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Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression., Competing Interests: Declaration of interests R.G.M. and J.L.N. serve on the scientific advisory board for Veralox Therapeutics. J.L.N. is a co-inventor on a patent for selective inhibitors of 12-lipoxygenase., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this overview is to discuss the development, implementation, data content, and structure of the Uniformed Services University Pain Registry Biobank. Additionally, procedures and policies for accessing samples for pain-related research purposes are detailed., Design: Cross-sectional overview., Setting: Multiple military treatment facilities., Subjects: Adult beneficiaries seeking care within the Military Health System., Methods: Participants complete a baseline battery of biopsychosocial survey measures, including Patient-Reported Outcomes Measurement Information System (PROMIS®) measures, and provide biological samples (e.g., blood and saliva). Relevant health history, including medications and surgical history, is extracted from medical records. During the course of the subsequent year, enrolled participants complete surveys and provide biological samples at 3 months, 6 months, and 12 months. Thereafter, participants are contacted once annually to complete self-reported assessments and provide biological samples., Results: In the first year alone, 86 subjects have participated in the Uniformed Services University Pain Registry Biobank and provided 390 observations (e.g., biological samples and biopsychosocial patient-reported outcomes). The Uniformed Services University Pain Registry Biobank's integration of biological samples, patient-reported outcomes, and health record data over a longitudinal period across a diverse sample recruited from multiple military facilities addresses many of the limitations faced by other pain-related registries or biorepositories., Conclusions: The Uniformed Services University Pain Registry Biobank will serve as a platform for conducting research closely aligned with the Federal Pain Research Strategy. The inclusion of active duty service members, beneficiaries, and civilians living with and without acute or chronic pain provides a unique data repository for all investigators interested in advancing pain science., (Published by Oxford University Press on behalf of the American Academy of Pain Medicine.)

Objective: Many studies have documented significant associations between religion and spirituality (R/S) and health, but relatively few prospective analyses exist that can support causal inferences. To date, there has been no systematic analysis of R/S survey items collected in US cohort studies. We conducted a systematic content analysis of all surveys ever fielded in 20 diverse US cohort studies funded by the National Institutes of Health (NIH) to identify all R/S-related items collected from each cohort's baseline survey through 2014., Design: An R|S Ontology was developed from our systematic content analysis to categorise all R/S survey items identified into key conceptual categories. A systematic literature review was completed for each R/S item to identify any cohort publications involving these items through 2018., Results: Our content analysis identified 319 R/S survey items, reflecting 213 unique R/S constructs and 50 R|S Ontology categories. 193 of the 319 extant R/S survey items had been analysed in at least one published paper. Using these data, we created the R|S Atlas (https://atlas.mgh.harvard.edu/), a publicly available, online relational database that allows investigators to identify R/S survey items that have been collected by US cohorts, and to further refine searches by other key data available in cohorts that may be necessary for a given study (eg, race/ethnicity, availability of DNA or geocoded data)., Conclusions: R|S Atlas not only allows researchers to identify available sources of R/S data in cohort studies but will also assist in identifying novel research questions that have yet to be explored within the context of US cohort studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A high index of suspicion is needed to initiate appropriate testing for tuberculosis due to its protean symptoms, yet health-care providers in low-incidence settings are becoming less familiar with the disease as rates decline. We aimed to estimate delays in tuberculosis diagnosis and treatment at the US national level between 2008 and 2016., Methods: In this retrospective observational cohort study, we repurposed private insurance claims data provided by Aetna (Connecticut, USA), to measure health-care delays in tuberculosis diagnosis in the USA in 2008-16. Active tuberculosis was determined by diagnosis codes and the filling of anti-tuberculosis treatment prescriptions. Health-care delays were defined as the duration between the first health-care visit for a tuberculosis symptom and the initiation of anti-tuberculosis treatment. We assessed if delays varied over time, and by patient and system variables, using multivariable regression. We estimated household tuberculosis transmission and respiratory complications after treatment initiation., Findings: We confirmed 738 active tuberculosis cases (incidence 1·45 per 100 000 person-years) with a median health-care delay of 24 days (IQR 10-45). Multivariable regression analysis showed that longer delays were associated with older age (8·4% per 10 year increase [95% CI 4·0 to 13·1]; p<0·0086) and non-HIV immunosuppression (19·2% [15·1 to 60·0]; p=0·0432). Presenting with three or more symptoms was associated with a shorter delay (-22·5% [-39·1 to -2·0]; p=0·0415), relative to presenting with one symptom, as did use of chest imaging (-24·9% [-37·9 to -8·9]; p<0·0098), tuberculosis nucleic acid amplification tests (-19·2% [-32·7 to -3·1]; p=0·0241), and care by a tuberculosis specialist provider (-17·2% [-33·1 to -22·3]; p<0·0087). Longer delays were associated with an increased rate of respiratory complications even after controlling for patient characteristics, and an increased rate of secondary tuberculosis among dependents., Interpretation: In the USA, the median health-care delay for privately insured patients with tuberculosis exceeds WHO-recommended levels of 21 days (3 weeks). The results suggest the need for health-care provider education on best practices in tuberculosis diagnosis, including the use of molecular tests and the maintenance of a high index of suspicion for the disease., Funding: US National Institutes of Health., Competing Interests: Declaration of interests KF reports personal fees from Aetna, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The aim of this study was to develop a simple method to map the French International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) with the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10 CM). We sought to map these terminologies forward (ICD-10 to ICD-10 CM) and backward (ICD-10 CM to ICD-10) and to assess the accuracy of these two mappings. We used several terminology resources such as the Unified Medical Language System (UMLS) Metathesaurus, Bioportal, the latest version available of the French ICD-10 and several official mapping files between different versions of the ICD-10. We first retrieved existing partial mapping between the ICD-10 and the ICD-10 CM. Then, we automatically matched the ICD-10 with the ICD-10-CM, using our different reference mapping files. Finally, we used manual review and natural language processing (NLP) to match labels between the two terminologies. We assessed the accuracy of both methods with a manual review of a random dataset from the results files. The overall matching was between 94.2 and 100%. The backward mapping was better than the forward one, especially regarding exact matches. In both cases, the NLP step was highly accurate. When there are no available experts from the ontology or NLP fields for multi-lingual ontology matching, this simple approach enables secondary reuse of Electronic Health Records (EHR) and billing data for research purposes in an international context.

Objective: To determine if the perioperative administration of valproic acid reduces the incidence of chronic pain three months after amputation or revision surgery., Design: Multicenter, randomized, double-blind, placebo-controlled trial., Setting: Academic, military, and veteran medical centers., Subjects: One hundred twenty-eight patients undergoing amputation or amputation revision surgery at Duke University Hospital, Walter Reed National Military Medical Center, or the Durham Veterans Affairs Medical Center for either medical disease or trauma., Methods: Patients were randomized to placebo or valproic acid for the duration of hospitalization and treated with multimodal analgesic care, including regional anesthetic blockade. Primary outcome was the proportion of patients with chronic pain at three months (average numeric pain score intensity of 3/10 or greater). Secondary outcomes included functional trajectories (assessed with the Brief Pain Inventory short form and the Defense and Veterans Pain Rating Scale)., Results: The overall rate of chronic pain was 68.2% in the 107 patients who completed the end point assessment. There was no significant effect of perioperative valproic acid administration, with a rate of 65.45% (N = 36) in the treatment group and a rate of 71.15% (N = 37) in the placebo group. Overall, pain scores decreased from baseline to follow-up (median = -2 on the numeric pain scale). Patients additionally experienced improvements in self-perceived function., Conclusions: The rate of chronic pain after amputation surgery is not significantly improved with the perioperative administration of valproic acid. In this cohort treated with multimodal perioperative analgesia and regional anesthetic blockade, we observed improvements in both pain severity and function., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chronic postsurgical pain impacts most amputees, with more than half experiencing neuralgic residual limb pain. The transition from normal acute postamputation pain to chronic residual limb pain likely involves both peripheral and central inflammatory mechanisms. As part of the Veterans Integrated Pain Evaluation Research study, we investigated links between systemic inflammatory mediator levels and chronic residual limb pain. Subjects included 36 recent active duty military traumatic amputees with chronic residual limb pain and 40 without clinically significant pain. Blood samples were obtained and plasma concentrations of an array of inflammatory mediators were analyzed. Residual limb pain intensity and pain catastrophizing were assessed to examine associations with inflammatory mediators. Pro-inflammatory mediators including tumor necrosis factor (TNF)-α, TNF-β, interleukin (IL)-8, ICAM-1, Tie2, CRP, and SAA were elevated in patients with chronic residual limb pain. Across all patients, residual limb pain intensity was associated positively with levels of several proinflammatory mediators (IL-8, TNF-α, IL-12, TNF-β, PIGF, Tie2, SAA, and ICAM-1), and inversely with concentrations of the anti-inflammatory mediator IL-13, as well as IL-2 and Eotaxin-3. Pain catastrophizing correlated positively with IL-8, IL-12, TNF-β, PIGF, and ICAM-1, and inversely with IL-13. Significant associations between catastrophizing and residual limb pain intensity were partially mediated by TNF-α, TNF- β, SAA, and ICAM-1 levels. Results suggest that chronic postamputation residual limb pain is associated with excessive inflammatory response to injury or to inadequate resolution of the postinjury inflammatory state. Impact of pain catastrophizing on residual limb pain may be because of part to common underlying inflammatory mechanisms., Competing Interests: Authors have no financial conflicts of interest to report.

The National Health and Nutrition Examination Survey (NHANES) is a population survey implemented by the Centers for Disease Control and Prevention (CDC) to monitor the health of the United States whose data is publicly available in hundreds of files. This Data Descriptor describes a single unified and universally accessible data file, merging across 255 separate files and stitching data across 4 surveys, encompassing 41,474 individuals and 1,191 variables. The variables consist of phenotype and environmental exposure information on each individual, specifically (1) demographic information, physical exam results (e.g., height, body mass index), laboratory results (e.g., cholesterol, glucose, and environmental exposures), and (4) questionnaire items. Second, the data descriptor describes a dictionary to enable analysts find variables by category and human-readable description. The datasets are available on DataDryad and a hands-on analytics tutorial is available on GitHub. Through a new big data platform, BD2K Patient Centered Information Commons (http://pic-sure.org), we provide a new way to browse the dataset via a web browser (https://nhanes.hms.harvard.edu) and provide application programming interface for programmatic access., Competing Interests: The authors declare no competing financial interests.

Objective: To define clinical phenotypes of postamputation pain and identify markers of risk for the development of chronic pain., Design: Cross-sectional study of military service members enrolled 3-18 months after traumatic amputation injury., Setting: Military Medical Center., Subjects: 124 recent active duty military service members., Methods: Study subjects completed multiple pain and psychometric questionnaires to assess the qualities of phantom and residual limb pain. Medical records were reviewed to determine the presence/absence of a regional catheter near the time of injury. Subtypes of residual limb pain (somatic, neuroma, and complex regional pain syndrome) were additionally analyzed and associated with clinical risk factors., Results: A majority of enrolled patients (64.5%) reported clinically significant pain (pain score ≥ 3 averaged over previous week). 61% experienced residual limb pain and 58% experienced phantom pain. When analysis of pain subtypes was performed in those with residual limb pain, we found evidence of a sensitized neuroma in 48.7%, somatic pain in 40.8%, and complex regional pain syndrome in 19.7% of individuals. The presence of clinically significant neuropathic residual limb pain was associated with symptoms of PTSD and depression. Neuropathic pain of any severity was associated with symptoms of all four assessed clinical risk factors: depression, PTSD, catastrophizing, and the absence of regional analgesia catheter., Conclusions: Most military service members in this cohort suffered both phantom and residual limb pain following amputation. Neuroma was a common cause of neuropathic pain in this group. Associated risk factors for significant neuropathic pain included PTSD and depression. PTSD, depression, catastrophizing, and the absence of a regional analgesia catheter were associated with neuropathic pain of any severity., (Published by Oxford University Press on behalf of the American Academy of Pain Medicine. 2016. This work is written by US Government employees and is in the public domain in the US.)

In Type 1 diabetic (T1D) human monocytes, STAT5 aberrantly binds to epigenetic regulatory sites of two proinflammatory genes, CSF2 (encoding granulocyte-macrophage colony-stimulating factor) and PTGS2 (encoding prostaglandin synthase 2/cyclooxygenase 2). Bicongenic B6.NOD C11bxC1tb mice re-create this phenotype of T1D monocytes with only two nonobese diabetic (NOD) Idd subloci (130.8 Mb-149.7 Mb, of Idd5 on Chr 1 and 32.08-53.85 Mb of Idd4.3 on Chr11) on C57BL/6 genetic background. These two Idd loci interact through STAT5 binding at upstream regulatory regions affecting Csf2 (Chr 11) and Ptgs2 (Chr 1) expression. B6.NODC11bxC1tb mice exhibited hyperglycemia and immune destruction of pancreatic islets between 8 and 30 weeks of age, with 12%-22% penetrance. Thus, B6.NODC11bxC1tb mice embody NOD epigenetic dysregulation of gene expression in myeloid cells, and this defect appears to be sufficient to impart genetic susceptibility to diabetes in an otherwise genetically nonautoimmune mouse.

Background: Alignment of amino acid sequences is the main sequence comparison method used in computational molecular biology. The selection of the amino acid substitution matrix best suitable for a given alignment problem is one of the most important decisions the user has to make. In a conventional amino acid substitution matrix all elements are fixed and their values cannot be easily adjusted. Moreover, most existing amino acid substitution matrices account for the average (dis)similarities between amino acid types and do not distinguish the contribution of a specific biochemical property to these (dis)similarities., Findings: PR2ALIGN is a stand-alone software program and a web-server that provide the functionality for implementing flexible user-specified alignment scoring functions and aligning pairs of amino acid sequences based on the comparison of the profiles of biochemical properties of these sequences. Unlike the conventional sequence alignment methods that use 20x20 fixed amino acid substitution matrices, PR2ALIGN uses a set of weighted biochemical properties of amino acids to measure the distance between pairs of aligned residues and to find an optimal minimal distance global alignment. The user can provide any number of amino acid properties and specify a weight for each property. The higher the weight for a given property, the more this property affects the final alignment. We show that in many cases the approach implemented in PR2ALIGN produces better quality pair-wise alignments than the conventional matrix-based approach., Conclusions: PR2ALIGN will be helpful for researchers who wish to align amino acid sequences by using flexible user-specified alignment scoring functions based on the biochemical properties of amino acids instead of the amino acid substitution matrix. To the best of the authors' knowledge, there are no existing stand-alone software programs or web-servers analogous to PR2ALIGN. The software is freely available from http://pr2align.rit.albany.edu.