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It is an unmet need to estimate survival duration for patients with progressive supranuclear palsy (PSP). The objective of this study was to identify factors associated with the survival duration in patients with PSP. We followed up 23 patients with probable PSP-RS (Richardson syndrome) or PSP-P (parkinsonism) in our PSP center until death from 2011 to 2019. We prospectively and quantitatively rated their downgaze palsy whenever first noticed in our clinic. This was utilized along with the disease duration, motor function, medication use for parkinsonism, sex, age at onset of PSP, comorbid pulmonary and cardiovascular diseases, and the total survival duration from the onset of PSP to death for prediction analysis. A well-fitted linear regression model and a multivariant Cox model were applied to identify predicting factors for total survival duration. All patients had the specific hummingbird sign on brain MRI for PSP when downgaze palsy was documented. We found that the severity of downgaze palsy and the disease duration at the assessment were consistently correlated with the total survival duration in both models. The total survival duration could be further estimated by a formed regression equation. We conclude that severity and time to develop downgaze palsy could help to estimate the total survival duration in patients with probable PSP-RS and PSP-P, the major forms of PSP, which has significant clinical applications in clinical counseling and trial enrollment.

Aspiration secondary to impaired swallow function, or dysphagia, is one of the major causes of mortality in patients with Parkinson’s disease (PD). Dysphagia usually does not respond well to medications. Despite its effectiveness on motor fluctuation, dyskinesia and tremor in patients with PD, deep brain stimulation (DBS) is not as effective on axial symptoms of balance, freezing of gait (FOG), speech and swallow function. Studies even raise concerns about axial symptoms under usual high-frequency stimulation (HFS) of the subthalamic nucleus (STN), particularly ON medication.1 STN DBS has various effects on swallow function.2–4 Swallowing involves multiple phases, with oral and pharyngeal phases most critical for bolus clearance and airway protection. However, the impact of different oral textures on aspiration with or without DBS in patients with PD has not been studied.2 Fast-flowing liquids may be more likely to aspirate before and during the swallow, although with less risk of post-swallow aspiration of residue compared with more viscous solids. Dynamic changes in swallow parameters have not been well characterised either.2 A comprehensive evaluation in a randomised double-blind study under various DBS conditions over time is therefore of significant importance. We hypothesised that liquids would more likely yield aspiration than solids, regardless of DBS conditions and assessment timing, and that swallowing measures could worsen in a year. ### Standard protocol approval, registrations and patient consents The study was approved by the institutional review board, with written consents by patients.3 Unlike our previous publications in which only the whole aspiration events (a combination of liquid and solid bolus) were reported using the Penetration-Aspiration Scale (PAS) on the videofluoroscopic swallow study (VFSS),3 the current study (1) further delineated the impact of different oral textures (liquid vs solid bolus) on aspiration and (2) characterised the swallow dynamics across oral and pharyngeal phases, based on the previously obtained VFSS …

10005 Background: Next generation sequencing (NGS) assays are now a standard part of clinical care for many adult solid cancers. The significance of molecular tumor profiling for the care of children with cancer is not well understood.We aimed to determine the clinical impact of identifying genomic alterations by NGS for young patients with relapsed, refractory, or high-risk extracranial solid tumors. Methods: We report on the first 389 participants in a prospective cohort study enrolling patients at 12 institutions with extracranial solid tumors diagnosed at age 30 years or less. Targeted DNA NGS was performed on one or more tumor samples from each patient. Selected patients also had tumors subjected to RNA sequencing. Test results were returned to the treating oncologist and follow-up treatment and response data were collected.Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to targeted therapy matched to an identified alteration (matched targeted therapy, MTT) using established guidelines. Response to MTT was determined and reported as a response if either there was radiographic response according to RECIST or the duration of therapy was > 4 months. Results: Molecular tumor profiling (MTP) was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma). Two hundred and ninety-nine patients with MTP results (87%) had one or more alterations of clinical significance. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 208 (60%), 51 (15%) and 240 (70%) patients, respectively. Of the 240 patients with tumors harboring genomic alterations designated as having therapeutic impact, 23 (11%) had Tier 1 molecular findings. 205 patients were eligible to receive MTT based on having a molecular alteration with therapeutic significance and sufficient follow-up; 31 of these patients (15%) received MTT. Seven patients (23%) receiving MTT responded, 6 of these were kinase fusions. All of the responders received targeted therapy matched to a fusion and 78% of diagnostically significant alterations were fusions. Conclusions: Molecular tumor profiling has a significant impact on diagnosis and treatment recommendations for young patients with extracranial solid tumors. These results emphasize the importance of fusion detection for patients with sarcomas and rare tumors. Clinical trial information: NCT02520713.

Ibrutinib has generated remarkable responses in patients with chronic lymphocytic leukemia (CLL), including those with an unfavorable cytogenetic profile. However, patients develop resistance, with poor outcomes and no established treatment options. Mutations in BTK and PLCG2 have emerged as main mechanisms of drug resistance, but not all patients carry these mutations. Further understanding of mechanisms of resistance is urgently needed and will support rational development of new therapeutic strategies. To that end, we characterized the genomic profiles of serial samples from 9 patients with ibrutinib-relapsed disease, including 6 who had Richter transformation. Mutations, indels, copy-number aberrations, and loss of heterozygosity were assessed using next-generation sequencing and single-nucleotide polymorphism array. We found that 18p deletion (del(18p)), together with del(17p)/TP53 mutations, was present in 5 of 9 patients before ibrutinib therapy. In addition to BTKC481 , we identified BTKT316A , a structurally novel mutation located in the SH2 domain of BTK. Minor BTK clones with low allele frequencies were captured in addition to major BTK clones. Although TP53 loss predisposes patients for relapse, clone size of TP53 loss may diminish during disease progression while mutant BTK clone expands. In patients who had Richter transformation, we found that the transformed cells were clonal descendants of circulating leukemia cells but continued to undergo evolution and drifts. Surprisingly, transformed lymphoma cells in tissue may acquire a different BTK mutation from that in the CLL leukemia cells. Collectively, these results provide insights into clonal evolution underlying ibrutinib relapse and prompt further investigation on genomic abnormalities that have clinical application potential.

Intro: Relapsed/refractory diffuse large B cell lymphoma (r/r DLBCL) is associated with poor outcomes, and remains an area of unmet clinical need. Emerging data indicate that a key macrophage immune checkpoint termed CD47 can be effectively targeted in r/r DLBCL. CD47 is a potent "don't eat me" signal and impairs tumor cell phagocytosis by engaging the inhibitory macrophage receptor, SIRPα. Importantly, early clinical studies demonstrate that blocking CD47-SIRPα interactions with an anti-CD47 antibody (magrolimab) yields promising activity in r/r DLBCL patients, particularly when combined with rituximab, which further potentiates lymphoma cell phagocytosis via its Fc domain. Moving forward, it will be crucial to identify combinatorial strategies that improve the efficacy of anti-CD47 therapy in r/r DLBCL. Tumor-associated macrophages (TAMs) contribute to an immunosuppressive environment in cancer through secretion of cytokines, metabolites, and expression of immune checkpoints. Sustained PI3K-γ signaling is critical to maintain immune suppressive TAM functions, and PI3K-γ inhibition polarizes TAMs into a pro-inflammatory state that culminates in potent anti-tumor T cell responses, sensitizing cancers to PD-1 blockade therapy. We hypothesized that activating TAMs through PI3K-δ/γ inhibition would also augment their inherent phagocytic capacity and synergize with phagocytosis-targeting treatments such as CD47 blockade. Thus, we investigated the impact of the dual PI3K-δ/γ inhibitor, duvelisib, on expression of key phagocytic receptors and pathways in human macrophages, as well as its effect on enhancing lymphoma cell phagocytosis with the anti-CD47 antibody, magrolimab. Results: RNA sequencing of duvelisib-treated human monocyte-derived macrophages revealed that PI3K-δ/γ inhibition induced broad transcriptional changes suggestive of an activated macrophage state (Fig 1A), including upregulation of interferon response genes (IRF9) and costimulatory molecules (CD86), while decreasing expression of immune suppressive cytokines (IL10) and inhibitory ligands (PDL1). Moreover, duvelisib upregulated transcription of canonical pro-phagocytic receptors (LRP1, FCGR2A,CD44), lysosomal degradation components (LYZ, CTSS) and phosphatidylserine-bridging genes (MFG-E8, GAS6), while inhibiting metabolic pathways, most notably mTOR, each of which has been associated with increased and more efficient phagocytosis. Given these findings, we evaluated the effect of dual PI3K-δ/γ inhibition on macrophage phagocytosis of DLBCL cells in the context of CD47 blockade in vitro. Across a broad panel of human DLBCL cell lines and multiple monocyte donors, pre-treatment of macrophages with duvelisib significantly increased lymphoma cell phagocytosis by magrolimab (Fig 1B-C). This effect reflected a direct increase in the phagocytic capacity of treated macrophages, as lymphoma cells were not exposed to duvelisib. In separate experiments, we found that duvelisib rarely induced full apoptosis of DLBCL cells, but did promote the expression of "eat me" signals, such as calreticulin and phosphatidylserine on many of the cell lines examined (Fig 1D). Collectively, these results suggest that PI3K-δ/γ inhibition enhances the inherent phagocytic capacity of macrophages, while also sensitizing lymphoma cells for engulfment. Similarly, potent effects were not observed with PI3K-δ- or PI3K-γ-specific inhibitors, suggesting that combined PI3K-δ/γ inhibition is critical to mediating these beneficial effects. Finally, to determine whether duvelisib impacted the efficacy of magrolimab in vivo, we treated human DLBCL xenografts and observed that while duvelisib had minimal impact on lymphoma growth, the combination of duvelisib and magrolimab induced complete tumor rejection in a high proportion of mice, leading to increased survival compared to mice treated with magrolimab alone (Fig 1E). Conclusion: Collectively, our findings suggest that targeting the PI3K-δ/γ axis favorably induces key macrophage phagocytic pathways, while simultaneously upregulating important "eat me" signals on lymphoma cells. Together, these alterations lower the phagocytic threshold of TAMs and dramatically increase the efficacy of anti-CD47 therapy in DLBCL xenograft models. This work paves the way for early-phase studies of duvelisib and magrolimab in r/r DLBCL and other lymphomas. Disclosures Godfrey: Verastem: Research Funding; Merck: Research Funding; Gilead: Research Funding. Coma:Verastem Oncology, Inc: Current Employment, Current equity holder in publicly-traded company. Maute:Gilead Sciences, Inc.: Current Employment. Chao:Gilead Sciences: Current Employment. Pachter:Verastem Therapeutics: Current Employment. Kline:Kite/Gilead: Speakers Bureau; Merck: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction: Tumor profiling is becoming a more routine part of clinical care. Many academic centers and commercial entities offer tumor sequencing of cancer-related genes without matched germline profiling. We hypothesize that tumor-only sequencing may limit full clinical interpretation and have decreased sensitivity to identify significant germline variants. Methods: The Genomic Assessment Improves Novel Therapy (GAIN) Consortium is a clinical cancer genomics study for patients with high-risk solid malignancies. Patients in this study were selected for subanalysis if panel sequencing of 447 genes was performed on a tumor and interpreted by an expert panel prior to the availability of matched germline sequencing. Interpretation of tumor sequencing included both therapeutic recommendations and a curation of cancer-related variants of potential clinical significance if present in the germline. Germline sequencing was separately performed targeting 147 genes (a subset of the somatic panel) and analyzed with a germline-specific pipeline to identify and filter variants. We examined clinical recommendations in the somatic reports that were based on single-nucleotide variants identified from the 147 overlapping genes. We compared these interpretations with results from the matched germline data. Results: We identified 159 participants with somatic and germline sequencing reports meeting the eligibility criteria. Germline sequencing identified 38 pathogenic or likely pathogenic (P/LP) germline variants in 35 of 159 patients (22%). Of those 35 patients, 17 (49%) had a P/LP variant in an autosomal dominant cancer predisposition gene, 19 (54%) in an autosomal recessive gene, and 1 (2.9%) in a noncancer gene. Of the 38 total variants, 21 (55%) were identified by the analytic pipeline used for somatic sequencing and noted as potential germline variants in the somatic reports. Forty treatment recommendations were made from the somatic data within the overlapping genes. Ten (25%) treatment recommendations were based on variants that were later determined to be germline. These included variants in TP53, SDHA, SMARCA4, TSC2, FAM175A, CHEK2, and AKT1, many of which were noted in the somatic reports to be variants of uncertain significance or possibly germline. Conclusions: In this study, we found that clinically actionable germline variants were under-reported when relying on analytical pipelines and clinical interpretations developed for the analysis of tumor samples. In the absence of germline sequencing, we also found that cancer treatment recommendations can be made based on mutations identified from tumor sequencing that are germline variants. In many cases, these recommendations remain appropriate (e.g., PARP inhibitors for BRCA1/2) while in other cases germline data facilitated a more nuanced interpretation of actionability. These findings support the use of germline genetic testing and paired tumor-germline analysis in precision cancer medicine studies. Citation Format: Jaclyn Schienda, Catherine M. Clinton, Laura B. Corson, Alma Imamovic-Tuco, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Vear, Margaret E. Macy, Mark A. Applebaum, Rochelle Bagatell, Amit J. Sabnis, Daniel A. Weiser, Julia L. Glade-Bender, Samuel L. Volchenboum, Wenjun Kang, Danielle Manning, Jonathan Nowak, Joshua Schiffman, Neal I. Lindeman, Alanna J. Church, Katherine A. Janeway, Brian D. Crompton, Junne Kamihara. The added value of examining germline variants in a precision cancer therapy study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A06.

Background: Gene variants with potential therapeutic significance have been reported in 30-60% of childhood malignancies. The 12-institution Genomic Assessment Informs Novel therapy (GAIN) consortium is conducting the individualized cancer therapy 2 (iCat2) study (NCT02520713) with the objective of evaluating the impact of tumor profiling on outcome. We provide an interim report on patients enrolled on the ongoing GAIN/iCat2 study. Methods and Objectives: Patients are eligible if they have a high-risk, recurrent/refractory (RR), or difficult-to-diagnose extracranial solid tumor diagnosed at ≤30 years and adequate sample available for sequencing. A next-generation targeted panel assay is performed. Results are returned with a GAIN report containing clinical interpretation, including an individualized cancer therapy (iCat) recommendation if there is evidence supporting a link between an identified variant and response to molecularly targeted therapy. iCat recommendations are tiered from 1 to 5 based on the level of clinical and preclinical support, with tier 1 being the highest and tier 5 the lowest. Potential extraordinary responders are selected for further review based on having treatment duration of ≥1 year for chemotherapy or ≥4 months or a partial response for targeted therapy. Results: 388 eligible patients were enrolled by 1/1/2019 with the most common diagnoses being osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. 366 patients (94%) have had at least one successful sequencing result, with 349 having molecular and GAIN reports suitable for inclusion in this analysis. 68% of patients (237/349) have received iCat recommendations, with 41% (143/349) having the highest tier of 1-2 and 27% (94/349) having a highest tier of 3-5. Common genes for which tier 1-2 iCat recommendations were made include TP53 (15%), SMARCB1 (4%), PIK3CA (3%), CDK4 (2%), and KRAS (2%). Common alterations for which tier 3-5 recommendations were made include EWSR1 fusions (12%), MYC/MYCN amplifications (8%), and CDKN2A deletions (7%). Of 170 RR patients with treatment follow-up data entered as of June 2019, 15% (25/170) have received matched targeted therapy. Six of these (24%) are considered extraordinary responders. Of note, extraordinary responses were also seen with some second-line chemotherapy and multitargeted kinase inhibitors. Conclusions: The proportion of patients with clinically significant gene variants is higher in this study than in some previous reports. Providing an iCat recommendation for alterations in genes such as TP53 where evidence is mixed, increased availability of molecularly targeted therapy trials, and more evidence may all be responsible for this increased rate. Reassessment of iCat recommendation tiers based on current evidence is ongoing. Extraordinary responses occur in a subset of children with extracranial solid malignancies who receive matched targeted therapy. Study enrollment is ongoing with further assessments of the impact of tumor profiling on outcome planned. Citation Format: Laura B. Corson, Alanna J. Church, Deirdre Reidy, Pei-Chi Kao, Wenjun Kang, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Vear, Margaret E. Macy, Mark A. Applebaum, Lobin A. Lee, Duong Doan, R. Seth Pinches, Seong Choi, Suzanne J. Forrest, Catherine M. Clinton, Brian D. Crompton, Laura E. MacConaill, Samuel L. Volchenboum, Neal I. Lindeman, Steven G. DuBois, Wendy B. London, Katherine A. Janeway. Targeted sequencing in 388 patients with high-risk or recurrent/refractory pediatric extracranial solid malignancies: An interim report from the GAIN Consortium/iCat2 Study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A28.

Improved systems for detection of measurable residual disease (MRD) in acute myeloid leukemia (AML) are urgently needed, however attempts to utilize broad-scale next-generation sequencing (NGS) panels to perform multi-gene surveillance in AML post-induction have been stymied by persistent premalignant mutation-bearing clones. We hypothesized that this technology may be more suitable for evaluation of fully engrafted patients following hematopoietic cell transplantation (HCT). To address this question, we developed a hybrid-capture NGS panel utilizing unique molecular identifiers (UMIs) to detect variants at 0.1% VAF or below across 22 genes frequently mutated in myeloid disorders and applied it to a retrospective sample set of blood and bone marrow DNA samples previously evaluated as negative for disease via standard-of-care short tandem repeat (STR)-based engraftment testing and hematopathology analysis in our laboratory. Of 30 patients who demonstrated trackable mutations in the 22 genes at eventual relapse by standard NGS analysis, we were able to definitively detect relapse-associated mutations in 18/30 (60%) at previously disease-negative timepoints collected 20–100 days prior to relapse date. MRD was detected in both bone marrow (15/28, 53.6%) and peripheral blood samples (9/18, 50%), while showing excellent technical specificity in our sample set. We also confirmed the disappearance of all MRD signal with increasing time prior to relapse (>100 days), indicating true clinical specificity, even using genes commonly associated with clonal hematopoiesis of indeterminate potential (CHIP). This study highlights the efficacy of a highly sensitive, NGS panel-based approach to early detection of relapse in AML and supports the clinical validity of extending MRD analysis across many genes in the post-transplant setting.

ObjectiveTo evaluate the long-term effect of 60 Hz stimulation of the subthalamic nucleus (STN) on dysphagia, freezing of gait (FOG) and other motor symptoms in patients with Parkinson’s disease (PD) who have FOG at the usual 130 Hz stimulation.MethodsThis is a prospective, sequence randomised, crossover, double-blind study. PD patients with medication refractory FOG at 130 Hz stimulation of the STN were randomised to the sequences of 130 Hz, 60 Hz or deep brain stimulation off to assess swallowing function (videofluoroscopic evaluation and swallowing questionnaire), FOG severity (stand–walk–sit test and FOG questionnaire) and motor function (Unified PD Rating Scale, Part III motor examination (UPDRS-III)) at initial visit (V1) and follow-up visit (V2, after being on 60 Hz stimulation for an average of 14.5 months), in their usual medications on state. The frequency of aspiration events, perceived swallowing difficulty and FOG severity at 60 Hz compared with 130 Hz stimulation at V2, and their corresponding changes at V2 compared with V1 at 60 Hz were set as primary outcomes, with similar comparisons in UPDRS-III and its subscores as secondary outcomes.ResultsAll 11 enrolled participants completed V1 and 10 completed V2. We found the benefits of 60 Hz stimulation compared with 130 Hz in reducing aspiration frequency, perceived swallowing difficulty, FOG severity, bradykinesia and overall axial and motor symptoms at V1 and persistent benefits on all of them except dysphagia at V2, with overall decreasing efficacy when comparing V2 to V1.ConclusionsThe 60 Hz stimulation, when compared with 130 Hz, has long-term benefits on reducing FOG, bradykinesia and overall axial and motor symptoms except dysphagia, although the overall benefits decrease with long-term use.Clinical trial registrationNCT02549859; Pre-results.

A previous randomized controlled trial (RCT) by Schiffman et al. (2007)15 compared four treatments strategies for temporomandibular joint (TMJ) disc displacement without reduction with limited mouth opening (closed lock). In this parallel group RCT, 106 patients with magnetic resonance imaging (MRI)-confirmed TMJ closed lock were randomized between medical management, non-surgical rehabilitation, arthroscopic surgery, and arthroplasty. Surgical groups also received rehabilitation post-surgically. The current paper reassesses the effectiveness of these four treatment strategies using outcome measures recommended by the International Association of Oral and Maxillofacial Surgeons (IAOMS). Clinical assessments at baseline and at follow-up (3, 6, 12, 18, 24, and 60 months) included intensity and frequency of TMJ pain, mandibular range of motion, TMJ sounds, and impairment of chewing. TMJ MRIs were performed at baseline and 24 months, and TMJ tomograms at baseline, 24 and 60 months. Most IAOMS recommended outcome measures improved significantly over time (P ≤ 0.0003). There was no difference between treatment strategies relative to any treatment outcome at any follow-up (P ≥ 0.16). Patient self-assessment of treatment success correlated with their ability to eat, with pain-free opening ≥35 mm, and with reduced pain intensity. Given no difference between treatment strategies, non-surgical treatment should be employed for TMJ closed lock before considering surgery.

Chronic pain conditions are the top reason patients seek care, the most common reason for disability and addiction, and the biggest driver of healthcare costs; their treatment costs more than cancer, heart disease, dementia, and diabetes care. The personal impact in terms of suffering, disability, depression, suicide, and other problems is incalculable. There has been much effort to prevent many medical and dental conditions, but little effort has been directed toward preventing chronic pain. To address this deficit, a massive open online course (MOOC) was developed for students and healthcare professionals. "Preventing Chronic Pain: A Human Systems Approach" was offered by the University of Minnesota through the online platform Coursera. The first offering of this free open course was in the spring of 2014 and had 23 650 participants; 53% were patients or consumers interested in pain. This article describes the course concepts in preventing chronic pain, the analytic data from course participants, and postcourse evaluation forms.慢性疼痛疾病是寻求医疗护理的 第一大原因、残疾和成瘾的最常 见原因，以及推动医疗护理成本 升高的最大原因，且慢性疼痛疾 病 治 疗 的 费 用 多 于 癌 症 、 心 脏 病、老年痴呆症和糖尿病。但无 法 计 算 患 病 的 痛 苦 、 残 疾 、 抑 郁、自杀和其他问题对人产生的 影响。为预防许多医学和牙科疾 病，我们已作出了许多努力，但 直接针对预防慢性疼痛的努力仍 很少。为弥补此不足，我们为学 生和医疗保健专业人员开展了一 项大型网络公开课 (MOOC)。明尼 苏达大学通过 www.Coursera.org 提供了“预防慢性疼痛：一种人 类系统法”公开课。此免费公开 课于 2014 年春天首次开播，有 23650 人参加学习；其中 53% 的 参加者是患者或关注疼痛治疗的 消费者。本文描述了预防慢性疼 痛的课程理念、课程参与者的分 析数据和课后评价表。.Las afecciones de dolor crónico son el principal motivo de búsqueda de asistencia sanitaria, la causa más frecuente de discapacidad y toxicomanía, y el factor generador de costos sanitarios más importante, con un coste mayor al generado por el cáncer, la cardiopatía, la demencia y la diabetes. Las repercusiones en cuanto a sufrimiento, discapacidad, depresión, suicidio y otros problemas son incalculables. Se han consagrado grandes esfuerzos a la prevención de muchas enfermedades médicas y dentales, pero no se han dirigido los suficientes hacia la prevención del dolor crónico. Para hacer frente a este déficit, se ha desarrollado un curso en línea masivo y abierto (massive open online course, MOOC) para estudiantes y profesionales sanitarios. La Universidad de Minnesota ofreció el curso “Prevención del dolor crónico: enfoque de un sistema humanista” a través del sitio www.Coursera.org. La primera oferta de este curso abierto y gratuito se hizo en primavera de 2014 y acogió a 23 650 participantes; de los cuales un 53 % eran pacientes o clientes interesados en el dolor. En este artículo se describen los conceptos del curso en la prevención del dolor crónico, los datos analíticos de los participantes y los formularios de evaluación posteriores al curso.

Background Radiolabeled metaiodobenzylguanidine (MIBG) is sensitive and specific for detecting neuroblastoma. The extent of MIBG-avid disease is assessed using Curie scores. Although Curie scoring is prognostic in patients with high-risk neuroblastoma, there is no standardized method to assess the response of specific sites of disease over time. The goal of this study was to develop approaches for Curie scoring to facilitate the calculation of scores and comparison of specific sites on serial scans. Procedure We designed three semiautomated methods for determining Curie scores, each with increasing degrees of computer assistance. Method A was based on visual assessment and tallying of MIBG-avid lesions. For method B, scores were tabulated from a schematic that associated anatomic regions to MIBG-positive lesions. For method C, an anatomic mesh was used to mark MIBG-positive lesions with automatic assignment and tallying of scores. Five imaging physicians experienced in MIBG interpretation scored 38 scans using each method, and the feasibility and utility of the methods were assessed using surveys. Results There was good reliability between methods and observers. The user-interface methods required 57 to 110 seconds longer than the visual method. Imaging physicians indicated that it was useful that methods B and C enabled tracking of lesions. Imaging physicians preferred method B to method C because of its efficiency. Conclusions We demonstrate the feasibility of semiautomated approaches for Curie score calculation. Although more time was needed for strategies B and C, the ability to track and document individual MIBG-positive lesions over time is a strength of these methods.

Aims: We assessed and compared the diagnostic accuracy of two sets of diagnostic criteria for headache secondary to temporomandibular disorders (TMD). Methods: In 373 headache subjects with TMD, a TMD headache reference standard was defined as: self-reported temple headache, consensus diagnosis of painful TMD and replication of the temple headache using TMD-based provocation tests. Revised diagnostic criteria for Headache attributed to TMD were selected using the RPART (recursive partitioning and regression trees) procedure, and refined in half of the data set. Using the remaining half of the data, the diagnostic accuracy of the revised criteria was compared to that of the International Headache Society’s International Classification of Headache Diseases (ICHD)-II criteria A to C for Headache or facial pain attributed to temporomandibular joint (TMJ) disorder. Results: Relative to the TMD headache reference standard, ICHD-II criteria showed sensitivity of 84% and specificity of 33%. The revised criteria for Headache attributed to TMD had sensitivity of 89% with improved specificity of 87% ( p Conclusion: Having significantly better specificity than the ICHD-II criteria A to C, the revised criteria are recommended to diagnose headache secondary to TMD.

Although most cases of temporomandibular muscle and joint disorders (TMJD) are mild and self-limiting, about 10% of TMJD patients develop severe disorders associated with chronic pain and disability. It has been suggested that depression and catastrophizing contributes to TMJD chronicity. This article assesses the effects of catastrophizing and depression on clinically significant TMJD pain (Graded Chronic Pain Scale [GCPS] II-IV). Four hundred eighty participants, recruited from the Minneapolis/St. Paul area through media advertisements and local dentists, received examinations and completed the GCPS at baseline and at 18-month follow-up. In a multivariable analysis including gender, age, and worst pain intensity, baseline catastrophizing (β 3.79, P

Although most cases of temporomandibular muscle and joint disorders (TMJD) are mild and self-limiting, about 10% of TMJD patients develop severe disorders associated with chronic pain and disability. It has been suggested that fibromyalgia and widespread pain play a significant role in TMJD chronicity. This paper assessed the effects of fibromyalgia and widespread pain on clinically significant TMJD pain (GCPS II-IV). Four hundred eighty-five participants recruited from the Minneapolis/St. Paul area through media advertisements and local dentists received examinations and completed the Graded Chronic Pain Scale (GCPS) at baseline and at 18 months. Baseline widespread pain (OR: 2.53, P = .04) and depression (OR: 5.30, P = .005) were associated with onset of clinically significant pain (GCPS II-IV) within 18 months after baseline. The risk associated with baseline fibromyalgia was moderate, but not significant (OR: 2.74, P = .09). Persistence of clinically significant pain was related to fibromyalgia (OR: 2.48, P = .02) and depression (OR: 2.48, P = .02). These results indicate that these centrally generated pain conditions play a role in the onset and persistence of clinically significant TMJD. Perspective Fibromyalgia and widespread pain should receive important consideration when evaluating and developing a treatment plan for patients with TMJD.

Whole exome sequencing has facilitated the discovery of causal genetic variants associated with human diseases at deep coverage and low cost. In particular, the detection of somatic mutations from tumor/normal pairs has provided insights into the cancer genome. Although there is an abundance of publicly-available software for the detection of germline and somatic variants, concordance is generally limited among variant callers and alignment algorithms. Successful integration of variants detected by multiple methods requires in-depth knowledge of the software, access to high-performance computing resources, and advanced programming techniques. We present ExScalibur, a set of fully automated, highly scalable and modulated pipelines for whole exome data analysis. The suite integrates multiple alignment and variant calling algorithms for the accurate detection of germline and somatic mutations with close to 99% sensitivity and specificity. ExScalibur implements streamlined execution of analytical modules, real-time monitoring of pipeline progress, robust handling of errors and intuitive documentation that allows for increased reproducibility and sharing of results and workflows. It runs on local computers, high-performance computing clusters and cloud environments. In addition, we provide a data analysis report utility to facilitate visualization of the results that offers interactive exploration of quality control files, read alignment and variant calls, assisting downstream customization of potential disease-causing mutations. ExScalibur is open-source and is also available as a public image on Amazon cloud.