HERMES: Holographic Equivariant neuRal network model for Mutational Effect and Stability prediction.

Predicting the stability and fitness effects of amino acid mutations in proteins is a cornerstone of biological discovery and engineering. Various experimental techniques have been developed to measure mutational effects, providing us with extensive datasets across a diverse range of proteins. By training on these data, traditional computational modeling and more recent machine learning approaches have advanced significantly in predicting mutational effects. Here, we introduce HERMES, a 3D rotationally equivariant structure-based neural network model for mutational effect and stability prediction. Pre-trained to predict amino acid propensity from its surrounding 3D structure, HERMES can be fine-tuned for mutational effects using our open-source code. We present a suite of HERMES models, pre-trained with different strategies, and fine-tuned to predict the stability effect of mutations. Benchmarking against other models shows that HERMES often outperforms or matches their performance in predicting mutational effect on stability, binding, and fitness. HERMES offers versatile tools for evaluating mutational effects and can be fine-tuned for specific predictive objectives.

Comparison of Measurement and Prognostic Power of SUV Between High-Definition and Standard PET Imaging in Non-Small Cell Lung Cancer Patients.

This study aimed to evaluate the measurement and prognostic ability of the SUVmax of whole-body tumors (SUVmaxwb) in non-small cell lung cancer (NSCLC) patients, comparing high-definition (HD) PET imaging with standard-definition (SD) PET imaging. Methods: The study included 242 consecutive NSCLC patients who underwent baseline 18F-FDG PET/CT from April 2018 to January 2021. Two imaging techniques were used: HD PET (using ordered-subsets expectation maximization with point-spread function modeling and time-of-flight techniques and smaller voxels) and SD PET (with ordered-subsets expectation maximization and time-of-flight techniques). SUVmaxwb was determined by measuring all the tumor lesions in the whole body, and tumor-to-background ratio (TBR) was calculated using the background SUVmean of various body parts. Results: The patient cohort had an average age of 68.3 y, with 59.1% being female. During a median follow-up of 29.6 mo, 83 deaths occurred. SUVmaxwb was significantly higher in HD PET than SD PET, with respective medians of 17.4 and 11.8. The TBR of 1,125 tumoral lesions was also higher in HD PET. Univariate Cox regression analysis showed that SUVmaxwb from both HD and SD PET were significantly associated with overall survival. However, after adjusting for TNM (tumor, node, metastasis) stage, only SUVmaxwb from SD PET remained significantly associated with survival. Conclusion: HD PET imaging in NSCLC patients yields higher SUVmaxwb and TBR, enhancing tumor visibility. Despite this, its prognostic value is less significant than SD PET after adjusting clinical TNM stage. Thus, consideration should be given to using HD PET reconstruction to increase tumor visibility, and SD PET is recommended for NSCLC patient prognostication and therapeutic evaluation, as well as for the classification of lung nodules.

Patient preferences for systemic sclerosis treatment: A descriptive study within an Italian cohort.

Objectives: The aim of this study is to ascertain systemic sclerosis patients' preferences regarding the formulations of the medications they use. Methods: We undertook questionnaires and interviews aimed at understanding systemic sclerosis patients' preferences with respect to the medications they used. Results: Among 160 systemic sclerosis patients, we found that the majority does not have difficulty taking their medication. However, preferences were identified (81.25% - 65/80 - preferred oral meds and 47.50% - 38/80 - disliked rectal/vaginal meds), as well as some systemic sclerosis patients have significant difficulties using their medications. In fact, factors such as swallowing and fine finger motion difficulties were frequent, while intravenous/intramuscular/subcutaneous medicines were usually not preferred because they are felt as inconvenient (intravenous = 33.4% and subcutaneous/intramuscular = 10%) or painful (intravenous = 37.50% and subcutaneous/intramuscular = 10%). Conclusion: Most systemic sclerosis patients are able to take their medication despite having some difficulties. However, as there were clear preferences, we could improve patients' adherence to drug therapy if taking these preferences into account.

A protocol for a systematic review and meta-analysis to identify measures of breakthrough pain and evaluate their psychometric properties.

INTRODUCTION: Breakthrough pain is common in children and adults with cancer and other conditions, including those approaching end-of-life, although it is often poorly managed, possibly partly due to a lack of validated assessment tools. This review aims to (1) identify all available instruments measuring breakthrough pain in infants, children, adolescents or adults and (2) critically appraise, compare and summarise the quality of the psychometric properties of the identified instruments using COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. METHODS AND ANALYSIS: Two searches will be carried out between October 2019 and January 2020, one for each aim of the review. The Cochrane Library, International Prospective Register of Systematic Reviews, Embase, Cumulative Index of Nursing and Allied Health Literature, Medical Literature Analysis and Retrieval System Online (MEDLINE), PsycINFO, Web of Science Core Collection, Google Scholar, the ProQuest Dissertations & Theses Database, Evidence Search and OpenGrey databases will be searched from database inception until the date the search is conducted. Reference lists of eligible articles will be screened and authors in the field contacted. For search 1, articles will be screened by two reviewers by abstract, and full-text where necessary, to identify if a breakthrough pain assessment was used. Search 2 will then be conducted to identify studies evaluating measurement properties of these assessments. Two reviewers will screen articles from search 2 by title and abstract. All potentially relevant studies will be screened by full text by both reviewers. For search 2, data will be extracted in parallel with the quality assessment process, as recommended by COSMIN. Two reviewers will assess methodological quality using the COSMIN Risk of Bias checklist and the COSMIN updated criteria for good measurement properties. Findings will be summarised and, if possible, data will be pooled using meta-analysis. The quality of the evidence will be graded and summarised using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) guidelines. ETHICS AND DISSEMINATION: Results of this review will be submitted for publication in a peer review journal and presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42019155583.

Internet-delivered attentional bias modification training (iABMT) for the management of chronic musculoskeletal pain: a protocol for a randomised controlled trial.

INTRODUCTION: Chronic musculoskeletal pain is a complex medical condition that can significantly impact quality of life. Patients with chronic pain demonstrate attentional biases towards pain-related information. The therapeutic benefits of modifying attentional biases by implicitly training attention away from pain-related information towards neutral information have been supported in a small number of published studies. Limited research however has explored the efficacy of modifying pain-related biases via the internet. This protocol describes a randomised, double-blind, internet-delivered attentional bias modification intervention, aimed to evaluate the efficacy of the intervention on reducing pain interference. Secondary outcomes are pain intensity, state and trait anxiety, depression, pain-related fear, and sleep impairment. This study will also explore the effects of training intensity on these outcomes, along with participants' perceptions about the therapy. METHODS AND ANALYSIS: The study is a double-blind, randomised controlled trial with four arms exploring the efficacy of online attentional bias modification training versus placebo training theorised to offer no specific therapeutic benefit. Participants with chronic musculoskeletal pain will be randomised to one of four groups: (1) 10-session attentional modification group; (2) 10-session placebo training group; (3) 18-session attentional modification group; or (4) 18-session placebo training group. In the attentional modification groups, the probe-classification version of the visual-probe task will be used to implicitly train attention away from threatening information towards neutral information. Following the intervention, participants will complete a short interview exploring their perceptions about the online training. In addition, a subgroup analysis for participants aged 16-24 and 25-60 will be undertaken. ETHICS AND DISSEMINATION: This study has been approved by the University of Southampton Research Ethics Committee. Results will be published in peer-reviewed journals, academic conferences, and in lay reports for pain charities and patient support groups. TRIAL REGISTRATION NUMBER: NCT02232100; Pre-results.

Association between quantitative sensory testing and pain or disability in paediatric chronic pain: protocol for a systematic review and meta-analysis.

INTRODUCTION: This protocol describes the objective and methods of a systematic review of the association between quantitative sensory testing (QST) measures and pain intensity or disability in paediatric chronic pain (PCP). The review will also assess whether the relationship strength is moderated by variables related to the QST method and pain condition; the use of QST in PCP (modalities, outcome measures and anatomical test sites as well as differentiating between pain mechanisms (eg, neuropathic vs nociceptive) and in selecting analgesics); the reliability of QST across the paediatric age range; the ability of QST to differentiate patients with chronic pain from healthy controls; and differences between anatomical test sites. METHODS AND ANALYSIS: Medline, PsycINFO, CINHAL, Web of Science, Scopus, Cochrane Library and OpenGrey will be searched. English language studies will be eligible if they recruit a sample aged 6-24 (inclusive) with chronic pain, including primary and secondary pain; apply at least one of the following QST modalities: chemical, electrical, mechanical (subgroups include pressure, punctate/brush and vibratory) or thermal stimulus to measure perception of noxious or innocuous stimuli applied to skin, muscle or joint; use a testing protocol to control for stimulus properties: modality, anatomical site, intensity, duration and sequence. Following title and abstract screening, the full texts of relevant records will be independently assessed by two reviewers. For eligible studies, one reviewer will extract study characteristics and data, and another will check for accuracy. Both will undertake independent quality assessments using the Appraisal Tool for Cross-Sectional Studies. A qualitative synthesis will be presented with discussion centred around different QST modalities. Where eligible data permit, meta-analyses will be performed separately for different QST modalities using comprehensive meta-analysis. ETHICS AND DISSEMINATION: Review findings will be reported in a peer-reviewed journal and presented at conferences. The study raises no ethical issues. PROSPERO REGISTRATION NUMBER: CRD42019134069.

Barriers and facilitators experienced by patients, carers and healthcare professionals when managing symptoms in infants, children and young people at end-of-life: a mixed methods systematic review protocol.

INTRODUCTION: This protocol describes the objective and methods of a systematic review of barriers and facilitators experienced by patients, carers and healthcare professionals when managing symptoms in infants, children and young people (ICYP) at end-of-life. METHODS AND ANALYSIS: The Cochrane Library, PROSPERO, CINAHL, MEDLINE, PsycINFO, Web of Science Core Collection, ProQuest Dissertations & Theses Database, Evidence Search and OpenGrey will be electronically searched. Reference screening of relevant articles and inquiries to researchers in the field will be undertaken. Studies will be selected if they apply qualitative, quantitative or mixed-methods designs to explore barriers and facilitators experienced by patients, carers and healthcare professionals when managing symptoms in ICYP at end-of-life.Articles will be screened by title and abstract by one reviewer with a second reviewer assessing 10% of the articles. Both reviewers will read and screen all remaining potentially relevant articles. For included articles, one reviewer will extract study characteristics and one will check this.Both reviewers will undertake independent quality assessments of included studies using established and appropriate checklists including The Critical Appraisal Skills Programme Qualitative Checklist; The evaluative criteria of credibility, transferability, dependability and confirmability; The Quality Assessment Tool for Quantitative Studies, and The Mixed Methods Appraisal Tool. Data synthesis methods will be decided after data extraction and assessment. ETHICS AND DISSEMINATION: This review will inform our understanding of symptom management in ICYP at end-of-life. The findings will be reported in a peer-reviewed journal and presented at conferences. The study raises no ethical issues. PROSPERO REGISTRATION NUMBER: CRD42019124797.

Effectiveness of interdisciplinary interventions in paediatric chronic pain management: a systematic review and subset meta-analysis.

BACKGROUND: Paediatric chronic pain is a significant problem that can have devastating impacts on quality of life. Multimodal interdisciplinary interventions are the mainstay of paediatric treatment. The aim of this article is to provide a comprehensive review of the effectiveness of interdisciplinary interventions in the management of paediatric chronic pain. METHODS: Studies were identified via a search of nine databases. The search strategy included concept blocks pertaining to type of pain, study population, and type of intervention. Eligible studies reported the effects of an intervention co-ordinated by two or more healthcare professionals of different disciplines, and recruited a sample aged 22 yr or below with chronic pain. Twenty-eight studies were included, and 21 provided data for inclusion in between- and within-groups meta-analyses. RESULTS: Patients randomised to interdisciplinary interventions reported significantly lower pain intensity 0-1 month post-intervention compared with patients randomised to the control groups. Within-groups analysis of patients receiving interdisciplinary interventions showed significant improvements pre- to post-intervention in pain intensity, functional disability, anxiety, depression, catastrophising, school attendance, school functioning, and pain acceptance. Few differences were found between interventions delivered in inpatient vs outpatient settings. Significant heterogeneity due mainly to differing outcome variables and intervention content was found in most analyses. CONCLUSIONS: Overall, interdisciplinary interventions show promise in providing a range of clinical benefits for children with chronic pain. Methodologically robust randomised controlled trials using standardised outcome measures are needed, however, to guide clinical care.

Small bowel obstruction with multiple perforations post chestnut ingestion.

Phytobezoars are a rare cause of small bowel obstruction (SBO), which consists of vegetable matter such as seeds, skins, fibres of fruit and vegetables that have solidified. We present the case of a 61-year-old man with no previous surgery who presented with central abdominal pain, nausea and vomiting. An abdominal CT scan demonstrated SBO with a transition point in the left anterior abdomen. He proceeded to a laparoscopy, which revealed multiple perforations throughout the small bowel, from the proximal jejunum to the terminal ileum. Laparotomy was performed, and undigested chestnuts were milked out through the largest perforation and the perforations were oversewn. While obstruction due to phytobezoars is rare, this case demonstrates the importance of considering small bowel trauma and perforation due to phytobezoars and highlights the need for close inspection of the entire gastrointestinal tract for complications in the setting of phytobezoar-related bowel obstruction.

Incidence of pulmonary embolism in patients with newly diagnosed colorectal cancer.

BACKGROUND: Studies have suggested a benefit from extended venous thromboprophylaxis post-operatively in colorectal cancer with an assumed base rate of zero venous thromboembolic events prior to treatment. We aim to establish the incidence of pulmonary embolism in patients with newly diagnosed stage III or IV colorectal cancer prior to any treatment. METHOD: Consecutive patients presenting to a single health service with a new diagnosis of stage III or IV colorectal cancer were identified from a prospective database, for the period between January 2011 and September 2014. Contemporaneous clinical data was reviewed. Included patients had a computerized tomography (CT) chest scan for pre-operative staging for cancer. The diagnosis of pulmonary emboli was made on chest CT. RESULTS: Of 330 patients identified, 224 had baseline CT chest imaging available for review, of which 107 (47.8%) were technically adequate scans. Pulmonary emboli were identified on five (4.7%) of these 107, including one of five patients (1.7%) with stage III and four of five patients (8.3%) with stage IV disease. None of the 107 patients with adequate scans had post-operative pulmonary emboli or deep vein thrombosis. CONCLUSION: There is a clinically significant baseline rate of asymptomatic pulmonary emboli in patients with stage III and IV colorectal cancer that can be demonstrated on the staging chest CT scan. Pulmonary emboli described as a post-operative event in previous series may have been present prior to surgery.

The evolution of no-cost resistance at sub-MIC concentrations of streptomycin in Streptomyces coelicolor.

At the high concentrations used in medicine, antibiotics exert strong selection on bacterial populations for the evolution of resistance. However, these lethal concentrations may not be representative of the concentrations bacteria face in soil, a recognition that has led to questions of the role of antibiotics in soil environments as well as the dynamics of resistance evolution during sublethal challenge. Here we examine the evolution of resistance to sub-minimal inhibitory concentrations (sub-MIC) of streptomycin in the filamentous soil bacterium Streptomyces coelicolor. First, we show that spontaneous resistance to streptomycin causes an average fitness deficit of ~21% in the absence of drugs; however, these costs are eliminated at concentrations as low as 1/10 the MIC of susceptible strains. Using experimental evolution, we next show that resistance to >MIC levels of streptomycin readily evolves when bacteria are exposed to sub-MIC doses for 500 generations. Furthermore, the resistant clones that evolved at sub-MIC streptomycin concentrations carry no fitness cost. Whole-genome analyses reveal that evolved resistant clones fixed some of the same mutations as those isolated at high drug concentrations; however, all evolved clones carry additional mutations and some fixed mutations that either compensate for costly resistance or have no associated fitness costs. Our results broaden the conditions under which resistance can evolve in nature and suggest that rather than low-concentration antibiotics acting as signals, resistance evolves in response to antibiotics used as weapons.

Endoscopic balloon dilatation of Crohn's strictures: a safe method to defer surgery in selective cases.

BACKGROUND: Endoscopic balloon dilatation (EBD) provides a valuable alternative to surgery for strictures in Crohn's disease (CD). Data are lacking regarding the factors that improve the safety and effectiveness of EBD in CD. The aim of this study is to determine the safety and efficacy of EBD and the clinical variables, which are predictive of successful treatment of CD strictures with EBD. METHODS: The records of all patients with CD in whom EBD was attempted between 2008 and 2013 were reviewed. Procedures were conducted at a single tertiary referral centre using a Boston Scientific CRE® TTS balloon. Technical success was defined as the ability to traverse the stricture with the endoscope and clinical success as the resolution of obstructive symptoms at review. RESULTS: Forty-seven patients with a total of 58 strictures (19 primary and 39 anastomotic strictures) were treated with EBD with median follow-up of 37 months. A total of 161 dilatation procedures were performed, with technical success reported in 139/158 (88%) cases and clinical success reported in 105/137 (76.7%) cases with complete data. Complications occurred in 7/161 dilatations (4.3% dilatations, 15% patients), three patients with perforation, one with acute bleeding and three admitted with abdominal pain. Eighteen of the 47 patients required surgery (38%). Strictures of <50 mm (P = 0.04) and those dilated to a diameter of ≥15 mm (P = 0.031) were less likely to require surgical resection. CONCLUSIONS: EBD is safe for both primary and post-surgical strictures. Stricture length and diameter of dilatation are predictive of success. In selected patients, treatment with EBD may reduce or delay the need for surgery.

Approximating the Generalized Voronoi Diagram of Closely Spaced Objects.

We present an algorithm to compute an approximation of the generalized Voronoi diagram (GVD) on arbitrary collections of 2D or 3D geometric objects. In particular, we focus on datasets with closely spaced objects; GVD approximation is expensive and sometimes intractable on these datasets using previous algorithms. With our approach, the GVD can be computed using commodity hardware even on datasets with many, extremely tightly packed objects. Our approach is to subdivide the space with an octree that is represented with an adjacency structure. We then use a novel adaptive distance transform to compute the distance function on octree vertices. The computed distance field is sampled more densely in areas of close object spacing, enabling robust and parallelizable GVD surface generation. We demonstrate our method on a variety of data and show example applications of the GVD in 2D and 3D.

VolRoverN: enhancing surface and volumetric reconstruction for realistic dynamical simulation of cellular and subcellular function.

Establishing meaningful relationships between cellular structure and function requires accurate morphological reconstructions. In particular, there is an unmet need for high quality surface reconstructions to model subcellular and synaptic interactions among neurons and glia at nanometer resolution. We address this need with VolRoverN, a software package that produces accurate, efficient, and automated 3D surface reconstructions from stacked 2D contour tracings. While many techniques and tools have been developed in the past for 3D visualization of cellular structure, the reconstructions from VolRoverN meet specific quality criteria that are important for dynamical simulations. These criteria include manifoldness, water-tightness, lack of self- and object-object-intersections, and geometric accuracy. These enhanced surface reconstructions are readily extensible to any cell type and are used here on spiny dendrites with complex morphology and axons from mature rat hippocampal area CA1. Both spatially realistic surface reconstructions and reduced skeletonizations are produced and formatted by VolRoverN for easy input into analysis software packages for neurophysiological simulations at multiple spatial and temporal scales ranging from ion electro-diffusion to electrical cable models.

Avoidable morbidity in a patient with pseudoaneurysm of the uterine artery after cesarean section.

We report the case of a 25-year-old female who presented to the emergency department with vaginal bleeding after a cesarean section. A diagnosis of pseudoaneurysm of the uterine artery was established radiologically; however, failure to consider this potentially life-threatening complication of cesarean section resulted in unnecessary morbidity. Doppler sonography and CT have been shown to be excellent tools for accurate diagnosis of uterine artery pseudoaneurysms, and selective arterial embolization remains the intervention of choice.