Patterns of joint involvement in juvenile idiopathic arthritis and prediction of disease course: A prospective study with multilayer non-negative matrix factorization.

BACKGROUND: Joint inflammation is the common feature underlying juvenile idiopathic arthritis (JIA). Clinicians recognize patterns of joint involvement currently not part of the International League of Associations for Rheumatology (ILAR) classification. Using unsupervised machine learning, we sought to uncover data-driven joint patterns that predict clinical phenotype and disease trajectories. METHODS AND FINDINGS: We analyzed prospectively collected clinical data, including joint involvement using a standard 71-joint homunculus, for 640 discovery patients with newly diagnosed JIA enrolled in a Canada-wide study who were followed serially for five years, treatment-naïve except for nonsteroidal anti-inflammatory drugs (NSAIDs) and diagnosed within one year of symptom onset. Twenty-one patients had systemic arthritis, 300 oligoarthritis, 125 rheumatoid factor (RF)-negative polyarthritis, 16 RF-positive polyarthritis, 37 psoriatic arthritis, 78 enthesitis-related arthritis (ERA), and 63 undifferentiated arthritis. At diagnosis, we observed global hierarchical groups of co-involved joints. To characterize these patterns, we developed sparse multilayer non-negative matrix factorization (NMF). Model selection by internal bi-cross-validation identified seven joint patterns at presentation, to which all 640 discovery patients were assigned: pelvic girdle (57 patients), fingers (25), wrists (114), toes (48), ankles (106), knees (283), and indistinct (7). Patterns were distinct from clinical subtypes (P \u3c 0.001 by χ2 test) and reproducible through external data set validation on a 119-patient, prospectively collected independent validation cohort (reconstruction accuracy Q2 = 0.55 for patterns; 0.35 for groups). Some patients matched multiple patterns. To determine whether their disease outcomes differed, we further subdivided the 640 discovery patients into three subgroups by degree of localization-the percentage of their active joints aligning with their assigned pattern: localized (≥90%; 359 patients), partially localized (60%-90%; 124), or extended ( CONCLUSIONS: Multilayer NMF identified patterns of joint involvement that predicted disease trajectory in children with arthritis. Our hierarchical unsupervised approach identified a new clinical feature, degree of localization, which predicted outcomes in both cohorts. Detailed assessment of every joint is already part of every musculoskeletal exam for children with arthritis. Our study supports both the continued collection of detailed joint involvement and the inclusion of patterns and degrees of localization to stratify patients and inform treatment decisions. This will advance pediatric rheumatology from counting joints to realizing the potential of using data available from uncovering patterns of joint involvement

Safety and feasibility of a home-based six week resistance training program in juvenile idiopathic arthritis

BACKGROUND: Juvenile idiopathic arthritis (JIA), among the most common chronic diseases of childhood, can be associated with attenuated physical activity levels, reduced fitness, decreased functionality and pain. This pilot study aimed to determine the safety, feasibility and effect of a six week resistance training program in children with JIA. METHODS: Youth (8-18 years) with JIA participated in a home-based resistance training program. Participants reported pain on an electronic diary once a day for one week prior to training, then once a day on non-exercise days and three times a day (before-exercise, after-exercise, and end-of-day) on exercise days for the subsequent six weeks of training. Secondary outcome measures included inflammation (assessed by ultrasound), muscle size (assessed by ultrasound), muscle strength (assessed by dynamometer) and functional ability (assessed by childhood health assessment questionnaire), measured at baseline and post-training. Participants were also instructed to wear an accelerometer one week prior to training to estimate baseline physical activity levels. Statistical analyses included safety (pain changes and any adverse events), feasibility (adherence to program and modifications made to exercises) and effect of program (differences in secondary measures pre and post training). An alpha level of p < 0.05 was accepted as significant. RESULTS: Seven participants completed an average of 12.7 ± 3.4 (range 8-17) exercise sessions out of a possible 18 (70.6%). No adverse events were reported and pain did not increase over the seven weeks. Secondary measures revealed a significant increase in vastus lateralis thickness from pre to post training (p < 0.05). End-of-day pain intensity was correlated to end-of-day stiffness, fatigue and mood (r = .864, r = .581, r = -.637, respectively, p < 0.001). Pain intensity was also correlated with ratings of perceived exertion of the exercise (r = 0.324, p < 0.01). Only two children met the recommended 60 minutes of moderate to vigorous physical activity per day. CONCLUSIONS: A six week home-based resistance training program is both safe (absence of pain changes or adverse events over the six weeks) and feasible (comparable adherence rates to other exercise studies involving JIA and individually modifiable) in children with JIA

Blocking Zika virus vertical transmission.

The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity

An Empirical Comparison of Tree-Based Methods for Propensity Score Estimation

To illustrate the use of ensemble tree-based methods (random forest classification [RFC] and bagging) for propensity score estimation and to compare these methods with logistic regression, in the context of evaluating the effect of physical and occupational therapy on preschool motor ability among very low birth weight (VLBW) children

LI Jianmin“ Silk Sutures: Trachea Surgery in Sixteenth-Century China

本文は、李建民「明代《外科正宗・救自刎断喉法》考釈」(『九州学林』32、香港城市大学中国文化中心、2013)の翻訳である。著者の李建民氏(台湾 中央研究院歴史語言研究所)は中国医学史を専門とし、著書に『死生之域-周秦漢脈学之源流』(2000)『生命史学-従医療看中国歴史』(2005)『旅行者的史学-中国医学史的旅行』(2009)『華佗隠蔵的手術-外科的中国医学史』(2011)等、また日本語による論文に「考古学上の発見と任脈学説の新認識」(荒川緑訳、『中国-社会と文化』18、2003)がある。本文は中医史のうちでも「手術史」という注目されることの少ない分野に焦点を当てたもので、その研究に当たっては、中医史の主流をなす内科的枠組からも、また西洋医学との安直な比較からも距離を置き、むしろ不連続でしばしば突発的でさえある諸事例をそれ自体として扱う「先例」分析法を適用すべきことを提唱する。なお紙幅の都合上、後記および注の一部を割愛した

Cancer risk in childhood-onset systemic lupus

INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian; mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this interval, only three invasive cancers were expected. However, 14 invasive cancers occurred with an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1 to 15.2). The SIRs stratified by age group and sex, were similar across these strata. There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis. CONCLUSIONS: These results suggest an increased cancer risk in pediatric onset SLE versus the general population. In absolute terms, this represents relatively few events. Of note, risk may be highest only after patients have transferred to adult care

Translational Medicine - doing it backwards

In recent years the concept of "translational medicine" has been advanced in an attempt to catalyze the medical applications of basic biomedical research. However, there has been little discussion about the readiness of scientists themselves to respond to what we believe is a required new approach to scientific discovery if this new concept is to bear fruit. The present paradigm of hypothesis-driven research poorly suits the needs of biomedical research unless efforts are spent in identifying clinically relevant hypotheses. The dominant funding system favors hypotheses born from model systems and not humans, bypassing the Baconian principle of relevant observations and experimentation before hypotheses. Here, we argue that that this attitude has born two unfortunate results: lack of sufficient rigor in selecting hypotheses relevant to human disease and limitations of most clinical studies to certain outcome parameters rather than expanding knowledge of human pathophysiology; an illogical approach to translational medicine. If we wish to remain true to our responsibility and duty of performing research relevant to human disease, we must begin to think about fundamental new approaches