Understanding Local Alcohol Control in Wisconsin: Building a Database of Local Municipal Alcohol Policies.

In Wisconsin, many alcohol policies are regulated at the local level. To examine the relationship between local policies, alcohol use and health outcomes, our team developed a database to collect local alcohol policies. Initial results highlight differences in how policies are defined, enforced, and made available to the public.

A review of the outcomes of children with designated additional needs receiving cochlear implantation for severe to profound hearing loss.

OBJECTIVE: To evaluate one year outcomes of children with additional needs receiving cochlear implantation at the Yorkshire Auditory Implant Service (YAIS) over a ten-year period. METHODS: Retrospective chart review yielded 270 children who received cochlear implants (CIs) at YAIS between 2007 and 2017; 49 children were classified as having additional needs. Audiological performance scales (Meaningful Auditory Information Scale (MAIS), Meaningful Use of Speech Scale (MUSS), Listening in Progress (LIP), Categories of Auditory Performance (CAP), and Speech Intelligibility Rating Scale (SIR)) were analysed pre- and 12 months post-implantation. Comparison was made with children without additional needs. RESULTS: Children with additional needs demonstrated significantly lower pre-implantation audiological performance in MAIS, LIP, and MUSS (P <0.05). Despite showing improvement, children with additional needs consistently achieved lower scores in all metrics at one year (P < 0.05). Similarly, the rate of change was statistically significantly lower in children with additional needs. CONCLUSION: All children were able to gain access to sound following CI. Improvements were seen in all outcome measures especially in the MAIS, CAP and LIP whereas limited improvement was seen in measures assessing speech production and improvement. The rate of improvement was statistically significantly lower in children with additional needs.

Physical and Physiological Determinants of Rock Climbing.

PURPOSE: Rock climbing performance relies on many characteristics. Herein, the authors identified the physical and physiological determinants of peak performance in rock climbing across the range from lower grade to elite. METHODS: Forty four male and 33 female climbers with onsight maximal climbing grades 5a-8a and 5a-7b+, respectively, were tested for physical, physiological, and psychological characteristics (independent variables) that were correlated and modeled by multiple regression and principal component analysis to identify the determinants of rock climbing ability. RESULTS: In males, 23 of 47 variables correlated with climbing ability (P < .05, Pearson correlation coefficients .773-.340), including shoulder endurance, hand and finger strength, shoulder power endurance, hip flexibility, lower-arm grip strength, shoulder power, upper-arm strength, core-body endurance, upper-body aerobic endurance, hamstrings and lower-back flexibility, aerobic endurance, and open-hand finger strength. In females, 10 of 47 variables correlated with climbing ability (P < .05, Pearson correlation coefficients .742-.482): shoulder endurance and power, lower-arm grip strength, balance, aerobic endurance, and arm span. Principal component analysis and univariate multiple regression identified the main explanatory variables. In both sexes, shoulder power and endurance measured as maximum pull-ups, average arm crank power, and bent-arm hang, emerged as the main determinants (P < .01; adjusted R2 = .77 in males and .62 in females). In males, finger pincer (P = .07) and grip strength also had trends (P = .09) toward significant effects. Finally, in test-of-principle training studies, they trained to increase main determinants 42% to 67%; this improved climbing ability 2 to 3 grades. CONCLUSIONS: Shoulder power and endurance majorly determines maximal climbing. Finger, hand, and arm strength, core-body endurance, aerobic endurance, flexibility, and balance are important secondary determinants.

Childhood maltreatment moderates the effect of combat exposure on cingulum structural integrity.

Limbic white matter pathways link emotion, cognition, and behavior and are potentially malleable to the influences of traumatic events throughout development. However, the impact of interactions between childhood and later life trauma on limbic white matter pathways has yet to be examined. Here, we examined whether childhood maltreatment moderated the effect of combat exposure on diffusion tensor imaging measures within a sample of military veterans (N = 28). We examined five limbic tracts of interest: two components of the cingulum (cingulum, cingulate gyrus, and cingulum hippocampus [CGH]), the uncinate fasciculus, the fornix/stria terminalis, and the anterior limb of the internal capsule. Using effect sizes, clinically meaningful moderator effects were found only within the CGH. Greater combat exposure was associated with decreased CGH fractional anisotropy (overall structural integrity) and increased CGH radial diffusivity (perpendicular water diffusivity) among individuals with more severe childhood maltreatment. Our findings provide preliminary evidence of the moderating effect of childhood maltreatment on the relationship between combat exposure and CGH structural integrity. These differences in CGH structural integrity could have maladaptive implications for emotion and memory, as well as provide a potential mechanism by which childhood maltreatment induces vulnerability to later life trauma exposure.

Technology, Affordances and Occupational Identity Amongst Older Telecommunications Engineers: From Living Machines to Black-Boxes.

This article explores the relationship between technology and occupational identity based on working-life biographical interviews with older telecommunications engineers. In the construction of their own working-life biographical narratives, participants attached great importance to the technology with which they worked. The article contends that workers' relationship with technology can be more nuanced than either the sociology of technology literature or the sociology of work literature accommodates. Adopting the concept of affordances, it is argued that the physical nature of earlier electromechanical technology afforded engineers the opportunity to 'fix' things through the skilled application of tools and act as autonomous custodians of 'living' machines: factors that were inherent to their occupational identity. However, the change to digital technology denied the affordances to apply hands-on skill and undermined key elements of the engineering occupational identity. Rather than simply reflecting the nostalgic romanticizing of the past, the biographies captured deterioration in the material realities of work.

Radiotherapy With Curative Intent in Patients With Early-stage, Medically Inoperable, Non-Small-cell Lung Cancer: A Systematic Review.

Patients with early-stage non-small-cell lung cancer (NSCLC) who are unable to undergo surgery can be offered radiation therapy (RT). Previously, conventional RT was offered; however, newer techniques such as stereotactic body RT (SBRT) have become available. The objective of the present systematic review was to investigate the effectiveness of RT with curative intent in patients with early-stage medically inoperable NSCLC. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing stereotactic RT with curative intent compared with observation or other types of RT for early-stage, medically inoperable, NSCLC. Comparisons of radiation dosing or fractionation schedules for SBRT were included. We include 4 systematic reviews and 52 observational studies. The evidence suggests that SBRT compared with observation or other forms of RT, such as accelerated hypofractionated RT, 3-dimensional conformal RT, conventional fractionated RT, external beam RT, proton beam therapy, and carbon ion therapy, could have similar or improved results in survival or local control, with similar or fewer adverse effects. Evidence also suggests that local tumor control and survival were associated with the biologically effective dose (BED) for SBRT. Several studies suggested a cutoff of approximately 100 BED correlated significantly with patient outcomes. The presented evidence suggests that SBRT compared with other forms of RT is a reasonable treatment option for patients with medically inoperable early-stage NSCLC.

Effects of gender on locomotor sensitivity to amphetamine, body weight, and fat mass in regulator of G protein signaling 9 (RGS9) knockout mice.

Regulator of G-protein signaling (RGS) protein 9-2 is enriched in the striatum where it modulates dopamine and opioid receptor-mediated signaling. RGS9 knockout (KO) mice show increased psychostimulant-induced behavioral sensitization, as well as exhibit higher body weights and greater fat accumulation compared to wild-type (WT) littermates. In the present study, we found gender influences on each of these phenotypic characteristics. Female RGS9 KO mice exhibited greater locomotor sensitization to amphetamine (1.0mg/kg) treatment as compared to male RGS9 KO mice. Male RGS9 KO mice showed increased body weights as compared to male WT littermates, while no such differences were detected in female mice. Quantitative magnetic resonance showed that male RGS9 KO mice accumulated greater fat mass vs. WT littermates at 5months of age. Such observations could not be explained by increased caloric consumption since male and female RGS9 KO mice demonstrated equivalent daily food intake as compared to their respective WT littermates. Although indirect calorimetry methods found decreased oxygen consumption and carbon dioxide production during the 12-hour dark phase in male RGS9 KO vs. WT mice which are indicative of less energy expenditure, male RGS9 KO mice exhibited lower levels of locomotor activity during this period. Genotype had no effect on metabolic activities when KO and WT groups were compared under fasting vs. feeding treatments. In summary, these results highlight the importance of factoring gender into the experimental design since many studies conducted in RGS9 KO mice utilize locomotor activity as a measured outcome.

A Tet-on system for DRD1-expressing cells.

Cells expressing the dopamine D1 receptor (DRD1) have significant functional roles in diverse physiological processes including locomotion and drug addiction. The present work presents a novel in vivo DRD1-Bacterial Artificial Chromosome (BAC) Tet-on system allowing for the inducible activation of tet-operated transgenes specifically within DRD1-expressing cells of transgenic mice. It is shown that the DRD1-rtTA BAC-driven expression of a tet-operated reporter is under tight regulation by doxycycline and is restricted to DRD1-expressing brain regions. The model will be a useful research tool in studies of movement and reward and associated pathologies such as Parkinson's disease and addiction.

Analysis and correction of crosstalk effects in pathway analysis.

Identifying the pathways that are significantly impacted in a given condition is a crucial step in understanding the underlying biological phenomena. All approaches currently available for this purpose calculate a P-value that aims to quantify the significance of the involvement of each pathway in the given phenotype. These P-values were previously thought to be independent. Here we show that this is not the case, and that many pathways can considerably affect each other's P-values through a "crosstalk" phenomenon. Although it is intuitive that various pathways could influence each other, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena. Using real pathways and data, we show that in some cases pathways with significant P-values are not biologically meaningful, and that some biologically meaningful pathways with nonsignificant P-values become statistically significant when the crosstalk effects of other pathways are removed. We describe a technique able to detect, quantify, and correct crosstalk effects, as well as identify independent functional modules. We assessed this novel approach on data from four experiments involving three phenotypes and two species. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes.

Simultaneous electrical and plasmonic monitoring of potential induced ion adsorption on metal nanowire arrays.

Simultaneous LSPR and electronic sensing of potential induced ion adsorption onto gold nanowire arrays is presented. The formation of a Stern layer upon applying an electrochemical potential generated a complex optical response. Simulation of a lossy atomic layer on the nanowire array using the Multiple Multipole Program (MMP) corresponded very well to the experimentally observed peak position, intensity, and radius of curvature changes. Additionally, a significant voltage-dependent change in the resistance of the gold nanowire array was observed during the controlled formation of the electrical double layer. The results demonstrated that an applied electrochemical potential induces measurable changes in the optical and electrical properties of the gold nanowire surface. This is the first demonstration of combined plasmonic and nanowire resistance-based sensing of a surface process in the literature.

Evaluation of microscopic disease in oral tongue cancer using whole-mount histopathologic techniques: implications for the management of head-and-neck cancers.

PURPOSE: To map the distribution of microscopic disease (MD) in head-and-neck cancer by analyzing digital images of whole-mounted serial sections of tongue cancer specimens. METHODS AND MATERIALS: Ten T1-3 oral tongue cancer specimens were evaluated. The specimens were sliced into 3-mm blocks from which one or more 4-µm slides were taken and digitized to create whole-mounted serial sections. Gross tumor and microscopic disease were digitally contoured on each slide. Lines perpendicular to the gross tumor volume (GTV) edge were created at 0.05-mm intervals and the distance between GTV and MD measured. RESULTS: Of 88 slides assessed, 44 (50%) had evidence of MD. Of the 63,809 perpendicular lines drawn along the GTV edges, 2320 (3.6%) encountered microscopic disease along their path. The majority of MD abutted the GTV, and only 26.7% was noncontiguous with the GTV edge. The maximum distance from the border was 7.8 mm. Ninety-nine percent of all MD was within 4.75 mm and 95% was within 3.95 mm of the GTV. CONCLUSION: In this study we were able to assess the distribution of MD more accurately than has been possible with routine pathologic techniques. The results indicate that when the GTV is correctly identified, there is very little MD to be found outside this volume. This has implications for the volume of tissue resected at surgery and the volume included in the clinical target volume in conformal radiotherapy planning.

Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes.

Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.

High-dose methotrexate based chemotherapy with deferred radiation for treatment of newly diagnosed primary central nervous system lymphoma.

The addition of high-dose methotrexate (HD-MTX) to whole-brain radiation therapy (WBRT) has improved the survival of patients with primary central nervous system lymphoma (PCNSL). However, combined therapy is associated with increased neurotoxicity. In an effort to limit this toxicity, we treated a series of non-immunocompromised patients with HDMVP, a HD-MTX based regimen, with deferral of WBRT until progression. Twenty-three patients were treated with the HDMVP regimen consisting of MTX, vincristine, and procarbazine. The mean age at diagnosis was 60.9 years (range 45-79 years). The overall response rate was 65% (14 complete responses and one partial response). For patients achieving an initial response with HDMVP the median response duration was 40.4 months (95% confidence interval [CI] 19.5-61.3). The median progression-free survival was 4.6 months (95% CI 0.0-20.4) and median overall survival was 41.4 months (95% CI 0.0-95.5). Fourteen patients received WBRT for relapsed or progressive disease. The conclusion of this trial is that HDVMP results in good initial response rates but only moderate disease control. Ultimately the majority of the patients in this series required WBRT for salvage treatment, potentially enabling a delay in treatment-associated neurotoxicity.

On comparing the quality of head and neck IMRT plans delivered with two different linear accelerator manufacturers.

The purpose of this work was to determine whether 2 different types of linear accelerators manufacturers with similar MLC leaf widths deliver equivalent IMRT distributions for head and neck radiotherapy patients. In this study, plans delivered with Siemens linacs were re-optimized with an Elekta linac and vice versa. To test for significance, paired t-tests were computed to examine differences in target and normal tissue doses and monitor units. Dose distributions, dose-volume histograms, and dose to targets and normal tissues were found to be equivalent irrespective of the linac type. However, approximately 15% more monitor units were delivered when planned on the Elekta machine (p < 0.002). Both linear accelerators provide plans of comparable dosimetric quality; however, Elekta machines deliver slightly more monitor units than Siemens machines. This increase is likely due differences in geometric properties of the machine head designs, as modeled in the treatment planning system.

Controlled in situ nanoscale enhancement of gold nanowire arrays with plasmonics.

The controlled in situ growth of ordered gold nanoparticles and nanowire arrays has been studied by optically tracking changes in the local surface plasmon resonance (LSPR) spectrum. A spectrometer and custom-programmed analysis software track changes in the LSPR spectrum. The peak position, peak height (i.e. extinction intensity) and peak width (e.g. radius of curvature) were tracked over time to quantify the dynamic growth of gold as soon as the system was exposed to a commercial gold enhancement solution. This enables the controlled dynamic growth of nano-objects without the necessity of characterizing the growth and aggregation kinetics of the gold enhancement solution. The result was the successful enhancement of their electrically conductive and plasmonic properties, as well as the controlled growth and transformation of line-patterned nanoparticles into conductive particle-based nanowires.

Long-term results of hypofractionated radiation therapy for breast cancer.

BACKGROUND: The optimal fractionation schedule for whole-breast irradiation after breast-conserving surgery is unknown. METHODS: We conducted a study to determine whether a hypofractionated 3-week schedule of whole-breast irradiation is as effective as a 5-week schedule. Women with invasive breast cancer who had undergone breast-conserving surgery and in whom resection margins were clear and axillary lymph nodes were negative were randomly assigned to receive whole-breast irradiation either at a standard dose of 50.0 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). RESULTS: The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation as compared with 6.2% among the 622 women assigned to the hypofractionated regimen (absolute difference, 0.5 percentage points; 95% confidence interval [CI], -2.5 to 3.5). At 10 years, 71.3% of women in the control group as compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome (absolute difference, 1.5 percentage points; 95% CI, -6.9 to 9.8). CONCLUSIONS: Ten years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes. (ClinicalTrials.gov number, NCT00156052.)

Optical sensing with simultaneous electrochemical control in metal nanowire arrays.

This work explores the alternative use of noble metal nanowire systems in large-scale array configurations to exploit both the nanowires' conductive nature and localized surface plasmon resonance (LSPR). The first known nanowire-based system has been constructed, with which optical signals are influenced by the simultaneous application of electrochemical potentials. Optical characterization of nanowire arrays was performed by measuring the bulk refractive index sensitivity and the limit of detection. The formation of an electrical double layer was controlled in NaCl solutions to study the effect of local refractive index changes on the spectral response. Resonance peak shifts of over 4 nm, a bulk refractive index sensitivity up to 115 nm/RIU and a limit of detection as low as 4.5 × 10(-4) RIU were obtained for gold nanowire arrays. Simulations with the Multiple Multipole Program (MMP) confirm such bulk refractive index sensitivities. Initial experiments demonstrated successful optical biosensing using a novel form of particle-based nanowire arrays. In addition, the formation of an ionic layer (Stern-layer) upon applying an electrochemical potential was also monitored by the shift of the plasmon resonance.

Automated radiation targeting in head-and-neck cancer using region-based texture analysis of PET and CT images.

PURPOSE: A co-registered multimodality pattern analysis segmentation system (COMPASS) was developed to automatically delineate the radiation targets in head-and-neck cancer (HNC) using both (18)F-fluoro-deoxy glucose-positron emission tomography (PET) and computed tomography (CT) images. The performance of the COMPASS was compared with the results of existing threshold-based methods and radiation oncologist-drawn contours. METHODS AND MATERIALS: The COMPASS extracted texture features from corresponding PET and CT voxels. Using these texture features, a decision-tree-based K-nearest-neighbor classifier labeled each voxel as either "normal" or "abnormal." The COMPASS was applied to the PET/CT images of 10 HNC patients. Automated segmentation results were validated against the manual segmentations of three radiation oncologists using the volume, sensitivity, and specificity. The performance of the COMPASS was compared with three PET-based threshold methods: standard uptake value of 2.5, 50% maximal intensity, and signal/background ratio. RESULTS: The tumor delineations of the COMPASS were both quantitatively and qualitatively more similar to those of the radiation oncologists than the delineations from the other methods. The specificity was 95% +/- 2%, 84% +/- 9%, 98% +/- 3%, and 96% +/- 4%, and the sensitivity was 90% +/- 12%, 93% +/- 10%, 48% +/- 20%, and 68% +/- 25% for the COMPASS, for a standard uptake value of 2.5, 50% maximal intensity, and signal/background ratio, respectively. The COMPASS distinguished HNC from adjacent normal tissues with high physiologic uptake and consistently defined tumors with large variability in (18)F-fluoro-deoxy glucose uptake, which are often problematic with the threshold-based methods. CONCLUSION: Automated segmentation using texture analysis of PET/CT images has the potential to provide accurate delineation of HNC. This could lead to reduced interobserver variability, reduced uncertainty in target delineation, and improved treatment planning accuracy.

The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects.

Methylenetetrahydrofolate dehydrogenase)methenyltetrahydrofolate cyclohydrolase)formyltetrahydrofolate synthetase (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate (THF) derivatives for nucleotide synthesis. A common variant in MTHFD1, p.Arg653Gln (c.1958G>A), may increase the risk for neural tube defects (NTD). To examine the biological impact of this variant on MTHFD1 function, we measured enzyme activity and stability in vitro and assessed substrate flux in transfected mammalian cells. The purified Arg653Gln enzyme has normal substrate affinity but a 36% reduction in half)life at 42 degrees C. Thermolability is reduced by magnesium adenosine triphosphate and eliminated by the substrate analog folate pentaglutamate, suggesting that folate status may modulate impact of the variant. The mutation reduces the metabolic activity of MTHFD1 within cells: formate incorporation into DNA in murine Mthfd1 knockout cells transfected with Arg653Gln is reduced by 26%+/-7.7% (P<0.05), compared to cells transfected with wild)type protein, indicating a disruption of de novo purine synthesis. We assessed the impact of the variant on risk for congenital heart defects (CHD) in a cohort of Quebec children (158 cases, 110 controls) and mothers of children with heart defects (199 cases, 105 controls). The 653QQ genotype in children is associated with increased risk for heart defects (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.01-4.42), particularly Tetralogy of Fallot (OR, 3.60; 95% CI, 1.38-9.42) and aortic stenosis (OR, 3.13; 95% CI, 1.13-8.66). There was no effect of maternal genotype. Our results indicate that the Arg653Gln polymorphism decreases enzyme stability and increases risk for CHD. Further evaluation of this polymorphism in folate)related disorders and its potential interaction with folate status is warranted.

Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3).

PURPOSE: Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT. METHODS AND MATERIALS: A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system. RESULTS: Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025). CONCLUSION: In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy.