Nowhere to Run; Nowhere to Hide: The Reality of Being a Law Library Director in Times of Great Opportunity and Significant Challenges

This is an edited version of remarks presented at \u27Nowhere to Run, Nowhere to Hide\u27: The Reality of Being a Law Library Director in Times of Great Opportunity and Significant Challenges, January 5, 2015, at the Association of American Law Schools Annual Meeting, Washington, D.C

Genetic Determinants of UV-Susceptibility in Non-Melanoma Skin Cancer

A milieu of cytokines and signaling molecules are involved in the induction of UV-induced immune suppression and thus the etiology of non-melanoma skin cancer (NMSC). Targeting the UV-induced immunosuppression pathway, and using a large population based study of NMSC, we have investigated the risk associated with functional variants in 10 genes (IL10, IL4, IL4R, TNF, TNFR2, HTR2A, HRH2, IL12B, PTGS2, and HAL). The most prominent single genetic effect was observed for IL10. There was increasing risk for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with increasing number of variant IL10 haplotypes (BCC: ptrend = 0.0048; SCC: ptrend = 0.031). Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (ORBCC = 1.5, 95% CI 1.1–1.9; ORSCC = 1.4, 95% CI 1.0–1.9), and these associations were largely confined to women (ORBCC = 2.2, 95% CI 1.4–3.4; SCC: ORSCC = 1.8, 95% CI 1.1–3.0). To examine how combinations of these variants contribute to risk of BCC and SCC, we used multifactor dimensionality reduction (MDR) and classification and regression trees (CART). Results from both of these methods found that in men, a combination of skin type, burns, IL10, IL4R, and possibly TNFR2 were important in both BCC and SCC. In women, skin type, burns, and IL10 were the most critical risk factors in SCC, with risk of BCC involving these same factors plus genetic variants in HTR2A, IL12B and IL4R. These data suggest differential genetic susceptibility to UV-induced immune suppression and skin cancer risk by gender

Ethical and Regulatory Issues for Embedded Pragmatic Trials Involving People Living with Dementia

Embedded pragmatic clinical trials (ePCTs) present an opportunity to improve care for people living with dementia (PLWD) and their care partners, but they also generate a complex constellation of ethical and regulatory challenges. These challenges begin with participant identification. Interventions may be delivered in ways that make it difficult to identify who is a human subject and therefore who needs ethical and regulatory protections. The need for informed consent, a core human subjects protection, must be considered but can be in tension with the goals of pragmatic research design. Thus it is essential to consider whether a waiver or alteration of informed consent is justifiable. If informed consent is needed, the question arises of how it should be obtained because researchers must acknowledge the vulnerability of PLWD due in part to diminished capacity and also to increased dependence on others. Further, researchers should recognize that many sites where ePCTs are conducted will be unfamiliar with human subjects research regulations and ethics. In this report, the Regulation and Ethics Core of the National Institute on Aging Imbedded Pragmatic Alzheimer’s disease (AD) and AD-related dementias (AD/ADRD) Clinical Trials (IMPACT) Collaboratory discusses key ethical and regulatory challenges for ePCTs in PLWD. A central thesis is that researchers should strive to anticipate and address these challenges early in the design of their ePCTs as a means of both ensuring compliance and advancing science

Genus β human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study

Objective To investigate the association between genus β human papillomaviruses and the incidence of non-melanocytic skin cancer in the general population

A Population-Based Case–Control Study of Urinary Arsenic Species and Squamous Cell Carcinoma in New Hampshire, USA

Background: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States. Objective: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population. Methods: We conducted a population-based case–control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and summed these arsenic species (ΣAs). Because seafood contains arsenolipids and arsenosugars that metabolize into DMA through alternate pathways, participants who reported seafood consumption within 2 days before urine collection were excluded from the analyses. Results: In adjusted logistic regression analyses (323 cases, 319 controls), the SCC odds ratio (OR) was 1.37 for each ln-transformed microgram per liter increase in ln-transformed ΣAs concentration [ln(ΣAs)] (95% CI: 1.04, 1.80). Urinary ln(MMA) and ln(DMA) also were positively associated with SCC (OR = 1.34; 95% CI: 1.04, 1.71 and OR = 1.34; 95% CI: 1.03, 1.74, respectively). A similar trend was observed for ln(iAs) (OR = 1.20; 95% CI: 0.97, 1.49). Percent iAs, MMA, and DMA were not associated with SCC. Conclusions: These results suggest that arsenic exposure at levels common in the United States relates to SCC and that arsenic metabolism ability does not modify the association

Inotersen preserves or improves quality of life in hereditary transthyretin amyloidosis

Objective: To examine the impact on quality of life (QOL) of patients with hATTR amyloidosis with polyneuropathy treated with inotersen (Tegsedi™) versus placebo. Methods: Data were from the NEURO-TTR trial (ClinicalTrials.gov Identifier: NCT01737398), a phase 3, multinational, randomized, double-blind, placebo-controlled study of inotersen in patients with hATTR amyloidosis with polyneuropathy. At baseline and week 66, QOL measures-the Norfolk-QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2)-were assessed. Treatment differences in mean changes in QOL from baseline to week 66 were tested using mixed-effect models with repeated measures. Responder analyses compared the percentages of patients whose QOL meaningfully improved or worsened from baseline to week 66 in inotersen and placebo arms. Descriptive analysis of item responses examined treatment differences in specific activities and functions at week 66. Results: Statistically significant mean differences between treatment arms were observed for three of five Norfolk-QOL-DN domains and five of eight SF-36v2 domains, with better outcomes for inotersen than placebo in physical functioning, activities of daily living, neuropathic symptoms, pain, role limitations due to health problems, and social functioning. A larger percentage of patients in the inotersen arm than the placebo arm showed preservation or improvement in Norfolk-QOL-DN and SF-36v2 scores from baseline to week 66. Responses at week 66 showed more substantial problems with daily activities and functioning for patients in the placebo arm than in the inotersen arm. Conclusion: Patients with hATTR amyloidosis with polyneuropathy treated with inotersen showed preserved or improved QOL at 66 weeks compared to those who received placebo.This research was funded by Akcea Therapeutics and Ionis Pharmaceuticals, Incinfo:eu-repo/semantics/publishedVersio

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes