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Multilevel Analysis of Municipal Officials' Participation in Land Use Policies Supportive of Active Living: City and Individual Factors

Tue, 04/04/2017 - 10:34pm

PURPOSE: To investigate individual- and city-level factors associated with municipal officials' participation in a local land use policy that supports active living.

DESIGN: Cross-sectional study.

SETTING: Eighty-three cities in eight states.

SUBJECTS: Four hundred thirteen elected and appointed officials with various job functions including mayors, city councilors, aldermen, selectmen, city or town managers, and heads of departments of planning, community development, public works, transportation, engineering, parks and recreation, neighborhood services, and public health.

MEASURES: A Web-based survey assessed perceived importance of physical activity and livability issues to job responsibilities; perceived resident support of local government action to address physical activity and livability issues; and residence. City-level factors obtained from Census data included percentage of commuters by walking, bicycling, and public transit. The dependent variable was self-reported participation in developing, adopting, or implementing a local land use policy supportive of active living.

ANALYSIS: Hierarchical (two-level: municipal official-city) logistic regression model, using R.

RESULTS: Municipal officials living in the city where they worked were significantly more likely to be involved in a land use policy. Higher perceived importance of livability issues was associated with participation. Perceived importance of physical activity was inversely associated with land use policy involvement. Higher city-level bicycling rates resulted in increased odds of participation in a land use policy. City-level walking rates were inversely associated with land use policy participation.

CONCLUSION: Municipal officials who worked in cities with a higher proportion of bicycle commuters, who prioritized livability issues, and who resided in the city where they worked were more likely to engage in land use policies supportive of active living.

Decade-Long Trends in the Frequency of 90-Day Rehospitalizations After Hospital Discharge for Acute Myocardial Infarction

Tue, 04/04/2017 - 10:34pm

There are limited data available describing relatively contemporary trends in 90-day rehospitalizations in patients who survive hospitalization after an acute myocardial infarction (AMI) in a community setting. We examined decade-long (2001 to 2011) trends in, and factors associated with, 90-day rehospitalizations in patients discharged from 3 central Massachusetts (MA) hospitals after AMI. Residents of the Worcester, MA, metropolitan area discharged after AMI from 3 central MA hospitals on a biennial basis from 2001 to 2011 comprised the study population (n = 4,810). The average age of this population was 69 years, 42% were women, and 92% were white. From 2001 to 2011, 30.0% of patients were rehospitalized within 90 days after hospital discharge, and 38% of 90-day rehospitalizations occurred after the first month after hospital discharge. Crude 90-day rehospitalization rates decreased from 31.5% in 2001/2003 to 27.3% in 2009/2011. After adjusting for several sociodemographic characteristics, co-morbidities, and in-hospital factors, there was a reduced risk of being rehospitalized within 90 days after hospital discharge in 2009/2011 compared with 2001/2003 (risk ratio = 0.87, 95% CI = 0.77 to 0.98); this trend was slightly attenuated (risk ratio = 0.90, 95% CI = 0.79 to 1.02) after further adjustment for hospital treatment practices. Female sex, having several previously diagnosed co-morbidities, an increased hospital stay, and the in-hospital development of atrial fibrillation, cardiogenic shock, and heart failure were significantly associated with an increased risk of being rehospitalized. In conclusion, the likelihood of subsequent 90-day rehospitalizations remained frequent, and we did not observe a significant decrease in these rates during the years under study.

Immunology. An RNA twist to T(H)17 cells

Tue, 04/04/2017 - 10:34pm

T helper lymphocytes play essential roles in the adaptive immune system. They come in distinct types defined by unique transcriptional programs that control their development and functions. Among these, T helper 17 (TH17) cells are important in protecting mucosal surfaces against fungal and bacterial infections. In addition, TH17 cells contribute to the pathogenesis of multiple autoimmune diseases (1). A recent study (2) adds yet another layer of complexity to the biology of these complex cells—an RNA helicase and a long noncoding RNA (lncRNA) that act together to control their effector functions.

A Pilot Trial of Cisplatin/Etoposide/Radiotherapy Followed by Consolidation Docetaxel and the Combination of Bevacizumab (NSC-704865) in Patients With Inoperable Locally Advanced Stage III Non-Small-Cell Lung Cancer: SWOG S0533

Tue, 04/04/2017 - 3:32pm

BACKGROUND: The aim of this trial was to determine feasibility of incorporating bevacizumab (B) into concurrent chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Patients with unresectable stage III NSCLC, performance status of 0 to 1, and adequate organ function were accrued in 2 strata, low- and high-risk (squamous histology, hemoptysis, tumor with cavitation and/or adjacent to a major vessel). Cohort 1 patients received cisplatin 50 mg/m(2) days (d) 1 and 8, etoposide 50 mg/m(2) (d 1-5) for 2 cycles concurrent with radiotherapy (64.8 Gy) followed by docetaxel (D) 75 mg/m(2) and B 15 mg/kg for 3 cycles. If safety was established, then accrual would continue to cohort 2 (B, d 15, 36, 57) and then subsequently to cohort 3 (B, d 1, 22, 43).

RESULTS: Twenty-nine patients (17 low- and 12 high-risk) registered to cohort 1. Twenty-six patients (including 4 squamous, 1 adenosquamous) were assessable. Twenty-five completed CRT. Grade 3/4 toxicities during CRT included acceptable rates of hematologic toxicity, esophagitis, and pneumonitis. Of 21 assessable for safety with D/B consolidation, major adverse events were pneumonitis (2 Grade 3) and 2 episodes of fatal hemoptysis in the high-risk group, resulting in closure of this stratum. The low-risk stratum subsequently closed because of slow accrual. Median overall survival was 46 months for low-risk and 17 months for high-risk strata.

CONCLUSION: Bevacizumab was not safely integrated into CRT for stage III NSCLC in patients considered at high risk for hemoptysis. In lower risk patients, data are insufficient to determine safety or efficacy.

Imaging and Data Acquisition in Clinical Trials for Radiation Therapy

Tue, 04/04/2017 - 3:32pm

Cancer treatment evolves through oncology clinical trials. Cancer trials are multimodal and complex. Assuring high-quality data are available to answer not only study objectives but also questions not anticipated at study initiation is the role of quality assurance. The National Cancer Institute reorganized its cancer clinical trials program in 2014. The National Clinical Trials Network (NCTN) was formed and within it was established a Diagnostic Imaging and Radiation Therapy Quality Assurance Organization. This organization is Imaging and Radiation Oncology Core, the Imaging and Radiation Oncology Core Group, consisting of 6 quality assurance centers that provide imaging and radiation therapy quality assurance for the NCTN. Sophisticated imaging is used for cancer diagnosis, treatment, and management as well as for image-driven technologies to plan and execute radiation treatment. Integration of imaging and radiation oncology data acquisition, review, management, and archive strategies are essential for trial compliance and future research. Lessons learned from previous trials are and provide evidence to support diagnostic imaging and radiation therapy data acquisition in NCTN trials.

A Comparative Evaluation of Normal Tissue Doses for Patients Receiving Radiation Therapy for Hodgkin Lymphoma on the Childhood Cancer Survivor Study and Recent Children's Oncology Group Trials

Tue, 04/04/2017 - 3:32pm

PURPOSE: Survivors of pediatric Hodgkin lymphoma (HL) are recognized to have an increased risk of delayed adverse health outcomes related to radiation therapy (RT). However, the necessary latency required to observe these late effects means that the estimated risks apply to outdated treatments. We sought to compare the normal tissue dose received by children treated for HL and enrolled in the Childhood Cancer Survivor Study (CCSS) (diagnosed 1970-1986) with that of patients treated in recent Children's Oncology Group (COG) trials (enrolled 2002-2012).

METHODS AND MATERIALS: RT planning data were obtained for 50 HL survivors randomly sampled from the CCSS cohort and applied to computed tomography planning data sets to reconstruct the normal tissue dosimetry. For comparison, the normal tissue dosimetry data were obtained for all 191 patients with full computed tomography-based volumetric RT planning on COG protocols AHOD0031 and AHOD0831.

RESULTS: For early-stage patients, the mean female breast dose in the COG patients was on average 83.5% lower than that for CCSS patients, with an absolute reduction of 15.5 Gy. For advanced-stage patients, the mean breast dose was decreased on average by 70% (11.6 Gy average absolute dose reduction). The mean heart dose decreased on average by 22.9 Gy (68.6%) and 17.6 Gy (56.8%) for early- and advanced-stage patients, respectively. All dose comparisons for breast, heart, lung, and thyroid were significantly lower for patients in the COG trials than for the CCSS participants. Reductions in the prescribed dose were a major contributor to these dose reductions.

CONCLUSIONS: These are the first data quantifying the significant reduction in the normal tissue dose using actual, rather than hypothetical, treatment plans for children with HL. These findings provide useful information when counseling families regarding the risks of contemporary RT.

Effect of Standard Radiotherapy With Cisplatin vs Accelerated Radiotherapy With Panitumumab in Locoregionally Advanced Squamous Cell Head and Neck Carcinoma: A Randomized Clinical Trial

Tue, 04/04/2017 - 3:32pm

Importance: The Canadian Cancer Trials Group study HN.6 is the largest randomized clinical trial to date comparing the concurrent administration of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies with radiotherapy (RT) to standard chemoradiotherapy in locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).

Objective: To compare progression-free survival (PFS) in patients with LA-SCCHN treated with standard-fractionation RT plus high-dose cisplatin vs accelerated-fractionation RT plus the anti-EGFR antibody panitumumab. Design, Setting, and

Participants: A randomized phase 3 clinical trial in 17 Canadian centers. A total of 320 patients were randomized between December 2008 and November 2011. Interventions: Patients with TanyN+M0 or T3-4N0M0 LA-SCCHN were randomized 1:1 to receive standard-fractionation RT (70 Gy/35 over 7 weeks) plus cisplatin at 100 mg/m2 intravenous for 3 doses (arm A) vs accelerated-fractionation RT (70 Gy/35 over 6 weeks) plus panitumumab at 9 mg/kg intravenous for 3 doses (arm B). Main Outcomes and

Measures: Primary end point was PFS. Due to an observed declining event rate, the protocol was amended to a time-based analysis. Secondary end points included overall survival, local and regional PFS, distant metastasis-free survival, quality of life, adverse events, and safety.

Results: Of 320 patients randomized (268 [84%] male; median age, 56 years), 156 received arm A and 159 arm B. A total of 93 PFS events occurred. By intention-to-treat, 2-year PFS was 73% (95% CI, 65%-79%) in arm A and 76% (95% CI, 68%-82%) in arm B (hazard ratio [HR], 0.95; 95% CI, 0.60-1.50; P = .83). The upper bound of the HR 95% CI exceeded the prespecified noninferiority margin. Two-year overall survival was 85% (95% CI, 78%-90%) in arm A and 88% (95% CI, 82%-92%) in arm B (HR, 0.89; 95% CI, 0.54-1.48; P = .66). Incidence of any grade 3 to 5 nonhematologic adverse event was 88% in arm A and 92% in arm B (P = .25). Conclusions and

Relevance: With a median follow-up of 46 months, the PFS of panitumumab plus accelerated-fractionation RT was not superior to cisplatin plus standard-fractionation RT in LA-SCCHN and noninferiority was not proven. Despite having negative results, HN.6 has contributed important data regarding disease control and toxic effects of these treatment strategies.

Trial Registration: clinicaltrials.gov Identifier: NCT00820248.

Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial

Tue, 04/04/2017 - 3:32pm

Purpose: Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after definitive chemoradiation (CRT), associated with anogenital human papilloma virus, and often appears in HIV infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus-associated oropharyngeal SCC, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC.

Methods: Forty-five patients with stage I to III SCCAC and HIV infection received CRT: 45 to 54 Gy radiation therapy to the primary tumor and regional lymph nodes plus eight once-weekly doses of concurrent cetuximab and two cycles of cisplatin and fluorouracil. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided alpha, 0.10; power, 90%), assuming a 35% LRF rate from historical data.

Results: The 3-year LRF rate was 42% (95% CI, 28% to 56%; one-sided P = .9) by binomial proportional estimate using the prespecified end point (LRF or alive without LRF and followed < 3 years), and 20% (95% CI, 10% to 37%) by Kaplan-Meier estimate in post hoc analysis using definitions and methods consistent with historical data. Three-year rates by Kaplan-Meier estimate were 72% (95% CI, 56% to 84%) for progression-free survival and 79% (95% CI, 63% to 89%) for overall survival. Grade 4 toxicity occurred in 26%, and 4% had treatment-associated deaths.

Conclusion: HIV-associated SCCAC is potentially curable with definitive CRT. Although addition of cetuximab may result in less LRF, the 20% recurrence and 26% grade 4 toxicity rates indicate the continued need for more-effective and less-toxic therapies.

Systemic neoadjuvant chemotherapy for Group B intraocular retinoblastoma (ARET0331): A report from the Children's Oncology Group

Tue, 04/04/2017 - 3:32pm

PURPOSE: To evaluate a chemoreduction regimen using systemic vincristine and carboplatin (VC) and local ophthalmic therapies to avoid external-beam radiotherapy (EBRT) or enucleation in patients with Group B intraocular retinoblastoma.

PATIENTS AND METHODS: Twenty-one patients (25 eyes) were treated with six cycles of VC, accompanied by local ophthalmic therapies after cycle 1. The primary study objective was to determine the 2-year event-free survival (EFS) where an event was defined as the use of systemic chemotherapy in addition to vincristine or carboplatin, EBRT, and/or enucleation.

RESULTS: All patients had tumor regression after the first cycle of VC and only two patients had progression during therapy. There were seven treatment failures within 2 years of study enrollment, resulting in 2-year EFS of 65% and early study closure in accordance with the statistical design. The 2-year cumulative incidence of enucleation was 15%; for external beam radiation therapy, it was 10%; and for chemotherapy to control progressive disease, it was 10%. All patients sustaining a treatment failure were salvaged with additional therapy.

CONCLUSIONS: For the majority of patients with Group B intraocular retinoblastoma, chemoreduction with VC, without etoposide, in conjunction with local therapy provides excellent opportunity for ocular salvage. Local therapy given with every chemotherapy cycle and incorporation of etoposide may provide improved ocular salvage rates. Central review of group at diagnosis is critical in assigning appropriate therapies.

Cetuximab Plus Chemoradiotherapy in Immunocompetent Patients With Anal Carcinoma: A Phase II Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group Trial (E3205)

Tue, 04/04/2017 - 3:32pm

Purpose: Squamous cell carcinoma of the anal canal (SCCAC) is characterized by high locoregional failure (LRF) rates after sphincter-preserving definitive chemoradiation (CRT) and is typically associated with anogenital human papilloma virus infection. Because cetuximab enhances the effect of radiation therapy in human papilloma virus-associated oropharyngeal squamous cell carcinoma, we hypothesized that adding cetuximab to CRT would reduce LRF in SCCAC.

Methods: Sixty-one patients with stage I to III SCCAC received CRT including cisplatin, fluorouracil, and radiation therapy to the primary tumor and regional lymph nodes (45 to 54 Gy) plus eight once-weekly doses of concurrent cetuximab. The study was designed to detect at least a 50% reduction in 3-year LRF rate (one-sided alpha, 0.10; power 90%), assuming a 35% LRF rate from historical data.

Results: Poor risk features included stage III disease in 64% and male sex in 20%. The 3-year LRF rate was 23% (95% CI, 13% to 36%; one-sided P = .03) by binomial proportional estimate using the prespecified end point and 21% (95% CI, 7% to 26%) by Kaplan-Meier estimate in a post hoc analysis using methods consistent with historical data. Three-year rates were 68% (95% CI, 55% to 79%) for progression-free survival and 83% (95% CI, 71% to 91%) for overall survival. Grade 4 toxicity occurred in 32%, and 5% had treatment-associated deaths.

Conclusion: Although the addition of cetuximab to chemoradiation for SCCAC was associated with lower LRF rates than historical data with CRT alone, toxicity was substantial, and LRF still occurs in approximately 20%, indicating the continued need for more effective and less toxic therapies.

Outside-The-Box College Accommodations: Real Support for Real Students: Tools for School II

Mon, 04/03/2017 - 4:22pm

Most schools are used to providing typical accommodations such as: note taker, extra time for assignments, and assistive technology for students of many different disabilities. Yet, the challenges of having a mental health condition are unique. This tip sheet will help you to think “outside-the-box” to get the educational accommodations that help you with your unique struggles.

RNA2DNAlign: nucleotide resolution allele asymmetries through quantitative assessment of RNA and DNA paired sequencing data.

Mon, 04/03/2017 - 10:57am

We introduce RNA2DNAlign, a computational framework for quantitative assessment of allele counts across paired RNA and DNA sequencing datasets. RNA2DNAlign is based on quantitation of the relative abundance of variant and reference read counts, followed by binomial tests for genotype and allelic status at SNV positions between compatible sequences. RNA2DNAlign detects positions with differential allele distribution, suggesting asymmetries due to regulatory/structural events. Based on the type of asymmetry, RNA2DNAlign outlines positions likely to be implicated in RNA editing, allele-specific expression or loss, somatic mutagenesis or loss-of-heterozygosity (the first three also in a tumor-specific setting). We applied RNA2DNAlign on 360 matching normal and tumor exomes and transcriptomes from 90 breast cancer patients from TCGA. Under high-confidence settings, RNA2DNAlign identified 2038 distinct SNV sites associated with one of the aforementioned asymetries, the majority of which have not been linked to functionality before. The performance assessment shows very high specificity and sensitivity, due to the corroboration of signals across multiple matching datasets. RNA2DNAlign is freely available from http://github.com/HorvathLab/NGS as a self-contained binary package for 64-bit Linux systems.

Stability of the Infant Car Seat Challenge and Risk Factors for Oxygen Desaturation Events

Mon, 04/03/2017 - 10:20am

Research suggests that infants with poor neck and upper torso muscle tone experience lateral slouching and a compromised airway when placed in the semi-upright seating position. Studies reveal that 4-60% of premature infants (born at less than 3-7 weeks gestation) may experience oxygen desaturation events when in their child safety seats (CSS), potentially resulting in adverse neurodevelopmental outcomes. Therefore, the American Academy of Pediatrics recommends that premature infants be tested in their CSS prior to hospital discharge. However, neonatal healthcare providers are concerned that this method of testing might not be reliable. No formal studies have investigated the outcomes of repeat testing of premature infants, and little is known about the risk factors for oxygen desaturation events. Therefore, the purpose of this descriptive, non-experimental, observational study was to explore the stability of the one-point Infant Car Seat Challenge (ICSC) and risk factors that may be associated with oxygen desaturation events. A sample of 49 premature infants was used to explore the following variables: 1) pass/fail rates following two (ICSC) observation points, 2) oxygen saturation and desaturation patterns, sleep/wake activity, and a measure of head lag (using the pull-to-sit maneuver) during two ICSCs, and 3) the association between head lag, chronological age, time spent sleeping in the CSS and oxygen desaturation events. Data were analyzed by descriptive and nonparametric statistical tests. This study's findings indicated that 86% of premature infants had stable results, 8% passed rcsc 1 but not ICSC 2, and 6% failed ICSC l and passed ICSC 2. In addition the odds for oxygen desaturation events increased in infants that are born at a gestational age ≤ 34 weeks, were discharged home at a chronological age of > 7 days and had a corrected gestational age of ≤ 37 weeks. Neither head lag or sleep time influenced the ICSC outcomes. Furthermore the ICSC success rate for identifying at risk infants was equal to or better than that of other screening tests for newborn medical conditions. These findings will assist neonatal healthcare providers in making appropriate recommendations for safe travel.

An Exploratory Sequential Mixed Methods Approach to Understanding Researchers’ Data Management Practices at UVM: Integrated Findings to Develop Research Data Services

Fri, 03/31/2017 - 9:02am

This is the third in a series of articles reporting on a study of researcher data management practices and data services at the University of Vermont.

This article reports on the integrated findings of an exploratory sequential mixed methods research design aimed to understand data management behaviors and challenges of faculty at the University of Vermont (UVM) in order to develop relevant research data services. The exploratory sequential mixed methods design is characterized by an initial qualitative phase of data collection and analysis, followed by a phase of quantitative data collection and analysis, with a final phase of integration or linking of data from the two separate strands of data. A joint display was used to integrate data focused on the three primary research questions: How do faculty at UVM manage their research data, in particular how do they share and preserve data in the long-term?; What challenges or barriers do UVM faculty face in effectively managing their research data?; and What institutional data management support or services are UVM faculty interested in? As a result of the analysis, this study suggests four major areas of research data services for UVM to address: infrastructure, metadata, data analysis and statistical support, and informational research data services. The implementation of these potential areas of research data services is underscored by the need for cross-campus collaboration and support.

An Exploratory Sequential Mixed Methods Approach to Understanding Researchers’ Data Management Practices at UVM: Findings from the Quantitative Phase

Fri, 03/31/2017 - 9:02am

This is the second in a series of articles reporting on a study of researcher data management practices and data services at the University of Vermont.

This article reports on the second quantitative phase of an exploratory sequential mixed methods research design focused on researcher data management practices and related institutional support and services. The study aims to understand data management activities and challenges of faculty at the University of Vermont (UVM), a higher research activity Research University, in order to develop appropriate research data services (RDS). Data was collected via a survey, built on themes from the initial qualitative data analysis from the first phase of this study. The survey was distributed to a nonrandom census sample of full-time UVM faculty and researchers (P=1,190); from this population, a total of 319 participants completed the survey for a 26.8% response rate. The survey collected information on five dimensions of data management: data management activities; data management plans; data management challenges; data management support; and attitudes and behaviors towards data management planning. Frequencies, cross tabulations, and chi-square tests of independence were calculated using demographic variables including gender, rank, college, and discipline. Results from the analysis provide a snapshot of research data management activities at UVM, including types of data collected, use of metadata, short- and long-term storage of data, and data sharing practices. The survey identified key challenges to data management, including data description (metadata) and sharing data with others; this latter challenge is particular impacted by confidentiality issues and lack of time, personnel, and infrastructure to make data available. Faculty also provided insight to RDS that they think UVM should support, as well as RDS they were personally interested in. Data from this study will be integrated with data from the first qualitative phase of the research project and analyzed for meta-inferences to help determine future research data services at UVM.

An Exploratory Sequential Mixed Methods Approach to Understanding Researchers’ Data Management Practices at UVM: Findings from the Qualitative Phase

Fri, 03/31/2017 - 9:01am

This is the first in a series of articles reporting on a study of researcher data management practices and data services at the University of Vermont.

The objective of this article is to report on the first qualitative phase of an exploratory sequential mixed methods research design focused on researcher data management practices and related institutional research data services. The aim of this study is to understand data management behaviors of faculty at the University of Vermont (UVM), a higher-research activity Research University, in order to guide the development of campus research data management services. The population of study was all faculty who received National Science Foundation (NSF) grants between 2011 and 2014 who were required to submit a data management plan (DMP); qualitative data was collected in two forms: (1) semi-structured interviews and (2) document analysis of data management plans. From a population of 47 researchers, six were included in the interview sample, representing a broad range of disciplines and NSF Directorates, and 35 data management plans were analyzed. Three major themes were identified through triangulation of qualitative data sources: data management activities, including data dissemination and data sharing; institutional research support and infrastructure barriers; and perceptions of data management plans and attitudes towards data management planning. The themes articulated in this article will be used to design a survey for the second quantitative phase of the study, which will aim to more broadly generalize data management activities at UVM across all disciplines.

The Sodium Channel beta4 Auxiliary Subunit Selectively Controls Long-Term Depression in Core Nucleus Accumbens Medium Spiny Neurons

Wed, 03/29/2017 - 1:04pm

Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the brain, and the induction of synaptic plasticity. Although all brain neurons express one or several variants coding for the core pore-forming sodium channel alpha subunit, the expression of the beta (beta1-4) auxiliary subunits varies greatly. Of particular interest is the beta4 subunit, encoded by the Scn4b gene, that is highly expressed in dorsal and ventral (i.e., nucleus accumbens - NAc) striata compared to other brain regions, and that endows sodium channels with unique gating properties. However, its role on neuronal activity, synaptic plasticity, and behaviors related to drugs of abuse remains poorly understood. Combining whole-cell patch-clamp recordings with two-photon calcium imaging in Scn4b knockout (KO) and knockdown mice, we found that Scn4b altered the properties of APs in core accumbens medium spiny neurons (MSNs). These alterations are associated with a reduction of the probability of MSNs to evoke spike-timing-dependent long-term depression (tLTD) and a reduced ability of backpropagating APs to evoke dendritic calcium transients. In contrast, long-term potentiation (tLTP) remained unaffected. Interestingly, we also showed that amphetamine-induced locomotor activity was significantly reduced in male Scn4b KO mice compared to wild-type controls. Taken together, these data indicate that the Scn4b subunit selectively controls tLTD by modulating dendritic calcium transients evoked by backpropagating APs.

Leukoaraiosis, intracerebral hemorrhage, and functional outcome after acute stroke thrombolysis

Wed, 03/29/2017 - 1:04pm

OBJECTIVE: To perform a systematic review and pooled meta-analysis of published studies to assess whether the presence of leukoaraiosis on neuroimaging before treatment with thrombolysis (IV or intra-arterial) is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome.

METHODS: We included studies of patients with acute ischemic stroke, treated with IV or intra-arterial thrombolysis, which assessed functional outcome (3-month modified Rankin Scale [mRS]) or sICH in relation to leukoaraiosis on pretreatment neuroimaging (CT or MRI). We used random-effects models to calculate pooled relative risks (RR) of sICH and poor functional outcome (mRS > /= 2) for any vs no leukoaraiosis (using any rating scale) and for no to mild vs moderate to severe leukoaraiosis (using the Van Swieten or Fazekas Schmidt scale).

RESULTS: We identified 15 studies (total n = 6,967). For sICH outcome, the RR was 1.65 (n = 5,551; 95% confidence interval [CI] 1.26-2.16, p = 0.001) with an absolute risk (AR) increase of 2.5% for any leukoaraiosis vs none. The RR was 2.4 (n = 4,192; 95% CI 1.83-3.14, p = 0.001) with an AR increase of 6.2% for moderate to severe vs no to mild leukoaraiosis. For poor functional outcome; the RR was 1.30 (n = 3,401; 95% CI 1.19-1.42, p = 0.001) with an AR increase of 15.4% for any leukoaraiosis vs none. The RR was 1.31 (n = 3,659; 95% CI 1.22-1.42, p = 0.001) with an AR increase of 17.5% for moderate to severe vs no to mild leukoaraiosis. No statistical heterogeneity was noted for any of the analyses.

CONCLUSIONS: Leukoaraiosis presence and severity are consistently associated with an increased risk of sICH and poor functional outcome after IV or intra-arterial thrombolysis for acute ischemic stroke.

Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring

Wed, 03/29/2017 - 1:04pm

Paternal environmental conditions can influence phenotypes in future generations, but it is unclear whether offspring phenotypes represent specific responses to particular aspects of the paternal exposure history, or a generic response to paternal 'quality of life'. Here, we establish a paternal effect model based on nicotine exposure in mice, enabling pharmacological interrogation of the specificity of the offspring response. Paternal exposure to nicotine prior to reproduction induced a broad protective response to multiple xenobiotics in male offspring. This effect manifested as increased survival following injection of toxic levels of either nicotine or cocaine, accompanied by hepatic upregulation of xenobiotic processing genes, and enhanced drug clearance. Surprisingly, this protective effect could also be induced by a nicotinic receptor antagonist, suggesting that xenobiotic exposure, rather than nicotinic receptor signaling, is responsible for programming offspring drug resistance. Thus, paternal drug exposure induces a protective phenotype in offspring by enhancing metabolic tolerance to xenobiotics.

Data quality assurance and control in cognitive research: Lessons learned from the PREDICT-HD study

Wed, 03/29/2017 - 1:04pm

We discuss the strategies employed in data quality control and quality assurance for the cognitive core of Neurobiological Predictors of Huntington's Disease (PREDICT-HD), a long-term observational study of over 1,000 participants with prodromal Huntington disease. In particular, we provide details regarding the training and continual evaluation of cognitive examiners, methods for error corrections, and strategies to minimize errors in the data. We present five important lessons learned to help other researchers avoid certain assumptions that could potentially lead to inaccuracies in their cognitive data.