Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure

AbstractThe design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here

Characterization of the severe phenotype of pyruvate kinase deficiency

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/2/ajh25926.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162766/1/ajh25926_am.pd

Age and Disability Employment Discrimination: Occupational Rehabilitation Implications

Introduction As concerns grow that a thinning labor force due to retirement will lead to worker shortages, it becomes critical to support positive employment outcomes of groups who have been underutilized, specifically older workers and workers with disabilities. Better understanding perceived age and disability discrimination and their intersection can help rehabilitation specialists and employers address challenges expected as a result of the evolving workforce. Methods Using U.S. Equal Employment Opportunity Commission Integrated Mission System data, we investigate the nature of employment discrimination charges that cite the Americans with Disabilities Act or Age Discrimination in Employment Act individually or jointly. We focus on trends in joint filings over time and across categories of age, types of disabilities, and alleged discriminatory behavior. Results We find that employment discrimination claims that originate from older or disabled workers are concentrated within a subset of issues that include reasonable accommodation, retaliation, and termination. Age-related disabilities are more frequently referenced in joint cases than in the overall pool of ADA filings, while the psychiatric disorders are less often referenced in joint cases. When examining charges made by those protected under both the ADA and ADEA, results from a logit model indicate that in comparison to charges filed under the ADA alone, jointly-filed ADA/ADEA charges are more likely to be filed by older individuals, by those who perceive discrimination in hiring and termination, and to originate from within the smallest firms. Conclusion In light of these findings, rehabilitation and workplace practices to maximize the hiring and retention of older workers and those with disabilities are discussed

A multi-center population-based case–control study of ovarian cancer in African-American women: the African American Cancer Epidemiology Study (AACES)

Abstract: Background: Ovarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population. Methods: The African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case–control study of OVCA in AA in 10 geographic locations, aiming to recruit 850 women with invasive epithelial OVCA and 850 controls age- and geographically-matched to cases. Rapid case ascertainment and random-digit-dialing systems are in place to ascertain cases and controls, respectively. A telephone survey focuses on risk factors as well as factors of particular relevance for AAs. Food-frequency questionnaires, follow-up surveys, biospecimens and medical records are also obtained. Results: Current accrual of 403 AA OVCA cases and 639 controls exceeds that of any existing study to date. We observed a high proportion (15%) of deceased non-responders among the cases that in part is explained by advanced stage at diagnosis. A logistic regression model did not support that socio-economic status was a factor in advanced stage at diagnosis. Most risk factor associations were in the expected direction and magnitude. High BMI was associated with ovarian cancer risk, with multivariable adjusted ORs and 95% CIs of 1.50 (0.99-2.27) for obese and 1.27 (0.85- 1.91) for morbidly obese women compared to normal/underweight women. Conclusions: AACES targets a rare tumor in AAs and addresses issues most relevant to this population. The importance of the study is accentuated by the high proportion of OVCA cases ascertained as deceased. Our analyses indicated that obesity, highly prevalent in this population (>60% of the cases), was associated with increased OVCA risk. While these findings need to be replicated, they suggest the potential for an effective intervention on the risk in AAs. Upon completion of enrollment, AACES will be the largest epidemiologic study of OVCA in AA women

Effectiveness of a coordinated support system linking public hospitals to a health coaching service compared with usual care at discharge for patients with chronic low back pain: protocol for a randomised controlled trial

Background Although many people with chronic low back pain (LBP) improve following conservative treatment, one in five will experience worsening symptoms after discharge from treatment and seek health care again. The current LBP clinical care pathway in many health services lacks a well-integrated, systematic approach to support patients to remain physically active and self-manage their symptoms following discharge from treatment. Health coaching can support people to improve physical activity levels and may potentially reduce health care utilisation for LBP. The primary aim of this study is to evaluate the effect of introducing a coordinated support system (linking hospital outpatient physiotherapy services to a public health coaching service) at discharge from LBP treatment, on the future use of hospital, medical, and health services for LBP, compared with usual care provided at discharge. Methods Three hundred and seventy-four adults with chronic non-specific LBP will be recruited from the outpatient physiotherapy departments of public hospitals in New South Wales, Australia. Participants will be individually randomised to a support system (n = 187) or usual care group (n = 187). All participants will receive usual care provided at discharge from treatment. Participants allocated to the support system will also receive up to 10 telephone-based health coaching sessions, delivered by the Get Healthy Service®, over a 6-month period. Health coaches will monitor and support participants to improve physical activity levels and achieve personal health-related goals. The primary outcome is the total number of encounters with hospital, medical, and health services for LBP, at 12 months from baseline. A within-trial economic evaluation will quantify the incremental costs and benefits of the support system from a health system perspective, to support reimbursement decision making. Discussion This study will establish the effect of a coordinated support system, introduced at discharge from treatment, on the future use of hospital, medical, and health services for LBP and various health outcomes. Conclusion Innovative community-driven solutions to support people with chronic LBP after discharge from treatment are urgently needed. Study findings will help inform health care policy and clinical practice in Australia

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment