Revealing the Progression of Pain Pathways and Identifying Chronification of Pain Predictors After an Isolated Lateral Ankle Sprain: Project RECOIL

Kyle B Kosik,1 Matthew C Hoch,1 Ilana Patlan,1 Stacey Slone,2 Danielle M Torp,1 Joshua J Van Wyngaarden,3 Megan H Roach4– 6 1Department of Athletic Training & Clinical Nutrition – Sports Medicine Research Institute, University of Kentucky, Lexington, KY, 40536, USA; 2Dr Bing Zhang Department of Statistics, University of Kentucky, Lexington, KY, 40536, USA; 3Army-Baylor University, Doctoral Program of Physical Therapy, Baylor University, San Antonio, TX, USA; 4Extremity Trauma and Amputation Center of Excellence, Defense Health Agency, Falls Church, VA, 22042, USA; 5Department of Clinical Investigations, Womack Army Medical Center, Fort Bragg, NC, 28310, USA; 6Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USACorrespondence: Kyle B Kosik, Department of Athletic Training & Clinical Nutrition – Sports Medicine Research Institute, University of Kentucky, Lexington, KY, 40536, USA, Tel +1-859-323-9850, Email [email protected]: Persistent pain is a common complaint among civilians and military personnel after a lateral ankle sprain (LAS). Most individuals who experience pain after an LAS self-report a moderate pain intensity level that interferes with activity. This pain experience is mostly described through study designs and outcomes that limit the understanding of the acute to chronic pain transition after an LAS. The purpose of this prospective study is to quantify the prevalence rate of chronic ankle pain at 6-months post-injury and identify susceptibility and resiliency factors that contribute to pain chronification after an LAS. The objective of this study will be accomplished through a two-site prospective cohort study design with data collected at four timepoints (< 7 days post-LAS, 3-, 6-, and 12-months post-LAS). A target sample size of 200 men or women (100 per site) between 18 and 45 years of age who sustain an acute LAS within the previous 7-days will be enrolled. Participants will complete a series of standardized electronic surveys at each timepoint to self-report the presence of chronic ankle pain, healthcare utilization patterns, subsequent musculoskeletal injury, and new co-morbid conditions. Additionally, participants will complete validated patient-reported outcomes (PROs) electronically to characterize the pain burden and undergo quantitative sensory testing to assess mechanical pain sensitivity via pressure pain thresholds, pain facilitation via temporal summation, and pain inhibition via a conditioned pain modulation response at all timepoints. Lastly, clinician-based outcomes will be completed at 3-, 6-, and 12-months post-LAS to examine dynamic postural control, functional performance, and walking mechanics. We hypothesize that 30% of participants will self-report chronic ankle pain at 6-months post-injury. In addition, chronic pain at 6-months will be predicted by a combination of healthcare utilization patterns, prolonged levels of peripheral sensitization and pain facilitation, and worse functional performance and PROs.Keywords: comorbidity, epidemiology, dynamic balance, healthcare utilization, patient-reported outcomes, prospective, observational, quantitative sensory techniques, walkin

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Summary Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Necessary condition for the existence of an intertwining operator and classification of transmutations on its basis

The authors study second-order ordinary differential operators with functional coefficients for all derivatives and the Volterra integral operator with a definite kernel. Results of the paper establish a hyperbolic equation and additional conditions that allow one to construct a kernel according to the OD

Predictors of Shoulder Pain and Disability Index (SPADI) and work status after 1 year in patients with subacromial shoulder pain

<p>Abstract</p> <p>Background</p> <p>Shoulder pain is a common complaint in primary health care and has an unfavourable outcome in many patients. The objectives were to identify predictors for pain and disability (SPADI) and work status in patients with subacromial shoulder pain.</p> <p>Methods</p> <p>Secondary analyses of data from a randomized clinical controlled trial were performed. Outcome measures were the absolute values of the combined Shoulder Pain and Disability Index (SPADI) and work status 1 year after treatment with supervised exercises (SE) or radial extracorporeal shockwave therapy (rESWT). Predictors of outcome were investigated using multiple linear regression (SPADI) and logistic regression (work status).</p> <p>Results</p> <p>104 patients were included. Low education (≤ 12 years), previous shoulder pain, and a high baseline SPADI score predicted poor results with these variables explaining 29.9% of the variance in SPADI score at 1 year. Low education and poor self-reported health status predicted a work status of "not working": Odds Ratio, OR = 4.3(95% CI (1.3 to 14.9)), p = 0.02 for education, and OR = 1.06 (95% CI (1.0 to 1.1)), p = 0.001 for self-reported health status, respectively. Adjustments for age, gender, and treatment group were performed, but did not change the results.</p> <p>Conclusion</p> <p>Education was the most consistent predictor of pain and disability, and work status at 1 year follow-up. Also, baseline SPADI score, previous shoulder pain and self-reported health status predicted outcome.</p> <p>Trial registration</p> <p>Clinical trials NCT00653081</p

Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome

Jet modification via π 0 -hadron correlations in Au+Au collisions at √sNN = 200 GeV

High-momentum two-particle correlations are a useful tool for studying jet-quenching effects in the quark-gluon plasma. Angular correlations between neutral-pion triggers and charged hadrons with transverse momenta in the range 4–12 GeV/c and 0.5–7 GeV/c, respectively, have been measured by the PHENIX experiment in 2014 for Au+Au collisions at √sNN = 200 GeV. Suppression is observed in the yield of high-momentum jet fragments opposite the trigger particle, which indicates jet suppression stemming from in-medium partonic energy loss, while enhancement is observed for low-momentum particles. The ratio and differences between the yield in Au+Au collisions and p+p collisions, IAA and ∆AA, as a function of the trigger-hadron azimuthal separation, ∆ϕ, are measured for the first time at the Relativistic Heavy Ion Collider. These results better quantify how the yield of low-pT associated hadrons is enhanced at wide angle, which is crucial for studying energy loss as well as medium-response effects

Systematic study of nuclear effects in p+Al, p+Au, d+Au, and 3He+Au collisions at √sNN = 200 GeV using π 0 production

The PHENIX collaboration presents a systematic study of inclusive π 0 production from p+p, p+Al, p+Au, d+Au, and 3He+Au collisions at √sNN = 200 GeV. Measurements were performed with different centrality selections as well as the total inelastic, 0%–100%, selection for all collision systems. For 0%–100% collisions, the nuclear-modification factors, RxA, are consistent with unity for pT above 8 GeV/c, but exhibit an enhancement in peripheral collisions and a suppression in central collisions. The enhancement and suppression characteristics are similar for all systems for the same centrality class. It is shown that for high-pT -π 0 production, the nucleons in the d and 3He interact mostly independently with the Au nucleus and that the counter intuitive centrality dependence is likely due to a physical correlation between multiplicity and the presence of a hard scattering process. These observations disfavor models where parton energy loss has a significant contribution to nuclear modifications in small systems. Nuclear modifications at lower pT resemble the Cronin effect – an increase followed by a peak in central or inelastic collisions and a plateau in peripheral collisions. The peak height has a characteristic ordering by system size as p+Au > d+Au > 3He+Au > p+Al. For collisions with Au ions, current calculations based on initial state cold nuclear matter effects result in the opposite order, suggesting the presence of other contributions to nuclear modifications, in particular at lower pT

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe