The open abdomen in mesenteric ischemia: A tool for patients undergoing revascularization.

BACKGROUND: We examined outcomes in Acute Mesenteric Ischemia (AMI) with the hypothesis that Open Abdomen (OA) is associated with decreased mortality. METHODS: We performed a cohort study reviewing NSQIP emergency laparotomy patients, 2016-2020, with a postoperative diagnosis of mesenteric ischemia. OA was defined using flags for patients without fascial closure. Logistic regression was used with outcomes of 30-day mortality and several secondary outcomes. RESULTS: Out of 5514 cases, 4624 (83.9%) underwent resection and 387 (7.0%) underwent revascularization. The OA rate was 32.6%. 10.8% of patients who were closed required reoperation. After adjustment for demographics, transfer status, comorbidities, preoperative variables including creatinine, white blood cell count, and anemia, as well as operative time, OA was associated with OR 1.58 for mortality (95% CI [1.38, 1.81], p < 0.001). Among revascularizations, there was no such association (p = 0.528). OA was associated with ventilator support >48 h (OR 4.04, 95% CI [3.55, 4.62], and p < 0.001). CONCLUSION: OA in AMI was associated with increased mortality and prolonged ventilation. This is not so in revascularization patients, and 1 in 10 patients who underwent primary closure required reoperation. OA should be considered in specific cases of AMI. LEVEL OF EVIDENCE: Retrospective cohort, Level III.

Effect of video angle on detection of induced front limb lameness in horses.

BACKGROUND: Lameness examinations are commonly performed in equine medicine. Advancements in digital technology have increased the use of video recordings for lameness assessment, however, standardization of ideal video angle is not available yielding videos of poor diagnostic quality. The objective of this study was to evaluate the effect of video angle on the subjective assessment of front limb lameness. A randomized, blinded, crossover study was performed. Six horses with and without mechanically induced forelimb solar pain were recorded using 9 video angles including horses trotting directly away and towards the video camera, horses trotting away and towards a video camera placed to the left and right side of midline, and horses trotting in a circle with the video camera placed on the inside and outside of the circle. Videos were randomized and assessed by three expert equine veterinarians using a 0-5 point scoring system. Objective lameness parameters were collected using a body-mounted inertial sensor system (Lameness Locator®, Equinosis LLC). Interobserver agreement for subjective lameness scores and ease of grading scores were determined. RESULTS: Induction of lameness was successful in all horses. There was excellent agreement between objective lameness parameters and subjective lameness scores (AUC of the ROC = 0.87). For horses in the "lame" trials, interobserver agreement was moderate for video angle 2 when degree of lameness was considered and perfect for video angle 2 and 9 when lameness was considered as a binary outcome. All other angles had no to fair agreement. For horses in the "sound" trials, interobserver agreement was perfect for video angle 5. All other video angles had slight to moderate agreement. CONCLUSIONS: When video assessment of forelimb lameness is required, a video of the horse trotting directly towards the video camera at a minimum is recommended. Other video angles may provide supportive information regarding lameness characteristics.

Operative and Nonoperative Outcomes of Emergency General Surgery Conditions: An Observational Study Using a Novel Instrumental Variable.

OBJECTIVE: To determine the effect of operative versus nonoperative management of emergency general surgery conditions on short-term and long-term outcomes. BACKGROUND: Many emergency general surgery conditions can be managed either operatively or nonoperatively, but high-quality evidence to guide management decisions is scarce. METHODS: We included 507,677 Medicare patients treated for an emergency general surgery condition between July 1, 2015, and June 30, 2018. Operative management was compared with nonoperative management using a preference-based instrumental variable analysis and near-far matching to minimize selection bias and unmeasured confounding. Outcomes were mortality, complications, and readmissions. RESULTS: For hepatopancreaticobiliary conditions, operative management was associated with lower risk of mortality at 30 days [-2.6% (95% confidence interval: -4.0, -1.3)], 90 days [-4.7% (-6.50, -2.8)], and 180 days [-6.4% (-8.5, -4.2)]. Among 56,582 intestinal obstruction patients, operative management was associated with a higher risk of inpatient mortality [2.8% (0.7, 4.9)] but no significant difference thereafter. For upper gastrointestinal conditions, operative management was associated with a 9.7% higher risk of in-hospital mortality (6.4, 13.1), which increased over time. There was a 6.9% higher risk of inpatient mortality (3.6, 10.2) with operative management for colorectal conditions, which increased over time. For general abdominal conditions, operative management was associated with 12.2% increased risk of inpatient mortality (8.7, 15.8). This effect was attenuated at 30 days [8.5% (3.8, 13.2)] and nonsignificant thereafter. CONCLUSIONS: The effect of operative emergency general surgery management varied across conditions and over time. For colorectal and upper gastrointestinal conditions, outcomes are superior with nonoperative management, whereas surgery is favored for patients with hepatopancreaticobiliary conditions. For obstructions and general abdominal conditions, results were equivalent overall. These findings may support patients, clinicians, and families making these challenging decisions.

The Conditional Effects of Multimorbidity on Operative Versus Nonoperative Management of Emergency General Surgery Conditions: A Retrospective Observational Study Using an Instrumental Variable Analysis.

OBJECTIVE: To understand how multimorbidity impacts operative versus nonoperative management of emergency general surgery (EGS) conditions. BACKGROUND: EGS is a heterogenous field, encompassing operative and nonoperative treatment options. Decision-making is particularly complex for older patients with multimorbidity. METHODS: Using an instrumental variable approach with near-far matching, this national, retrospective observational cohort study of Medicare beneficiaries examines the conditional effects of multimorbidity, defined using qualifying comorbidity sets, on operative versus nonoperative management of EGS conditions. RESULTS: Of 507,667 patients with EGS conditions, 155,493 (30.6%) received an operation. Overall, 278,836 (54.9%) were multimorbid. After adjustment, multimorbidity significantly increased the risk of in-hospital mortality associated with operative management for general abdominal patients (+9.8%; P = 0.002) and upper gastrointestinal patients (+19.9%, P < 0.001) and the risk of 30-day mortality (+27.7%, P < 0.001) and nonroutine discharge (+21.8%, P = 0.007) associated with operative management for upper gastrointestinal patients. Regardless of multimorbidity status, operative management was associated with a higher risk of in-hospital mortality among colorectal patients (multimorbid: + 12%, P < 0.001; nonmultimorbid: +4%, P = 0.003), higher risk of nonroutine discharge among colorectal (multimorbid: +42.3%, P < 0.001; nonmultimorbid: +55.1%, P < 0.001) and intestinal obstruction patients (multimorbid: +14.6%, P = 0.001; nonmultimorbid: +14.8%, P = 0.001), and lower risk of nonroutine discharge (multimorbid: -11.5%, P < 0.001; nonmultimorbid: -11.9%, P < 0.001) and 30-day readmissions (multimorbid: -8.2%, P = 0.002; nonmultimorbid: -9.7%, P < 0.001) among hepatobiliary patients. CONCLUSIONS: The effects of multimorbidity on operative versus nonoperative management varied by EGS condition category. Physicians and patients should have honest conversations about the expected risks and benefits of treatment options, and future investigations should aim to understand the optimal management of multimorbid EGS patients.

Conditional Effects of Race on Operative and Nonoperative Outcomes of Emergency General Surgery Conditions.

INTRODUCTION: Many emergency general surgery (EGS) conditions can be managed both operatively or nonoperatively; however, it is unknown whether the decision to operate affects Black and White patients differentially. METHODS: We identified a nationwide cohort of Black and White Medicare beneficiaries, hospitalized for common EGS conditions from July 2015 to June 2018. Using near-far matching to adjust for measurable confounding and an instrumental variable analysis to control for selection bias associated with treatment assignment, we compare outcomes of operative and nonoperative management in a stratified population of Black and White patients. Outcomes included in-hospital mortality, 30-day mortality, nonroutine discharge, and 30-day readmissions. An interaction test based on a t test was used to determine the conditional effects of operative versus nonoperative management between Black and White patients. RESULTS: A total of 556,087 patients met inclusion criteria, of which 59,519 (10.7%) were Black and 496,568 (89.3%) were White. Overall, 165,932 (29.8%) patients had an operation and 390,155 (70.2%) were managed nonoperatively. Significant outcome differences were seen between operative and nonoperative management for some conditions; however, no significant differences were seen for the conditional effect of race on outcomes. CONCLUSIONS: The decision to manage an EGS patient operatively versus nonoperatively has varying effects on surgical outcomes. These effects vary by EGS condition. There were no significant conditional effects of race on the outcomes of operative versus nonoperative management among universally insured older adults hospitalized with EGS conditions.

CH4 and N2 O emissions from smallholder agricultural systems on tropical peatlands in Southeast Asia.

There are limited data for greenhouse gas (GHG) emissions from smallholder agricultural systems in tropical peatlands, with data for non-CO2 emissions from human-influenced tropical peatlands particularly scarce. The aim of this study was to quantify soil CH4 and N2 O fluxes from smallholder agricultural systems on tropical peatlands in Southeast Asia and assess their environmental controls. The study was carried out in four regions in Malaysia and Indonesia. CH4 and N2 O fluxes and environmental parameters were measured in cropland, oil palm plantation, tree plantation and forest. Annual CH4 emissions (in kg CH4 ha-1 year-1 ) were: 70.7 ± 29.5, 2.1 ± 1.2, 2.1 ± 0.6 and 6.2 ± 1.9 at the forest, tree plantation, oil palm and cropland land-use classes, respectively. Annual N2 O emissions (in kg N2 O ha-1 year-1 ) were: 6.5 ± 2.8, 3.2 ± 1.2, 21.9 ± 11.4 and 33.6 ± 7.3 in the same order as above, respectively. Annual CH4 emissions were strongly determined by water table depth (WTD) and increased exponentially when annual WTD was above -25 cm. In contrast, annual N2 O emissions were strongly correlated with mean total dissolved nitrogen (TDN) in soil water, following a sigmoidal relationship, up to an apparent threshold of 10 mg N L-1 beyond which TDN seemingly ceased to be limiting for N2 O production. The new emissions data for CH4 and N2 O presented here should help to develop more robust country level 'emission factors' for the quantification of national GHG inventory reporting. The impact of TDN on N2 O emissions suggests that soil nutrient status strongly impacts emissions, and therefore, policies which reduce N-fertilisation inputs might contribute to emissions mitigation from agricultural peat landscapes. However, the most important policy intervention for reducing emissions is one that reduces the conversion of peat swamp forest to agriculture on peatlands in the first place.

National Cohort Study of Resource Utilization in Older Adults With Emergency General Surgery Conditions.

INTRODUCTION: Prior studies have sought to describe Emergency General Surgery (EGS) burden, but a detailed description of resource utilization for both operative and nonoperative management of EGS conditions has not been undertaken. METHODS: Patient and hospital characteristics were extracted from Medicare data, 2015-2018. Operations, nonsurgical procedures, and other resources (i.e., radiology) were defined using Current Procedural Terminology codes. RESULTS: One million eight hundred two thousand five hundred forty-five patients were included in the cohort. The mean age was 74.7 y and the most common diagnoses were upper gastrointestinal. The majority of hospitals were metropolitan (75.1%). Therapeutic radiology services were available in 78.4% of hospitals and operating rooms or endoscopy suites were available in 92.5% of hospitals. There was variability in resource utilization across EGS subconditions, with hepatobiliary (26.4%) and obstruction (23.9%) patients most frequently undergoing operation. CONCLUSIONS: Treatment of EGS diseases in older adults involves several interventional resources. Changes in EGS models, acute care surgery training, and interhospital care coordination may be beneficial to the treatment of EGS patients.

Soft windowing application to improve analysis of high-throughput phenotyping data.

MOTIVATION: High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors. RESULTS: Here we introduce 'soft windowing', a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype-phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources. AVAILABILITY AND IMPLEMENTATION: The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Pain Interference and Decreased Physical Function After Emergency General Surgery: Measuring Patient-Reported Outcomes.

INTRODUCTION: There is increasing emphasis on patient-reported outcomes (PROs) measures in healthcare, but this area remains largely unexplored in emergency general surgery (EGS) conditions. We hypothesized that postoperative patients in our EGS clinic would report detrimental changes in several domains of health-related quality of life (HRQoL). METHODS: We administered the PROMIS-29, a HRQoL measurement tool, to postoperative patients in our EGS clinic (11/2019-4/2020). Patients responded to measures of 7 domains. Domain scores were converted to t-scores, allowing comparison to average values within the general US population (set to 50 by definition). We report the mean scores within each domain. Higher scores in negatively worded domains (e.g., "Depression") are worse; vice versa for positively worded domains (e.g., "Physical Function"). Changes in scores at subsequent clinic visits were analyzed using the paired t-test. RESULTS: There were 97 patients who completed the PROMIS-29 at the first postoperative visit. Mean (SD) age was 54.1 (16.2) years; 51% were male. There was no difference in our patients from the average US population in the domains of Ability to Participate in Social Roles and Activities, Anxiety, Fatigue, and Sleep Disturbance. However, EGS patients experienced significantly greater Pain Interference (56.1 [54.1, 58.1]) and worse Physical Function (40.6 [38.4, 42.7]) than average. For patients seen in follow-up twice (13 patients, median interval between clinic visits 21 days), there were improvements in the domains of Physical Function (42.9 vs 37.3; p = 0.04) and Fatigue. CONCLUSION: We demonstrate room for improvement in the domains of pain interference and physical function. While positive changes over a relatively short period of time are encouraging, consideration should be given to patient perceptions of illness and lifestyle impact when managing EGS patients.

ANP32E is a histone chaperone that removes H2A.Z from chromatin.

H2A.Z is an essential histone variant implicated in the regulation of key nuclear events. However, the metazoan chaperones responsible for H2A.Z deposition and its removal from chromatin remain unknown. Here we report the identification and characterization of the human protein ANP32E as a specific H2A.Z chaperone. We show that ANP32E is a member of the presumed H2A.Z histone-exchange complex p400/TIP60. ANP32E interacts with a short region of the docking domain of H2A.Z through a new motif termed H2A.Z interacting domain (ZID). The 1.48 Å resolution crystal structure of the complex formed between the ANP32E-ZID and the H2A.Z/H2B dimer and biochemical data support an underlying molecular mechanism for H2A.Z/H2B eviction from the nucleosome and its stabilization by ANP32E through a specific extension of the H2A.Z carboxy-terminal α-helix. Finally, analysis of H2A.Z localization in ANP32E(-/-) cells by chromatin immunoprecipitation followed by sequencing shows genome-wide enrichment, redistribution and accumulation of H2A.Z at specific chromatin control regions, in particular at enhancers and insulators.

Epidural catheters are associated with an increased risk of venous thromboembolism in trauma.

Little is known about the association between epidural catheters (EC) and venous thromboembolism (VTE) in trauma. We sought to study this association and hypothesized that trauma patients with EC were more likely to develop VTE. Using the Pennsylvania Trauma Outcomes Study (PTOS) registry, we identified all adult trauma patients (age ≥ 18) admitted for at least 2 days between 1/2013 and 12/2017. Baseline characteristics and outcome variables were compared between patients who underwent EC placement and those who did not. The primary outcome was development of VTE. 147,721 patients met inclusion criteria; 2247 (1.5%) developed a VTE. Patients were mostly white (85%), male (56%), with blunt trauma (94%). 776 (0.5%) had an EC placed. Patients who underwent EC placement were more likely to develop a VTE (2.8% vs. 1.5%, p = 0.003). After adjusting for covariates, patients with EC were 1.6 times more likely to develop VTE (95% CI 1.1-2.5). The overall rate of VTE was low and associated with the use of EC. Future work should focus on determining the underlying mechanisms.

The Location and Timing of Failure-to-Rescue Events Across a Statewide Trauma System.

BACKGROUND: Failure to rescue (FTR) refers to death after a major complication. Defining the optimal context in which to reduce FTR after injury requires knowledge of where and when FTR events occur. MATERIALS AND METHODS: Retrospective observational study of patients >16 y with a minimum Abbreviated Injury Score ≥2 at all 30 level I and II Pennsylvania trauma centers (2007-2015). Location and timing of the first major complication were collected. Complication, mortality, and FTR rates were calculated by location (prehospital, emergency department, operating room, stepdown unit, interventional radiology, intensive care unit (ICU), radiology, and the surgical ward) and by postadmission day. Kruskal-Wallis and chi-squared tests were used to compare variables. RESULTS: Major complications occurred in 15,388 of 178,602 (8.6%) patients. The median age was 58 y (interquartile range [IQR] 37-77 y), 78% were Caucasian, 68% were male, 89% were bluntly injured, and the median Injury Severity Score was 19 (IQR 10-29). Death occurred in 2512 of 15,388 patients with a major complication, for an FTR rate of 16.3%. Compared with non-FTR, FTR had earlier major complications (median day 2 [IQR 0-5 d] versus day 4 [IQR 2-8 d], P < 0.001). FTR rates were highest in the prehospital setting (42%), the operating room (33%), and the emergency department (32%), but the greatest number (1608 of 2512 total FTR events, 64%) occurred in the ICU. Pulmonary (32%) and cardiac (26%) complications most frequently contributed to FTR deaths. CONCLUSIONS: Interventions designed to reduce FTR after injury should focus on pulmonary and cardiac complications in the ICU.

Resuscitative Endovascular Balloon Occlusion of the Aorta: Assessing Need in an Urban Trauma Center.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) has emerged as a bridge to definitive hemostasis in select patients with noncompressible torso hemorrhage. The number of patients who might benefit from this procedure, however, remains incompletely defined. We hypothesized that we could quantify the number of patients presenting to our center over a 2-year period who may have benefited from REBOA. METHODS: All patients presenting to our trauma center from 2014 to 2015 were included. Potential REBOA patients were identified based on anatomic injuries. We used ICD-9 codes to identify REBOA-amenable injury patterns and physiology. We excluded patients with injuries contraindicating REBOA. We then used chart review by two REBOA-experienced independent reviewers to assess each potential REBOA candidate, evaluate the accuracy of our algorithm, and to identify a cohort of confirmed REBOA candidates. RESULTS: Four thousand eight hundred eighteen patients were included of which 666 had injuries potentially amenable to REBOA. Three hundred thirty-five patients were hemodynamically unstable, and 309 patients had contraindications to REBOA. Sixty-four patients had both injury patterns and physiology amenable to REBOA with no contraindications, and these patients were identified as potential REBOA candidates. Of these, detailed independent two physician chart review identified 29 patients (45%) as confirmed REBOA candidates (interrater reliability kappa = 0.94, P < 0.001). CONCLUSIONS: Our database query identified patients with indications for REBOA but overestimated the number of REBOA candidates. To accurately quantify the REBOA candidate population at a given center, an algorithm to identify potential patients should be combined with chart review. STUDY TYPE: Therapeutic study, level V.

Training Disparities of Our Future Workforce: A Survey of Trauma Fellowship Candidates.

BACKGROUND: Training in Acute Care Surgery (ACS) is an integral component of general surgery residency and serves as a critical base experience for the added educational qualifications of fellowship. How this training varies between programs is not well characterized. We sought to describe the variation in clinical exposure between residencies in a sample of residents applying to an ACS fellowship. We hypothesized that applicants have significant variations in clinical exposure as well as unique and specific expectations for educational experiences. MATERIALS AND METHODS: We offered an anonymous 82-question survey focused on residency clinical exposure and self-perceived confidence in key areas of ACS training, as well as fellowship training and career expectations to all applicants interviewed at a single trauma, critical care, and emergency surgery fellowship program. Responses were assessed via absolute numbers and confidence via a 5-point Likert scale; data are reported using descriptive statistics and linear regression models. RESULTS: Forty-two interviewing applicants completed the survey, for a 96% response rate. Applicants reported heterogeneous levels of comfort across most ACS domains. There was good correlation between experience and comfort in most procedural areas. During fellowship training, respondents placed highest priority on operative experience, with 43% rating this as their highest priority, followed by penetrating trauma experience (33%). CONCLUSIONS: We found significant variations in both experience and comfort within key ACS domains among fellowship applicants. Despite training variability, there was good correlation between experience and self-reported comfort. Collaboration between residency and fellowship governing bodies may help address areas of limited exposure before entry into clinical practice.

Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress.

Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPKα. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.

Leaving Contaminated Trauma Laparotomy Wounds Open Reduces Wound Infections But Does Not Add Value.

BACKGROUND: The incidence of surgical site infection (SSI) has become a key quality indicator following clean and clean/contaminated surgical procedures. In contrast, contaminated and dirty wounds have garnered little attention with this quality metric because of the expected higher complication incidence. We hypothesized that wound management strategies in this high-risk population vary significantly and might not add value to the overall care. MATERIALS AND METHODS: This is a retrospective, observational study of trauma patients who underwent an exploratory laparotomy at an urban, academic, level 1 trauma center from 2014 to 2016. Deaths before hospital discharge were excluded. Wounds were classified using the Centers for Disease Control and Prevention definition on review of the operative reports. SSI was determined by review of the medical record, also per Centers for Disease Control and Prevention definition. Wound management strategies were categorized as either primary skin closure or closure by secondary intention. Outcomes were compared using Chi square or Kruskal-Wallis test. RESULTS: There were 128 patients who met study criteria. Fifty-five (42.9%) wounds were left open to close by secondary intention. In the wounds that were closed primarily (n = 73), eight (10.9%) developed an SSI. There were significant differences in the average length of stay (25.0 versus 11.6 d, P = 0.032), number of office visits (3.0 versus 1.8, P = 0.008), and time from last laparotomy to the last wound care office visit (112.8 versus 57.4, P = 0.012) between patients who were treated with secondary intention closure compared to those closed primarily who did not suffer from SSI. CONCLUSIONS: There is significant incidence of SSI in contaminated and dirty traumatic abdominal wounds; however, wound management strategies vary widely within this cohort. Closure by secondary intention requires significantly more resource utilization. Isolating risk factors for SSI may allow additional patients to undergo primary skin closure and avoid the morbidity of closure by secondary intention.

The International Mouse Phenotyping Consortium (IMPC): a functional catalogue of the mammalian genome that informs conservation.

The International Mouse Phenotyping Consortium (IMPC) is building a catalogue of mammalian gene function by producing and phenotyping a knockout mouse line for every protein-coding gene. To date, the IMPC has generated and characterised 5186 mutant lines. One-third of the lines have been found to be non-viable and over 300 new mouse models of human disease have been identified thus far. While current bioinformatics efforts are focused on translating results to better understand human disease processes, IMPC data also aids understanding genetic function and processes in other species. Here we show, using gorilla genomic data, how genes essential to development in mice can be used to help assess the potentially deleterious impact of gene variants in other species. This type of analyses could be used to select optimal breeders in endangered species to maintain or increase fitness and avoid variants associated to impaired-health phenotypes or loss-of-function mutations in genes of critical importance. We also show, using selected examples from various mammal species, how IMPC data can aid in the identification of candidate genes for studying a condition of interest, deliver information about the mechanisms involved, or support predictions for the function of genes that may play a role in adaptation. With genotyping costs decreasing and the continued improvements of bioinformatics tools, the analyses we demonstrate can be routinely applied.

Novel human neuronal tau model exhibiting neurofibrillary tangles and transcellular propagation.

Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, which are associated with the pathological aggregation of tau protein into neurofibrillary tangles (NFT). Studies have characterized tau as a "prion-like" protein given its ability to form distinct, stable amyloid conformations capable of transcellular and multigenerational propagation in clonal fashion. It has been proposed that progression of tauopathy could be due to the prion-like propagation of tau, suggesting the possibility that end-stage pathologies, like NFT formation, may require an instigating event such as tau seeding. To investigate this, we applied a novel human induced pluripotent stem cell (hiPSC) system we have developed to serve as a human neuronal model. We introduced the tau repeat domain (tau-RD) with P301L and V337M (tau-RD-LM) mutations into hiPSC-derived neurons and observed expression of tau-RD at levels similar to total tau in postmortem AD brains. Tau aggregation occurred without the addition of recombinant tau fibrils. The conditioned media from tau-RD cultures contained tau-RD seeds, which were capable of inducing aggregate formation in homotypic mode in non-transduced recipient neuronal cultures. The resultant NFTs were thioflavin-positive, silver stain-positive, and assumed fibrillary appearance on transmission electron microscopy (TEM) with immunogold, which revealed paired helical filament 1 (PHF1)-positive NFTs, representing possible recruitment of endogenous tau in the aggregates. Functionally, expression of tau-RD caused neurotoxicity that manifested as axon retraction, synaptic density reduction, and enlargement of lysosomes. The results of our hiPSC study were reinforced by the observation that Tau-RD-LM is excreted in exosomes, which mediated the transfer of human tau to wild-type mouse neurons in vivo. Our hiPSC human neuronal system provides a model for further studies of tau aggregation and pathology as well as a means to study transcellular propagation and related neurodegenerative mechanisms.

Firearm Deaths in America: Can We Learn From 462,000 Lives Lost?

OBJECTIVE: We sought to determine whether state firearm legislation correlated with firearm-related fatality rates (FFR) during a 15-year period. BACKGROUND: The politicized and controversial topic of firearm legislation has been grossly understudied when the relative impact of American firearm violence is considered. Scientific evidence regarding gun legislation effectiveness remains scant. METHODS: Demographic and intent data (1999-2013) were collected from the Centers for Disease Control and Prevention's Web-Based Injury Statistics Query and Reporting System database and compared by state firearm legislation rankings with respect to FFR. State scorecards were obtained from firearm-restrictive (Brady Campaign/Law Center against Gun Violence [BC/LC]) and less-restrictive (National Rifle Association) groups. FFR were compared between restrictive and least-restrictive states during 3 periods (1999-2003, 2004-2008, 2009-2013). RESULTS: During 1999 to 2013, 462,043 Americans were killed by firearms. Overall FFR did not change during the 3 periods (10.89 ±â€Š3.99/100,000; 10.71 ±â€Š3.93/100,000; 11.14 ±â€Š3.91/100,000; P = 0.87). Within each period, least-restrictive states had greater unintentional, pediatric, and adult suicide, White and overall FFR than restrictive states (all P < 0.05). Conversely, no correlation was seen, during any of the 3 time periods, with either homicide or Black FFR-population subsets accounting for 41.7% of firearm deaths. CONCLUSIONS: Restrictive firearm legislation is associated with decreased pediatric, unintentional, suicide, and overall FFR, but homicide and Black FFR appear unaffected. Future funding and research should be directed at both identifying the most effective aspects of firearm legislation and creating legislation that equally protects every segment of the American population.

Keep wetlands wet: the myth of sustainable development of tropical peatlands - implications for policies and management.

Pristine tropical peat swamp forests (PSFs) represent a unique wetland ecosystem of distinctive hydrology which support unique biodiversity and globally significant stores of soil carbon. Yet in Indonesia and Malaysia, home to 56% of the world's tropical peatland, they are subject to considerable developmental pressures, including widespread drainage to support agricultural needs. In this article, we review the ecology behind the functioning and ecosystem services provided by PSFs, with a particular focus on hydrological processes as well as the role of the forest itself in maintaining those services. Drawing on this, we review the suitability of current policy frameworks and consider the efficacy of their implementation. We suggest that policies in Malaysia and Indonesia are often based around the narrative of oil palm and other major monocrops as drivers of prosperity and development. However, we also argue that this narrative is also being supported by a priori claims concerning the possibility of sustainability of peat swamp exploitation via drainage-based agriculture through the adherence to best management practices. We discuss how this limits their efficacy, uptake and the political will towards enforcement. Further, we consider how both narratives (prosperity and sustainability) clearly exclude important considerations concerning the ecosystem value of tropical PSFs which are dependent on their unimpacted hydrology. Current research clearly shows that the actual debate should be focused not on how to develop drainage-based plantations sustainably, but on whether the sustainable conversion to drainage-based systems is possible at all.