure medical, Eden Prairie, MN) were printed on an Asiga MAX UV printer into discs 2 mm thick, with a diameter of 10 mm, and then post‐print processed as per manufacturer's instructions. Discs were immersed in 5 mL of coffee, tea, red wine, or distilled water for 7 days. Another group was subjected to accelerated aging in accordance with ISO Standard 4892‐2. Ten samples were produced per resin, per treatment condition. Colour measurements were taken on the discs before and after treatment using a spectrophotometer against white and black reference tiles to assess colour and translucency differences with the CIEDE2000 colour difference formula. Results: While initial colour of the printed resin discs was acceptable, all resin groups underwent significant colour change during the experiment. Red wine and coffee produced the greatest colour and translucency change, followed by tea, with accelerated aging producing the least change in colour and translucency. Conclusion: The 3D‐printed resins tested underwent significant changes in colour and translucency following exposure to endogenous and exogenous sources of staining, which may affect their acceptability for fabrication of aesthetic orthodontic brackets. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of printing material and air abrasion of bracket pads on the shear bond strength of 3D‐printed plastic orthodontic brackets when bonded to the enamel of extracted human teeth. Materials and Methods: Premolar brackets were 3D‐printed using the design of a commercially available plastic bracket in two biocompatible resins: Dental LT Resin and Dental SG Resin (n = 40/material). 3D‐printed brackets and commercially manufactured plastic brackets were divided into two groups (n = 20/group), one of which was air abraded. All brackets were bonded to extracted human premolars, and shear bond strength tests were performed. The failure types of each sample were classified using a 5‐category modified adhesive remnant index (ARI) scoring system. Results: Bracket material and bracket pad surface treatment presented statistically significant effects for shear bond strengths, and a significant interaction effect between bracket material and bracket pad surface treatment was observed. The non‐air abraded (NAA) SG group (8.87 ± 0.64 MPa) had a statistically significantly lower shear bond strength than the air abraded (AA) SG group (12.09 ± 1.23 MPa). In the manufactured brackets and LT Resin groups, the NAA and AA groups were not statistically significantly different within each resin. A significant effect of bracket material and bracket pad surface treatment on ARI score was observed, but no significant interaction effect between bracket material and pad treatment was found. Conclusion: 3D‐printed orthodontic brackets presented clinically sufficient shear bond strengths both with and without AA prior to bonding. The effect of bracket pad AA on shear bond strength depends on the bracket material. [ABSTRACT FROM AUTHOR]