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Previous studies have suggested mixed results about the effect of road lighting on crime. One potential explanation is that the effect of lighting, if any, varies with the type of crime. This was tested through analysis of the effect of change in ambient light level on crimes recorded in 11 cities in the USA for the 10-year period 2010–2019. The results suggest that ambient light level had a consistent effect on robbery, with darkness leading to an increase in robbery, but did not suggest a significant effect for other types of crime. [ABSTRACT FROM AUTHOR]

Ambient light level, one of the items recorded by police investigating a road traffic collision (RTC) was previously suggested to be incorrectly recorded in 5%–15% of cases. Significant erroneous categorisation of ambient light level, as suggested by the latter estimate, may lead to incorrect conclusions being drawn about the impact of light on RTCs which is critical where such data inform transport policy decisions. This study investigated the accuracy with which ambient light level was recorded in comparison to that determined using solar altitude at the time, date and location of the RTC. Data were drawn from the STATS19 database of RTCs in the UK for the period 2005 to 2015. Ambient light level was incorrectly reported in 103 021 (5.79%) of the 1 779 903 RTCs in that period. The percentage of errors was greater for RTCs occurring after dark than in daylight, and for RTCs where the scene was not attended by a police officer than those that were attended: ambient light level was incorrectly categorized in 8.72% unattended RTCs in darkness. The highest percentage of errors (57%) occurred within civil twilight; if these are omitted the overall percentage reduces to 2.81%, a similar error rate to that available for the determination of RTC location. [ABSTRACT FROM AUTHOR]

It is expected that the detection of peripheral objects, a key visual task for safe driving, is affected by cognitive distraction, by observer age and by the manner in which action is undertaken following detection. An experiment was conducted to measure these effects, using a fixation cross and peripheral target discs displayed on a screen. The experiment was repeated with young (18–25 years) and old (60+years) age groups, with six distraction tasks, and with simple and choice response modes. The older group was found to respond more slowly than the younger group and detected fewer targets. The results suggest that distraction impairs detection, with the degree of impairment depending on the difficulty of the distraction task. Participants were generally slower at responding with choice response but this did not lead to a greater number of missed targets. Where lighting standards are informed by the ability to detect peripheral hazards, the research should represent older people, choice responses and impaired detection due to distraction. [ABSTRACT FROM AUTHOR]

A recent paper proposed a more precise approach for investigating the impact of ambient light (daylight versus after dark) on road traffic collisions. The present paper first repeated that analysis of road traffic collisions in the UK to test reproducibility; it then extended the analysis to determine whether the greater precision affected the outcome of road traffic collision analyses. Results of the previous analysis were reproduced in terms of the direction of the effect, but the repeated analysis found greater differences between daylight and darkness. The odds ratio determined using the new method led to higher odds ratios than the analyses used in some past studies, suggesting that past studies may have underestimated the detrimental effect of darkness on road traffic collision risk. [ABSTRACT FROM AUTHOR]

There is a body of research showing how changes in lighting conditions affect hazard detection in the context of driving after dark. There is a separate body of research showing that driving is impaired by distraction. The two have yet to be integrated: this is critical for lighting design recommendations because giving consideration to distraction may affect the optimal conditions established in lighting studies. A first step in that process is establishing the critical type(s) of distraction that might then be simulated in lighting research. This paper reviews evidence for the prevalence of driving distractions as recorded by two methods: interviews with drivers following collision and observation of drivers on real roads. These data suggest that auditory distractions such as conversation with passengers and listening to music are prevalent distractions, and are therefore appropriate distractions to incorporate in further research of lighting and hazard detection experiments. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this study was to compare postoperative complications and outcomes of minimally invasive intramedullary fixation (IMF) versus plate fixation (PF) in the treatment of distal fibular fractures., Materials and Methods: A retrospective review was performed from identifying all consecutive ankle fracture patients aged ≥18-years-old surgically managed between August 2017 to September 2022 at a tertiary care center with minimum 6 months clinical follow-up. Patients were grouped into those receiving intramedullary versus extramedullary fibular fixation. The primary outcomes were relevant demographic factors (diabetes, osteoporosis, charlson comorbidity index [CCI]), surgical time, complication rates, reoperation rates. Secondary outcomes included time to definitive fracture fixation, fracture characteristics (AO/OTA and Lauge-Hansen classification), syndesmotic instability requiring fixation and discharge disposition., Results: Forty-one IMF patients (average age 55.3 ± 18.1yrs) and 162 PF patients (47.7 ± 17.4yrs) were identified and included in this study. Within the IMF group, 25 patients received IM nailing and 16 patients received percutaneous screw fixation. A greater proportion of IMF patients had diabetes (39 % vs 22 %, p < 0.001), osteoporosis (22 % vs 3 %, p < 0.001), and moderate or severe CCI (41 % vs 23 %, p = 0.017). Surgical time was significantly reduced when using IMF technique (80.4 ± 43.1 min vs 99.1 ± 43.1 min, p = 0.012). Overall complication rates or time to complication did not differ significantly between groups (p = 0.578 and p = 0.082, respectively); however, when sub-stratified, IMF patients trended towards experiencing fewer wound related complications versus PF patients (5 % vs 9 %, p = 0.291). No IMF patients experienced deep or superficial infections and only 2 (5 %) patients experienced wound dehiscence. Reoperation rates(15 % vs 10 %, p = 0.267) and time to fracture union (2.7 ± 2.2 mos vs 3.1 ± 2.0 mos, p = 0.301) did not differ significantly. At final follow-up (IMF: 15.0 ± 12.2 mos vs PF: 28.5 ± 19.5 mos), Olerud and Molander ankle score was significantly higher in IMF compared to PF (87.1 ± 14.2 vs 76.2 ± 22.6, p = 0.002)., Conclusion: Patients in the IMF group at baseline had several comorbid medical conditions that put them at high risk for wound related complications, however, postoperatively they demonstrated higher functional scores and similar complication rates compared to the PF group. It is important to note, however, while we expected a higher rate of wound issues with the PF group, there were no significant differences in infection rates. Either IMF and PF is reliable for fixation and outcomes, and thus with proper soft tissue, biologically friendly technique, either IMF or PF is a reliable choice in the fixation of fibula fractures., Level of Evidence: III, retrospective cohort comparison study., Competing Interests: Declaration of competing interest None in relation to the submitted work., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Recently, low human epidermal growth factor receptor 2 (HER2) protein expression has been proposed as a predictive biomarker for response to the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in metastatic breast cancer. HER2 expression in non-small cell lung cancer (NSCLC) patients has never been carefully measured, and little is known about the frequency of cases with unamplified but detectable levels of the protein. Although some HER2-targeted therapies have been studied in NSCLC patients, they have been restricted to those with genomic ERBB2 gene alterations, which only represent relatively rare cases of NSCLC. Still, emerging investigations of T-DXd in NSCLC have shown promise in patients with unamplified HER2. Taken together, we hypothesize that there may be many cases of NSCLC with levels of HER2 protein expression comparable with levels seen in breast cancer that benefit from T-DXd. Here, we used a previously validated, analytic, quantitative immunofluorescence (QIF) assay that is more sensitive than legacy clinical HER2 immunohistochemistry assays. We measured HER2 protein levels in NSCLC cases to determine the proportion of cases with detectable HER2 expression. Using cell line calibration microarrays alongside our QIF method enabled us to convert HER2 signal into units of attomoles per mm 2 . We found that over 63% of the 741 analyzed NSCLC cases exhibited HER2 expression above the limit of detection, with more than 17% of them exceeding the lower limit of quantification. Although the threshold for response to T-DXd in breast cancer is still unknown, many cases of NSCLC have expression in a range comparable to breast cancer cases with immunohistochemistry scores of 1+ or 2+. Our assay could potentially select NSCLC cases with a detectable target (ie, HER2) that might benefit from HER2 antibody-drug conjugates, irrespective of ERBB2 genomic alterations., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare acute outcomes between patients undergoing fix and replace (FaR) versus open-reduction and internal fixation (ORIF) alone in the treatment of geriatric acetabular fractures., Design: Retrospective Cohort Study., Setting: Single Level 2 Trauma Center., Patient Selection Criteria: Consecutive acetabular fracture patients ≥ 55 years of age treated by two orthopaedic trauma surgeons at one tertiary care center from January 2017 to April 2022 with FaR versus ORIF were identified. Included were those with complete datasets within the 180-day global period. Excluded were patients with previous ORIF of the acetabulum or femur, or revision total hip arthroplasty., Outcome Measures and Comparisons: The primary outcomes were length of hospital stay (LOS), postoperative weight-bearing status, postoperative disposition, time to postoperative mobilization, and 90-day readmission rates. Secondary outcomes compared included demographic information, injury mechanism, surgical time, complications, revisions, and preoperative and postoperative Hip Disability and Osteoarthritis Outcomes Score for Joint Replacement (HOOS Jr.) scores. These were compared between FaR and ORIF groups., Results: Seventeen FaR patients (average age 74.5 ± 9.0 years) and 11 ORIF patients (average age 69.4 ± 9.6 years) met inclusion criteria. Mean follow-up was 26.4 months (range: 6-75.6 months). More FaR group patients were ordered immediate weight-bearing as tolerated or partial weight-bearing compared with ORIF alone (70% vs. 9.0%, P = 0.03). More patients in the FaR group had pre-existing hip osteoarthritis compared with ORIF alone (71% vs. 27%, P = 0.05). Fracture classification ( P = 0.03) and Charlson Comorbidity Index ( P = 0.02) differed between the 2 groups. There were no other differences in demographics, LOS ( P = 0.99), postoperative disposition ( P = 0.54), time to postoperative mobilization ( P = 0.38), 90-day readmission rates ( P = 0.51), operative time ( P = 0.06), radiographic union ( P = 0.35), time to union ( P = 0.63), pre- ( P = 0.32) or postoperative HOOS Jr. scores ( P = 0.80), delta HOOS Jr. scores ( P = 0.28), or reoperation rates between groups ( P = 0.15)., Conclusions: FaR and ORIF seem to be sound treatment options in the management of geriatric acetabular fractures. Patients in the FaR group achieved immediate or partial weight-bearing earlier than the ORIF group; however, time to postoperative mobilization did not differ between the two groups. The remainder of acute postoperative outcomes (LOS, postoperative disposition, and 90-day readmission rates) did not differ between the two groups., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest. All authors declare no direct conflicts of interest in connection with the current work. However, interests outside of the current work that may be perceived as influencing the representation or interpretation of the reported results are reported by authors: I.S. Hong: LifeNet Health: Paid biostatistical consultant. R.S. Yoon: American Association of Hip and Knee Surgeons: Board or committee member, Arthrex, Inc: IP royalties; Paid consultant, Bicomposites: Research support, Biomet: Research support, COTA: Research support, DePuy, A Johnson & Johnson Company: Paid consultant, Foundation for Physician Advancement: Board or committee member, Foundation of Orthopaedic Trauma: Board or committee member, LifeNet Health: Paid consultant; Research support, MiCare Health: Paid consultant, OMEGA: Research support, Organogenesis: Research support, ORintelligence: Stock or stock Options, OrthoGrid: Paid consultant, Orthopaedic Trauma Association: Board or committee member, ORTHOXEL: Paid consultant, Pacira: Research support, SI Bone: Research support, SI-Bone: Paid consultant, Smith & Nephew: Research support, Springer: Publishing royalties, financial or material support, Stryker: IP royalties; Paid consultant, Synthes: Paid consultant; Research support, Use-Lab: Paid consultant, WNT Scientific: Stock or stock Options. F.A. Liporace: AAOS: Board or committee member, AO: Unpaid consultant, Biomet: IP royalties; Paid consultant; Paid presenter or speaker; Research support, DePuy, A Johnson & Johnson Company: IP royalties; Research support, Orthopaedic Trauma Association: Board or committee member, Stryker: IP royalties, Synthes: Paid consultant; Paid presenter or speaker., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Th17 cells play a critical role in both tissue homeostasis and inflammation during clearance of infections as well as autoimmune and inflammatory disorders. Despite numerous efforts to distinguish the homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells remains poorly understood. In this study, we demonstrate that the inflammatory Th17 cells involved in autoimmune colitis and those activated during colitogenic infection are distinguishable populations characterized by their differential responses to the pharmacological molecule, clofazimine (CLF). Unlike existing Th17 inhibitors, CLF selectively inhibits proautoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells partially by reducing the enzyme ALDH1L2. Overall, our study identifies two distinct subsets within the inflammatory Th17 compartment with distinct regulatory mechanisms. Furthermore, we highlight the feasibility to develop disease-promoting Th17 selective inhibitor for treating autoimmune diseases., (© 2023 Bouch et al.)

Decomposition of coarse detritus (e.g., dead organic matter larger than ~1 mm such as leaf litter or animal carcasses) in freshwater ecosystems is well described in terms of mass loss, particularly as rates that compress mass loss into one number (e.g., a first-order decay coefficient, or breakdown rate, "k"); less described are temporal changes in the elemental composition of these materials during decomposition, with important implications for elemental cycling from microbes to ecosystems. This stands in contrast with work in the terrestrial realm, where a focus on detrital elemental cycling has provided a sharper mechanistic understanding of decomposition, especially with specific processes such as immobilization and mineralization. Notably, freshwater ecologists often measure carbon (C), nitrogen (N), and phosphorus (P), and their stoichiometric ratios in decomposing coarse materials, including carcasses, wood, leaf litter, and more, but these measurements remain piecemeal. These detrital nutrients are measurements of the entire detrital-microbial complex and are integrative of numerous processes, especially nutrient immobilization and mineralization, and associated microbial growth and death. Thus, data relevant to an elemental, mechanistically focused decomposition ecology are available in freshwaters, but have not been fully applied to that purpose. We synthesized published detrital nutrient and stoichiometry measurements at a global scale, yielding 4038 observations comprising 810 decomposition time series (i.e., measurements within a defined cohort of decomposing material through time) to build a basis for understanding the temporality of elemental content in freshwater detritus. Specifically, the dataset focuses on temporally and ontogenetically (mass loss) explicit measurements of N, P, and stoichiometry (C:N, C:P, N:P). We also collected ancillary data, including detrital characteristics (e.g., species, lignin content), water physiochemistry, geographic location, incubation system type, and methodological variables (e.g., bag mesh size). These measurements are important to unlocking mechanistic insights into detrital ontogeny (the temporal trajectory of decomposing materials) that can provide a deeper understanding of heterotroph-driven C and nutrient cycling in freshwaters. Moreover, these data can help to bridge aquatic and terrestrial decomposition ecology, across plant or animal origin. By focusing on temporal trajectories of elements, this dataset facilitates cross-ecosystem comparisons of fundamental decomposition controls on elemental fluxes. It provides a strong starting point (e.g., via modeling efforts) for comparing processes such as immobilization and mineralization that are understudied in freshwaters. Time series from decomposing leaf litter, particularly in streams, are common in the dataset, but we also synthesized ontogenies of animal-based detritus, which tend to decompose rapidly compared with plant-based detritus that contains high concentrations of structural compounds such as lignin and cellulose. Although animal-based data were rare, comprising only three time series, their inclusion in this dataset underscores the opportunities to develop an understanding of decomposition that encompasses all detrital types, from carrion to leaf litter. There are no copyright or proprietary restrictions on the dataset; please cite this data paper when reusing these materials., (© 2023 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Decomposing organic matter forms a substantial resource base, fueling the biogeochemical function and secondary production of most aquatic ecosystems. However, detrital N (nitrogen) and P (phosphorus) dynamics remain relatively unexplored in aquatic ecosystems relative to terrestrial ecosystems, despite fundamentally linking microbial processes to ecosystem function across broad spatial scales. We synthesized 217 published time series of detrital carbon (C), N, P, and their stoichiometric ratios (C:N, C:P, N:P) from stream ecosystems to analyze the temporal nutrient dynamics of decomposing litter using generalized additive models. Model results indicated that detritus was a net source of N (irrespective of inorganic or organic form) to the environment, regardless of initial N content. In contrast, P sink/source dynamics were more strongly influenced by the initial P content, in which P-poor litters were sinks for nutrients until these shifted to net P mineralization after ~40% mass loss. However, large variations surrounded both the N and P predictions, suggesting the importance of nonmicrobial factors such as fragmentation by invertebrates. Detrital C:N ratios converged and became more similar toward the end of the decomposition, suggesting predictable microbial functional effects throughout detrital ontogeny. C:P and N:P ratios also converged to some degree, but these model predictions were less robust than for C:N, due in part to the lower number of published detrital C:P time series. The explorations of environmental covariate effects were frequently limited by a few coincident covariate measurements across studies, but temperature, N availability, and P tended to accelerate the existing ontogenetic patterns in C:N. Our analysis helps to unite organic matter decomposition across aquatic-terrestrial boundaries by describing the basic patterns of elemental flows catalyzed by decomposition in streams, and points to a research agenda with which to continue addressing gaps in our knowledge of detrital nutrient dynamics across ecosystems., (© 2023 The Authors. Ecology published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

The assessment of the expression of programmed cell death ligand-1 (PD-L1) using immunohistochemistry (IHC) has been controversial since its introduction. The methods of assessment and the range of assays and platforms contribute to confusion. Perhaps the most challenging aspect of PD-L1 IHC is the combined positive score (CPS) method of interpretation of IHC results. Although the CPS method is prescribed for more indications than any other PD-L1 scoring system, its reproducibility has never been rigorously assessed. In this study, we collected a series of 108 gastric or gastroesophageal junction cancer cases, stained them using the Food and Drug Administration-approved 22C3 assay, scanned them, and then circulated them to 14 pathologists at 13 institutions for the assessment of interpretative concordance for the CPS system. We found that higher cut points (10 or 20) performed better than a CPS of <1 or >1. We used the Observers Needed to Evaluate Subjective Tests algorithm to assess how the CPS system might perform in the real-world setting and found that the cut points of <1 or >1 showed an overall percent agreement of only 30% among the pathologist raters, with a plateau occurring at 8 raters. The raters performed better at higher cut points. However, the best cut point of <20 versus that of >20 was still disappointing, with a plateau at an overall percent agreement of 70% (at 7 raters). Although there is no ground truth for CPS, we compared the score with quantitative messenger RNA measurement and showed no relationship between the score (at any cut point) and messenger RNA amount. In summary, we showed that CPS shows high subjective variability among pathologist readers and is likely to perform poorly in the real-world setting. This system may be the root cause of the poor specificity and relatively low predictive value of IHC companion diagnostic tests for PD-1 axis therapies that use the CPS system., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

The HercepTest was approved 20+ years ago as the companion diagnostic test for trastuzumab in human epidermal growth factor 2 (HER2) or ERBB2 gene-amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. Although this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted on the basis of concordance among small numbers of pathologists without validation in a real-world setting. In this study, we evaluated the concordance and interrater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the Observers Needed to Evaluate Subjective Tests method to determine the plateau of concordance and the minimum number of pathologists needed to estimate interrater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (<1% agreement for 1+ and 3.6% agreement for 2+) in the 4-category HER2 IHC scoring system. The discordance within the IHC 0 cases is also substantial with an overall percent agreement (OPA) of only 25% and poor interrater reliability metrics (0.49 Fleiss' kappa, 0.55 intraclass correlation coefficient). This discordance can be partially reduced by using a 3-category system (28.8% vs 46.5% OPA for 4-category and 3-category scoring systems, respectively). Observers Needed to Evaluate Subjective Tests plots suggest that the OPA for the task of determining a HER2 IHC score 0 from not 0 plateaus statistically around 59.4% at 10 raters. Conversely, at the task of scoring HER2 IHC as 3+ or not 3+ pathologists' concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding the patients in whom the ERBB2 gene is amplified but unacceptably discordant in assigning HER2-low or HER2-negative status for the emerging HER2-low therapies., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

The drug-induced proliferation (DIP) rate is a metric of in vitro drug response that avoids inherent biases in commonly used metrics such as 72 h viability. However, DIP rate measurements rely on direct cell counting over time, a laborious task that is subject to numerous challenges, including the need to fluorescently label cells and automatically segment nuclei. Moreover, it is incredibly difficult to directly count cells and accurately measure DIP rates for cell populations in suspension. As an alternative, we use real-time luminescence measurements derived from the cellular activity of NAD(P)H oxidoreductase to efficiently estimate drug response in both adherent and suspension cell populations to a panel of known anticancer agents. For the adherent cell lines, we collect both luminescence reads and direct cell counts over time simultaneously to assess their congruency. Our results demonstrate that the proposed approach significantly speeds up data collection, avoids the need for cellular labels and image segmentation, and opens the door to significant advances in high-throughput screening of anticancer drugs.

The efficacy of the antibody drug conjugate (ADC) Trastuzumab deruxtecan (T-DXd) in HER2 low breast cancer patients suggests that the historical/conventional assays for HER2 may need revision for optimal patient care. Specifically, the conventional assay is designed to distinguish amplified HER2 from unamplified cases but is not sensitive enough to stratify the lower ranges of HER2 expression. Here we determine the optimal dynamic range for unamplified HER2 detection in breast cancer and then redesign an assay to increase the resolution of the assay to stratify HER2 expression in unamplified cases. We used the AQUA™ method of quantitative immunofluorescence to test a range of antibody concentrations to maximize the sensitivity within the lower range of HER2 expression. Then, using a cell line microarray with HER2 protein measured by mass spectrometry we determined the amount of HER2 protein in units of attomols/mm 2 . Then by calculation of the limits of detection, quantification, and linearity of this assay we determined that low HER2 range expression in unamplified cell lines is between 2 and 20 attomol/mm 2 . Finally, application of this assay to a serial collection of 364 breast cancer cases from Yale shows 67% of the population has HER2 expression above the limit of quantification and below the levels seen in HER2 amplified breast cancer. In the future, this assay could be used to determine the levels of HER2 required for response to T-DXd or similar HER2 conjugated ADCs., (© 2022. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

Tumor heterogeneity is a primary cause of treatment failure and acquired resistance in cancer patients. Even in cancers driven by a single mutated oncogene, variability in response to targeted therapies is well known. The existence of additional genomic alterations among tumor cells can only partially explain this variability. As such, nongenetic factors are increasingly seen as critical contributors to tumor relapse and acquired resistance in cancer. Here, we show that both genetic and nongenetic factors contribute to targeted drug response variability in an experimental model of tumor heterogeneity. We observe significant variability to epidermal growth factor receptor (EGFR) inhibition among and within multiple versions and clonal sublines of PC9, a commonly used EGFR mutant nonsmall cell lung cancer (NSCLC) cell line. We resolve genetic, epigenetic, and stochastic components of this variability using a theoretical framework in which distinct genetic states give rise to multiple epigenetic "basins of attraction," across which cells can transition driven by stochastic noise. Using mutational impact analysis, single-cell differential gene expression, and correlations among Gene Ontology (GO) terms to connect genomics to transcriptomics, we establish a baseline for genetic differences driving drug response variability among PC9 cell line versions. Applying the same approach to clonal sublines, we conclude that drug response variability in all but one of the sublines is due to epigenetic differences; in the other, it is due to genetic alterations. Finally, using a clonal drug response assay together with stochastic simulations, we attribute subclonal drug response variability within sublines to stochastic cell fate decisions and confirm that one subline likely contains genetic resistance mutations that emerged in the absence of drug treatment., Competing Interests: The authors have declared that no competing interests exist.

The current studies explored the roles of the visuospatial and phonological working memory subsystems on drivers' gap acceptance and memory for approaching vehicles at junctions. Drivers' behaviour was measured in a high-fidelity driving simulator when at a junction, with, and without a visuospatial or phonological load. When asked to judge when to advance across the junction, gap acceptance thresholds, memory for vehicles and eye movements were not different when there was a secondary task compared to control. However, drivers' secondary task performance was more impaired in the visuospatial than phonological domain. These findings suggest that drivers were able to accept impairment in the secondary task while maintaining appropriate safety margins and situational awareness. These findings can inform the development of in-car technologies, improving the safety of road users at junctions. Practitioner summary: Despite research indicating that concurrent performance on working memory tasks impairs driving, a matched visuospatial or phonological memory load did not change drivers' gap acceptance or situational awareness at junctions. Drivers displayed appropriate compensatory behaviour by prioritising the driving task over the visuospatial secondary task. Abbreviations: ROW: right of way; RIG: random time interval generation.

Melanomas harboring BRAF mutations can be treated with BRAF inhibitors ( BRAF i), but responses are varied and tumor recurrence is inevitable. Here we used an integrative approach of experimentation and mathematical flux balance analyses in BRAF -mutated melanoma cells to discover that elevated antioxidant capacity is linked to BRAF i sensitivity in melanoma cells. High levels of antioxidant metabolites in cells with reduced BRAF i sensitivity confirmed this conclusion. By extending our analyses to other melanoma subtypes in The Cancer Genome Atlas, we predict that elevated redox capacity is a general feature of melanomas, not previously observed. We propose that redox vulnerabilities could be exploited for therapeutic benefits and identify unsuspected combination targets to enhance the effects of BRAF i in any melanoma, regardless of mutational status. SIGNIFICANCE: An integrative bioinformatics, flux balance analysis, and experimental approach identify targetable redox vulnerabilities and show the potential for modulation of cancer antioxidant defense to augment the benefits of existing therapies in melanoma., (©2020 American Association for Cancer Research.)

The effect of ambient light level on road traffic collisions (RTCs) involving a motorcycle was investigated. Data were drawn from the STATS19 database of UK reported RTCs for the period 2005-2015. To isolate the effect of ambient light (daylight vs darkness) an odds ratio was used to compare RTCs at specific times of day in the weeks either side of the Spring and Autumn clock changes. This work extended previous studies by using a more precise method for distinguishing between RTCs in daylight and after dark, thus avoiding the ambiguity of twilight. Data for four-wheel motor vehicle (FWMV) RTCs were also investigated to provide a datum. As expected, the risk of an RTC occurring was significantly higher after dark compared to daylight for both motorcycles and FWMVs. Investigation of contextual factors suggests that risk after dark is significantly higher for motorcycles compared to FWMVs for RTCs with two-vehicles, on roads with low speed limits (≤30 mph), at T-junctions, and junctions controlled by a give way sign. These are the situations where visual aids for increasing conspicuity after dark have the greater potential for reducing motorcycle RTCs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Driving simulation is widely used to answer important applied research questions, however, it is vital for specific driving tasks to undergo appropriate behavioural validation testing. Many previous validation studies have used simple driving tasks and measured relatively low-level vehicle control. The purpose of the current study was to investigate whether drivers' visual attention at intersections with different levels of demand, are similar in the simulator and on the road. Unlike simpler driving tasks, crossing intersections requires complex interactions with other vehicles governed by sequences of head and eye movements that may not be accurately captured in a simulated environment. In the current study we directly compare performance at simulated junctions with the same participants' behaviour in a real car. We compared drivers' visual attention in a high-fidelity driving simulator (instrumented car, 360-degree screen) and on-road in both low and medium demand driving situations. The low and medium demand driving situations involved the same motor movements, containing straight on, right turn and left turn manoeuvres. The low demand situations were controlled by the road environment and traffic lights, whereas medium demand situations required the driver to scan the environment and decide when it was safe to pull out into the junction. Natural junctions in Nottingham were used for the on-road phase and the same junctions were recreated in the simulator with traffic levels matched to those that were encountered on the real roads. The frequency and size of drivers' head movements were not significantly different between manoeuvres performed in the simulator and those conducted when driving on real roads. This suggests that drivers' broad search strategies in the simulator are representative of real-world driving. These strategies did change as a function of task demand - compared to low demand situations, behaviour at the medium demand junctions was characterised by longer junction crossing times, more head movements, shorter fixation durations and larger saccadic amplitudes. Although patterns of head movements were equivalent on road and in the simulator, there were differences in more fine-grained measures of eye-movements. Mean fixation durations were longer in the simulator compared to on-road, particularly in low-demand situations. We interpret this as evidence for lower levels of visual engagement with the simulated environment compared to the real world, at least when the task demands are low. These results have important implications for driving research. They suggest that high fidelity driving simulators can be useful tools for investigating drivers' visual attention at junctions, particularly when the driving task is of at least moderate demand., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Motorcyclists are involved in an exceptionally high number of crashes for the distance they travel, with one of the most common incidents being where another road user pulls out into the path of an oncoming motorcycle frequently resulting in a fatal collision. These instances have previously been interpreted as failures of visual attention, sometimes termed 'Look but Fail to See' (LBFTS) crashes, and interventions have focused on improving drivers' visual scanning and motorcycles' visibility. Here we show from a series of three experiments in a high-fidelity driving simulator, that when drivers' visual attention towards and memory for approaching vehicles is experimentally tested, drivers fail to report approaching motorcycles on between 13% and 18% of occasions. This happens even when the driver is pulling out into a safety-critical gap in front of the motorcycle, and often happens despite the driver having directly fixated on the oncoming vehicle. These failures in reporting a critical vehicle were not associated with how long the driver looked at the vehicle for, but were associated with drivers' subsequent visual search and the time that elapsed between fixating on the oncoming vehicle and pulling out of the junction. Here, we raise the possibility that interference in short-term memory might prevent drivers holding important visual information during these complex manoeuvres. This explanation suggests that some junction crashes on real roads that have been attributed to LBFTS errors may have been misclassified and might instead be the result of 'Saw but Forgot' (SBF) errors. We provide a framework for understanding the role of short-term memory in such situations, the Perceive Retain Choose (PRC) model, as well as novel predictions and proposals for practical interventions that may prevent this type of crash in the future., Competing Interests: The authors have declared that no competing interests exist.

Background: Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life-threatening immune-related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies., Case Presentation: We describe herein a patient with metastatic melanoma who developed epididymo-orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo-orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad-spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next-generation sequencing assay, was negative. He received high-dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5-week taper of oral steroids., Discussion: Here, we report a case of epididymo-orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents., Key Points: Epididymo-orchitis is a rare and potentially life-threatening complication of anti-programmed death protein 1 (anti-PD-1) therapy.For patients on anti-PD-1 therapy who develop either epididymo-orchitis or epididymitis without clear infectious cause, immune-related adverse events should be considered in the differential diagnosis.If severe, epididymo-orchitis related to anti-PD-1 therapy may be treated with high-dose corticosteroids., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Medulloblastoma is the most common malignant pediatric brain tumor. Prior studies have concentrated their efforts studying the four molecular subgroups: SHH, Wnt, group 3, and group 4. SHH and Wnt are driven by their canonical pathways. Groups 3 and 4 are highly metastatic and associated with aberrations in epigenetic regulators. Recent developments in the field have revealed that these subgroups are not as homogenous as previously believed. The objective of this study is to investigate the involvement of somatic driver gene mutations in these medulloblastoma subgroups. We obtained medulloblastoma data from the Catalogue of Somatic Mutations in Cancer (COSMIC), which contains distinct samples that were not previously studied in a large cohort. We identified somatic driver gene mutations and the signaling pathways affected by these driver genes for medulloblastoma subgroups using bioinformatics tools. We have revealed novel infrequent drivers in these subgroups that contribute to our understanding of tumor heterogeneity in medulloblastoma. Normally SHH signaling is activated in the SHH subgroup, however, we determined gain-of-function mutations in ubiquitin ligase ( CUL1) that inhibit Gli-mediated transcription. This suggests a potential hindrance in SHH signaling for some patients. For group 3, gain-of-function in the inhibitor of proinflammatory cytokines ( HIVEP3 ) suggests an immunosuppressive phenotype and thus a more hostile tumor microenvironment. Surprisingly, group 4 tumors possess mutations that may prompt the activation of Wnt signaling through gain-of-function mutations in MUC16 and PCDH9 . These infrequent mutations detected in this study could be due to subclonal or spatially restricted alterations. The investigation of aberrant driver gene mutations can lead to the identification of new drug targets and a greater understanding of human medulloblastoma heterogeneity., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Objectives: The current study investigated the behavior and visual attention of two groups of drivers with differing pedal cycling experience (pedal cyclists and nonpedal cyclists) towards vulnerable road users at junctions in a driving simulator., Background: Pedal cyclists and motorcyclists are involved in a disproportionate number of crashes given the distance they travel, with a high proportion of these crashes occurring at junctions. Many studies have found that car drivers who also hold a motorcycle license have increased awareness towards motorcycles., Methods: The task involved approaching a T-junction and turning right when it was deemed to be safe. In Study 1, the junction was controlled by a give way sign, and in Study 2, the junction was controlled by a stop sign. Each T-junction contained a target vehicle (car, motorcycle, or pedal cycle), approaching from a near, medium, or far distance from the junction., Results: Participants did not look at pedal cycles approaching from a far distance for as long as they looked at approaching motorcycles and cars, despite all vehicles travelling at identical speeds. No differences were found between pedal cyclists and nonpedal cyclists on any visual attention measures, indicating that pedal cycling experience was not associated with differences in drivers' attention toward pedal cycles., Conclusions: Findings have implications for road safety, demonstrating subtle differences in drivers' everyday visual attention toward differing vehicle types., Applications: This research has the potential to inform the development of in-car technical assistive systems, improving the safety of vulnerable road users at junctions.

Motorcyclists are involved in a disproportionate number of crashes given the distance they travel, with a high proportion of these crashes occurring at junctions. Despite car drivers being solely responsible for many road crashes involving a motorcycle, previous research has mostly focussed on understanding motorcyclists' attitudes towards their own safety. We compared car drivers' (n = 102) and motorcyclists' (n = 579) opinions about junction crashes using a web-based questionnaire. Motorcyclists and car drivers were recruited in similar ways so that responses could be directly compared, accessing respondents through driver/rider forums and on social media. Car drivers' and motorcyclists' opinions were compared in relation to who they believe to be blameworthy in situations which varied in specificity, ranging from what road user they believe is most likely to cause a motorcyclist to have a road crash, to what road user is at fault in four specific scenarios involving a car and motorcycle at a junction. Two of these scenarios represented typical 'Right of way' (ROW) crashes with a motorcycle approaching from the left and right, and two scenarios involved a motorcycle overtaking another vehicle at the junction, known as 'Motorcycle Manoeuvrability Accidents' (MMA). Qualitative responses were analysed using LIWC software to detect objective differences in car drivers' and motorcyclists' language. Car drivers' and motorcyclists' opinions about the blameworthiness of accidents changed depending on how specific the situation was that was being presented. When respondents were asked about the cause of motorcycle crashes in a general abstract sense, car drivers' and motorcyclists' responses significantly differed, with motorcyclists more likely to blame car drivers, demonstrating an in-group bias. However, this in-group favouritism was reduced when asked about specific scenarios, especially in MMA situations which involve motorcyclists manoeuvring their motorcycles around cars at a junction. In the four specific scenarios, car drivers were more likely to blame the car driver, and motorcyclists were more likely to blame the motorcyclist. In the typical ROW scenarios, the responses given by both road users, as analysed by the LIWC, show that the law is taken into account, as well as a large emphasis on the lack of observation given around junctions, especially from car drivers. It is concluded that the perception of blameworthiness in crashes is very much dependent on the details of the crash, with a more specific situation eliciting a fairer evaluation by both car drivers and motorcyclists., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Genomic technologies including microarrays and next-generation sequencing have enabled the generation of molecular signatures of prostate cancer. Lists of differentially expressed genes between malignant and non-malignant states are thought to be fertile sources of putative prostate cancer biomarkers. However such lists of differentially expressed genes can be highly variable for multiple reasons. As such, looking at differential expression in the context of gene sets and pathways has been more robust. Using next-generation genome sequencing data from The Cancer Genome Atlas, differential gene expression between age- and stage- matched human prostate tumors and non-malignant samples was assessed and used to craft a pathway signature of prostate cancer. Up- and down-regulated genes were assigned to pathways composed of curated groups of related genes from multiple databases. The significance of these pathways was then evaluated according to the number of differentially expressed genes found in the pathway and their position within the pathway using Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis. The "transforming growth factor-beta signaling" and "Ran regulation of mitotic spindle formation" pathways were strongly associated with prostate cancer. Several other significant pathways confirm reported findings from microarray data that suggest actin cytoskeleton regulation, cell cycle, mitogen-activated protein kinase signaling, and calcium signaling are also altered in prostate cancer. Thus we have demonstrated feasibility of pathway analysis and identified an underexplored area (Ran) for investigation in prostate cancer pathogenesis.

Chemo-sensitization is used to improve the efficacy of chemotherapeutic agents against cancers, and understanding the precise molecular mechanisms of chemo-sensitization could lead to safer and more effective approaches to treat cancer. We have previously demonstrated that mitochondrial c-Jun N-terminal Kinase (JNK) signaling is a critical component of cell death. Mitochondrial JNK signaling is coordinated on the scaffold protein Sab. In this work, we developed a sub-chronic chemo-sensitization model by exposing HeLa cells to low-dose (2 μM) LY294002. We found that this treatment increased Sab expression on mitochondria, an effect not observed in acute exposures. To examine the role of Sab in chemo-sensitization, we ectopically expressed and silenced Sab in HeLa cells. We found that elevating Sab levels in HeLa cells increased the efficacy of chemotherapeutic agents, paclitaxel and cisplatin, while silencing Sab decreased the sensitivity of cells towards these agents. The effect of Sab-mediated signaling appeared to be dependent upon mitogen dependent protein kinases (MAPKs) as ablation of Sab's MAPK-binding motifs prevented chemo-sensitization. These results suggest that mitochondrial JNK signaling is an adaptable signaling pathway that can be enhanced or restored in cancer cells to improve therapeutic efficacy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sophisticated private equity investors in health services provide venture capital for early-stage companies, growth capital for mid-stage companies, and equity capital for buyouts of mid-stage and mature companies. They pursue opportunities in provider sectors that are large and have a stable reimbursement environment, such as acute care services; sectors with room to execute consolidation strategies, such as labs; alternative-site sectors, such as "storefront" medicine; and clinical services, such as behavioral health, that are subject to profitably increasing quality and lowering costs. The innovations created through private equity investments could challenge established health services organizations.

Minimize surprises on your financial statement by adopting a model for integrated risk management that: Examines interrelationships among operations, investments, and financing. Incorporates concepts of the capital asset pricing model to manage unexpected volatility

Despite the many graduate programs that specialize in health administration, healthcare leaders and practitioners have expressed concern about the quality of preparation of health administration graduates. The purpose of this study was to facilitate one part of an integrated approach to leadership development that spans academic and practitioner settings. The approach was to design a competency assessment tool for early careerists who have two to five years of postgraduate experience and who aspire to fill senior leadership positions in complex, provider-based healthcare organizations. Open-ended interviews with key informants and a comprehensive review of relevant literature were done to identify and categorize a set of competencies relevant to early careerists. Based on data from key informants, specific work experiences and academic courses were mapped to each competency, indicating where and how such competencies might be developed. A simple rating system was then added to assess each competency, which resulted in the completion of the tool. Finally, the tool was piloted in a practitioner setting at the Massachusetts General Hospital Administrative Fellowship Program and in an academic setting at the Yale University Health Management Program. The resulting tool includes 52 competencies categorized into four domains: (1) technical skills (operations, finance; information resources, human resources, and strategic planning/external affairs); (2) industry knowledge (clinical process and healthcare institutions); (3) analytic and conceptual reasoning; and (4) interpersonal and emotional intelligence. Early experience with the tool suggests that it can facilitate career planning among graduate students, early careerists, and their mentors. Further, the tool can help directors of both academic and practitioner programs identify strengths and gaps in their existing curricula or training programs. By offering specific competencies linked to work experiences and graduate courses, the tool is an initial step toward promoting collaborative efforts between academic and practitioner programs.

State attorneys general as well as creditors and the IRS are putting more pressure on not-for-profit boards to fulfill their fiduciary responsibilities. Here's a guide to help you avoid liability and ensure a better financial outcome for your organization.

The Trivers-Willard hypothesis joins the ideas of R.A. Fisher and A.J. Bateman to model parental investment strategies. Trivers and Willard argue that any overall investment bias favoring either daughters or sons would be maladaptive. Nevertheless, they suggest that, in effectively polygynous species, more complex, conditional sex biases could be adaptive. In particular, they predict that parents in good condition will bias their investment toward sons and that parents in poor condition will bias their investment toward daughters. Among a sample of approximately 900 U.S. mothers we examined several measures of maternal investment including birth weight, interbirth interval and lactational commitment. Maternal condition was assessed by income and by the presence or absence of a coresident adult male. Some measures of investment (five of 14 statistical tests) showed marked and significant sex-by-condition interactions of the type and in the direction predicted by Trivers and Willard; none showed significant effects in the opposite direction. No conscious mediation is required to produce the observed investment patterns.