Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique\u2014Subtype and Stage Inference (SuStaIn)\u2014able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer\u2019s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 7 10 124 ) or temporal stage (p = 3.96 7 10 125 ). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine

Thoracic epidural anesthesia for coronary bypass via left anterior thoracotomy in the conscious patient

Cardiac surgery is perceived to be maximally invasive and fraught with complications. Secondary to this, cardiothoracic surgeons have been refining traditional techniques to minimize their invasive nature. Epidural anesthesia has been utilized safely and effectively for numerous surgical procedures to reduce the associated morbidity. In hopes of achieving a similar result, we utilized thoracic epidural anesthesia for a coronary artery bypass via a left anterior thoracotomy, in an awake, spontaneously breathing patient. To the best of our knowledge, this is the first reported case utilizing this approach. Herein we report the results and technique utilized

Brainstem atrophy in Gulf War illness

Background Gulf War Illness (GWI) is a condition that affects about 30 % of veterans who served in the 1990-91 Persian Gulf War. Given its broad symptomatic manifestation, including chronic pain, fatigue, neurological, gastrointestinal, respiratory, and skin problems, it is of interest to examine whether GWI is associated with changes in the brain. Existing neuroimaging studies, however, have been limited by small sample sizes, inconsistent GWI diagnosis criteria, and potential comorbidity confounds. Objectives Using a large cohort of US veterans with GWI, we assessed regional brain volumes for their associations with GWI, and quantified the relationships between any regional volumetric changes and GWI symptoms. Methods Structural magnetic resonance imaging (MRI) scans from 111 veterans with GWI (Age = 49 ± 6, 88 % Male) and 59 healthy controls (age = 51 ± 9, 78 % male) were collected at the California War Related Illness and Injury Study Center (WRIISC-CA) and from a multicenter study of the Parkinson’s Progression Marker Initiative (PPMI), respectively. Individual MRI volumes were segmented and parcellated using FreeSurfer. Regional volumes of 19 subcortical, 68 cortical, and 3 brainstem structures were evaluated in the GWI cohort relative to healthy controls. The relationships between regional volumes and GWI symptoms were also assessed. Results We found significant subcortical atrophy, but no cortical differences, in the GWI group relative to controls, with the largest effect detected in the brainstem, followed by the ventral diencephalon and the thalamus. In a subsample of 58 veterans with GWI who completed the Chronic Fatigue Scale (CFS) inventory of Centers for Disease Control and Prevention (CDC), smaller brainstem volumes were significantly correlated with increased severities of fatigue and depressive symptoms. Conclusion The findings suggest that brainstem volume may be selectively affected by GWI, and that the resulting atrophy could in turn mediate or moderate GWI-related symptoms such as fatigue and depression. Consequently, the brain stem should be carefully considered in future research focusing on GWI pathology

Semantic enrichment by non-experts: Usability of manual annotation tools

Most of the semantic content available has been generated automatically by using annotation services for existing content. Automatic annotation is not of sufficient quality to enable focused search and retrieval: either too many or too few terms are semantically annotated. User-defined semantic enrichment allows for a more targeted approach. We developed a tool for semantic annotation of digital documents and conducted an end-user study to evaluate its acceptance by and usability for non-expert users. This paper presents the results of this user study and discusses the lessons learned about both the semantic enrichment process and our methodology of exposing non-experts to semantic enrichment

Effect and Safety of Meropenem–Vaborbactam versus Best-Available Therapy in Patients with Carbapenem-Resistant Enterobacteriaceae Infections: The TANGO II Randomized Clinical Trial

Introduction: Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) for CRE. Methods: A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem–vaborbactam (2 g/2 g over 3 h, q8h for 7–14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings. Results: Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) [95% confidence interval (CI) of difference, 3.3% to 61.3%; P = 0.03)] at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%; P = 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, − 44.7% to 9.3%) for meropenem–vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem–vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk–benefit analyses of composite clinical failure or nephrotoxicity favored meropenem–vaborbactam versus BAT (31.3% [10/32] versus 80.0% [12/15]; 95% CI of difference, − 74.6% to − 22.9%; P < 0.001). Conclusions: Monotherapy with meropenem–vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT. Clinical Trials Registration: NCT02168946. Funding: The Medicines Company. © 2018, The Author(s)

Minimal disease activity for rheumatoid arthritis: a preliminary definition.

Contains fulltext : 48816.pdf (publisher's version ) (Closed access)Agreement on response criteria in rheumatoid arthritis (RA) has allowed better standardization and interpretation of clinical trial reports. With recent advances in therapy, the proportion of patients achieving a satisfactory state of minimal disease activity (MDA) is becoming a more important measure with which to compare different treatment strategies. The threshold for MDA is between high disease activity and remission and, by definition, anyone in remission will also be in MDA. True remission is still rare in RA; in addition, the American College of Rheumatology definition is difficult to apply in the context of trials. Participants at OMERACT 6 in 2002 agreed on a conceptual definition of minimal disease activity (MDA): "that state of disease activity deemed a useful target of treatment by both the patient and the physician, given current treatment possibilities and limitations." To prepare for a preliminary operational definition of MDA for use in clinical trials, we asked rheumatologists to assess 60 patient profiles describing real RA patients seen in routine clinical practice. Based on their responses, several candidate definitions for MDA were designed and discussed at the OMERACT 7 in 2004. Feedback from participants and additional on-site analyses in a cross-sectional database allowed the formulation of 2 preliminary, equivalent definitions of MDA: one based on the Disease Activity Score 28 (DAS28) index, and one based on meeting cutpoints in 5 out the 7 WHO/ILAR core set measures. Researchers applying these definitions first need to choose whether to use the DAS28 or the core set definition, because although each selects a similar proportion in a population, these are not always the same patients. In both MDA definitions, an initial decision node places all patients in MDA who have a tender joint count of 0 and a swollen joint count of 0, and an erythrocyte sedimentation rate (ESR) no greater than 10 mm. If this condition is not met: * The DAS28 definition places patients in MDA when DAS28 < or = 2.85; * The core set definition places patients in MDA when they meet 5 of 7 criteria: (1) Pain (0-10) < or = 2; (2) Swollen joint count (0-28) < or = 1; (3) Tender joint count (0-28) < or = 1; (4) Health Assessment Questionnaire (HAQ, 0-3) < or = 0.5; (5) Physician global assessment of disease activity (0-10) < or = 1.5; (6) Patient global assessment of disease activity (0-10) < or = 2; (7) ESR < or = 20. This set of 2 definitions gained approval of 73% of the attendees. These (and other) definitions will now be subject to further validation in other databases