Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

Reductive Arylation of Nitroarenes with Chloroarenes: Reducing Conditions Enable New Reactivity from Palladium Catalysts.

Palladium-catalyzed C-N bond forming reactions are a key tool in modern synthetic organic chemistry. Despite advances in catalyst design enabling the use of a variety of aryl (pseudo)halides, the necessary aniline coupling partner is often synthesized in a discrete reduction step from a nitroarene. An ideal synthetic sequence would avoid the necessity of this step while maintaining the reliable reactivity of palladium catalysis. Herein, we describe how reducing conditions enable new chemical steps and reactivity from well-studied palladium catalysts, resulting in a new, useful transformation: the reductive arylation of nitroarenes with chloroarenes to form diarylamines. Mechanistic experiments suggest that under reducing conditions, BrettPhos-palladium complexes catalyze the dual N-arylation of typically inert azoarenes─generated via the in situ reduction of nitroarenes─via two distinct mechanisms. Initial N-arylation proceeds via a novel association-reductive palladation sequence followed by reductive elimination to yield an intermediate 1,1,2-triarylhydrazine. Arylation of this intermediate by the same catalyst via a traditional amine arylation sequence forms a transient tetraarylhydrazine, unlocking reductive N-N bond cleavage to liberate the desired product. The resulting reaction allows for the synthesis of diarylamines bearing a variety of synthetically valuable functionalities and heteroaryl cores in high yield.

Human vs. Machine Learning Based Detection of Facial Weakness Using Video Analysis.

Background: Current EMS stroke screening tools facilitate early detection and triage, but the tools' accuracy and reliability are limited and highly variable. An automated stroke screening tool could improve stroke outcomes by facilitating more accurate prehospital diagnosis and delivery. We hypothesize that a machine learning algorithm using video analysis can detect common signs of stroke. As a proof-of-concept study, we trained a computer algorithm to detect presence and laterality of facial weakness in publically available videos with comparable accuracy, sensitivity, and specificity to paramedics. Methods and Results: We curated videos of people with unilateral facial weakness (n = 93) and with a normal smile (n = 96) from publicly available web-based sources. Three board certified vascular neurologists categorized the videos according to the presence or absence of weakness and laterality. Three paramedics independently analyzed each video with a mean accuracy, sensitivity and specificity of 92.6% [95% CI 90.1-94.7%], 87.8% [95% CI 83.9-91.7%] and 99.3% [95% CI 98.2-100%]. Using a 5-fold cross validation scheme, we trained a computer vision algorithm to analyze the same videos producing an accuracy, sensitivity and specificity of 88.9% [95% CI 83.5-93%], 90.3% [95% CI 82.4-95.5%] and 87.5 [95% CI 79.2-93.4%]. Conclusions: These preliminary results suggest that a machine learning algorithm using computer vision analysis can detect unilateral facial weakness in pre-recorded videos with an accuracy and sensitivity comparable to trained paramedics. Further research is warranted to pursue the concept of augmented facial weakness detection and external validation of this algorithm in independent data sets and prospective patient encounters.

Uncertainty Potentiates Neural and Cardiac Responses to Visual Stimuli in Anxiety Disorders.

BACKGROUND: Intolerance of uncertainty and worry about future events are cardinal features of anxiety. However, the neurobiological and physiological mechanisms underlying these characteristics of anxiety remain to be fully elucidated. METHODS: Individuals with diagnosed anxiety disorders (n = 29, 22 female) and age-matched comparison subjects (n = 28, 17 female) completed a task in which pictures (aversive or neutral content) were preceded by cues indicating certainty or uncertainty about the emotional valence of the subsequent pictures. We assessed functional magnetic resonance imaging and heart rate activity with respect to the 1) cue period, 2) emotional valence of the pictures, and 3) modulatory effect of uncertainty on responses to subsequent pictures. RESULTS: Individuals with anxiety disorders and comparison subjects exhibited similar functional magnetic resonance imaging and cardiac activity during the cue period and for the aversive versus neutral picture contrast. However, individuals with anxiety disorders exhibited greater modulatory effects of uncertainty on their responses to subsequent pictures. Specifically, they displayed greater functional magnetic resonance imaging activity in a number of cortical regions (visual cortex, anterior cingulate cortex, superior temporal gyrus, and anterior insula), as well as significantly reduced cardiac deceleration to pictures preceded by the uncertainty cue. CONCLUSIONS: These findings suggest that heightened neural and autonomic reactivity to stimuli during conditions of uncertainty may be a key psychobiological mechanism of anxiety.

The prevalence, characteristics, and psychiatric correlates of traumatic brain injury in incarcerated individuals: an examination in two independent samples.

PRIMARY OBJECTIVE: Identify the prevalence, characteristics, and psychological correlates of traumatic brain injury (TBI) among incarcerated individuals. RESEARCH DESIGN: Three aims: (1) Determine the prevalence and characteristics of TBI in 1469 adults incarcerated in Wisconsin state prisons (1064 men, 405 women); (2) Characterize the relationship between mild TBI and mental illness in a sub-sample of men and women; (3) Reproduce the findings from Aim 1 and Aim 2 in an independent sample of 1015 adults incarcerated in New Mexico state prisons (600 men, 415 women). METHODS AND PROCEDURES: Standardized TBI assessment with structured clinical interviews and self-report questionnaires. MAIN OUTCOMES AND RESULTS: Rates of TBI were approximately five times greater than the general population, with a substantially higher rate of TBI caused by assault. In the Wisconsin sample, mild TBI was associated with greater levels of post-traumatic stress disorder (PTSD) among women (but not among men). In the New Mexico sample, TBI of any severity was associated with greater levels of major depressive disorder (MDD) among women (but not among men). CONCLUSIONS: This study thus provides novel data on TBI and its correlates among individuals incarcerated in state prisons, and highlights a specific treatment need within the prison population.

Suitability of Long-Term Frozen Rat Blood Samples for the Interrogation of Pig-a Gene Mutation by Flow Cytometry.

The rodent blood Pig-a assay has been undergoing international validation for use as an in vivo hematopoietic cell gene mutation assay, and given the promising results an Organization for Economic Co-operation and Development (OECD) Test Guideline is currently under development. Enthusiasm for the assay stems in part from its alignment with 3Rs principles permitting combination with other genotoxicity endpoint(s) and integration into repeat-dose toxicology studies. One logistical requirement and experimental design limitation has been that blood samples required antibody labeling and flow cytometric analysis within one week of collection. In the current report, we describe the performance of freeze-thaw reagents that enable storage and subsequent labeling and analysis of rat blood samples for at least seven months. Data generated from three laboratories are presented that demonstrate rat erythrocyte recoveries in the range of 80-90%. Despite some loss of erythrocytes, Pearson coefficients and Bland-Altman analyses based on fresh blood vs. frozen/thawed matched pairs indicate that mutant cell and reticulocyte frequencies are not significantly affected, as the measurements are highly correlated and exhibit low bias. Collectively, these data support the effectiveness and suitability of a freeze-thaw procedure that endows the assay with several new advantageous characteristics that include: flexibility in scheduling personnel/instrumentation; reliability when shipping samples from in-life facilities to analytical sites; 3Rs-friendly, as blood from positive control animals can be stored frozen to serve as analytical controls; and ability to defer a decision to generate Pig-a data until more toxicological information becomes available on a test substance. Environ. Mol. Mutagen. 60:47-55, 2019. © 2018 Wiley Periodicals, Inc.

The left temporal pole is a convergence region mediating the relation between names and semantic knowledge for unique entities: Further evidence from a "recognition-from-name" study in neurological patients.

Prior research has implicated the left temporal pole (LTP) as a critical region for naming semantically unique items, including famous faces, landmarks, and musical melodies. Most studies have used a confrontation naming paradigm, where a participant is presented with a stimulus and asked to retrieve its name. We have proposed previously that the LTP functions as a two-way, bidirectional convergence region brokering between conceptual knowledge and proper names for unique entities. Under this hypothesis, damage to the LTP should result in a "two way" impairment: (1) defective proper name retrieval when presented with a unique stimulus (as shown in prior work); and (2) defective concept retrieval when presented with a proper name. Here, we directly tested the second prediction using a "recognition-from-name" paradigm. Participants were patients with LTP damage, brain-damaged comparisons with damage outside the LTP, and healthy comparisons. Participants were presented with names of famous persons (e.g., "Marilyn Monroe"), landmarks (e.g., "Leaning Tower of Pisa"), or melodies (e.g., "Rudolph the Red-Nosed Reindeer") and were asked to provide conceptual knowledge about each. We found that individuals with damage to the LTP were significantly impaired at conceptual knowledge retrieval when given names of famous people and landmarks (but this finding did not hold for melodies). This outcome supports the theory that the LTP is a bidirectional convergence region for proper naming, but suggests that melody retrieval may rely on processes different from those supported by the LTP.

Human lesion studies of ventromedial prefrontal cortex.

Studies of neurological patients with focal lesions involving ventromedial prefrontal cortex (vmPFC) have demonstrated a critical role for this brain area in various aspects of cognition, emotion, and behavior. In this article, we review the key themes, methods, and findings from neuropsychological research on vmPFC lesion patients. Early case studies demonstrated profound disruptions in personality and behavior following vmPFC damage, including blunted affect, poor decision-making, and inappropriate social behavior. Subsequent laboratory investigations with groups of vmPFC lesion patients have revealed deficits in a host of interrelated functions, such as value-based decision-making, future and counterfactual thinking, physiological arousal to emotional stimuli, emotion recognition, empathy, moral judgment, and memory confabulation. The compendium of findings described here demonstrates that vmPFC is crucial for diverse aspects of adaptive function.

Sequelae of Occult Aggression Disqualifying Young, Socially Housed, Female New Zealand White Rabbits (Oryctolagus cuniculus) from Participation in Dermal Toxicology Studies.

International animal welfare organizations and federal, regional, and institutional oversight bodies encourage social housing of gregarious species, such as New Zealand white rabbits (Oryctolagus cuniculus), to promote animal wellbeing in research, teaching, testing and farming settings. At our institution, 2 groups of female New Zealand white rabbits (approximate age, 11 wk; mean weight, 2.35 kg), compatibly paired at the vendor for 5 wk, were paired in caging or group-housed in a floor pen. The rabbits appeared compatible, demonstrating primarily affiliative behaviors throughout 6 wk of daily observations. However, occult aggression that occurred between daily observations or nocturnally resulted in skin wounding. The skin injuries, first identified during prestudy clipping of fur from the back of each rabbit 6 wk after arrival, disqualified every animal from participation in skin toxicology and muscle implantation studies. Success meeting scientific research requirements while promoting animal welfare and health when socially housing New Zealand white rabbits requires examining the behavioral repertoire of their wild counterparts, European rabbits. Factors including age, sex, and housing density influence territoriality, dominance hierarchy, social ranking, and natural, agonistic, injurious, behavioral tendencies. IACUC and other relevant oversight bodies, researchers, and animal care staff should consider this case study and the species-specific natural history of New Zealand white rabbits when assessing the harm and benefit of social housing in regard to research utility and animal welfare.

Metal- and additive-free photoinduced borylation of haloarenes.

Boronic acids and esters have critical roles in the areas of synthetic organic chemistry, molecular sensors, materials science, drug discovery, and catalysis. Many of the current applications of boronic acids and esters require materials with very low levels of transition metal contamination. Most of the current methods for the synthesis of boronic acids, however, require transition metal catalysts and ligands that must be removed via additional purification procedures. This protocol describes a simple, metal- and additive-free method of conversion of haloarenes directly to boronic acids and esters. This photoinduced borylation protocol does not require expensive and toxic metal catalysts or ligands, and it produces innocuous and easy-to-remove by-products. Furthermore, the reaction can be carried out on multigram scales in common-grade solvents without the need for reaction mixtures to be deoxygenated. The setup and purification steps are typically accomplished within 1-3 h. The reactions can be run overnight, and the protocol can be completed within 13-16 h. Two representative procedures that are described in this protocol provide details for preparation of a boronic acid (3-cyanopheylboronic acid) and a boronic ester (1,4-benzenediboronic acid bis(pinacol)ester). We also discuss additional details of the method that will be helpful in the application of the protocol to other haloarene substrates.

Neurological damage disrupts normal sex differences in psychophysiological responsiveness to music.

Men and women often display different physiological responses to emotional stimuli, and these responses can be affected by brain damage. Here, we investigated how brain damage differentially affects electrodermal responses based on sex. We studied neurologically normal, healthy adults and a sample of neurological patients. Participants listened to music, an emotional stimulus that reliably elicits skin conductance responses (SCRs). Electrodermal activity was recorded while participants listened to musical clips. When analyzing the data without regard to sex, there were no differences between healthy and brain-damaged participants in their SCRs. However, we found a significant interaction between brain injury status and sex. For men, brain damage significantly reduced SCRs. For women, there were no differences between brain-damaged participants and neurologically healthy participants. These findings illustrate the importance of including demographic variables, such as sex, when investigating brain-behavior relationships with a psychophysiological dependent variable.

Screening CT angiography for detection of blunt carotid and vertebral artery injury in the setting of combat-related trauma.

Blunt carotid and vertebral artery injury (BCVI) is a relatively rare injury reported in the civilian sector and is associated with high morbidity and mortality. The purpose of our study was to use an optimized computed tomography angiography protocol in the deployed setting to determine the prevalence of BCVI in a consecutive patient population having experienced recent wartime-related traumatic injuries. From July 2008 to September 2009, a total of 307 consecutive trauma patients were included in this study. At least 233 (76%) patients were known to have experienced blast-related traumatic injuries. 135 (44%) patients had injuries to the head, face, or neck. 4 patients (1.3%) sustained BCVI. There was no statistically significant difference between the prevalence of BCVI in the deployed setting and the civilian sector. We speculate that in our study population, the relatively decreased prevalence of cervical spinal fractures (3.3%) observed may counter the theoretical increased risk of vascular injury from blast trauma, ultimately producing a similar prevalence of overall BCVI compared to civilian study populations. Based on our observations, we cannot advocate for or against more liberalized screening of BCVI in the deployed setting, and military physicians may elect to continue screening for these injuries with currently established and accepted practice guidelines developed in civilian trauma populations.

Operation BRAVE families: A preventive approach to lessening the impact of war on military families through preclinical engagement.

OBJECTIVES: Operation Building Resilience and Valuing Empowered Families (OBF) is a preventive, preclinical program that was developed by the Walter Reed National Military Medical Center's Child and Adolescent Psychiatry Service to form a working partnership with families of wounded warrior parents from the war in Iraq and Afghanistan. The OBF staff helps to identify the families' needs and collaborates with many organizations at Walter Reed National Military Medical Center to provide assistance. This article describes OBF, offers a case description, reviews current preventive programs for children exposed to trauma and disaster, and compares and contrasts OBF to these programs. METHODS: A literature review was performed, searching Ovid MEDLINE for keywords, such as posttraumatic stress disorder, child and adolescent, family, prevention, and disaster. RESULTS: There are an increasing number of preventive programs for children and adolescents throughout the country, especially over the past 10 years. These programs build upon past prevention models. There are few services that offer primary prevention. CONCLUSIONS: OBF is a military treatment facility-focused preventive program that can serve as a program model for other military treatment facilities and civilian hospitals with the mandate to care for the family members and children of parents who are trauma victims and require long-term care.

Combat-injured service members and their families: the relationship of child distress and spouse-perceived family distress and disruption.

Combat injury in military service members affects both child and family functioning. This preliminary study examined the relationship of child distress postinjury to preinjury deployment-related family distress, injury severity, and family disruption postinjury. Child distress postinjury was assessed by reports from 41 spouses of combat-injured service members who had been hospitalized at two military tertiary care treatment centers. Families with high preinjury deployment-related family distress and high family disruption postinjury were more likely to report high child distress postinjury. Spouse-reported injury severity was unrelated to child distress. Findings suggest that early identification and intervention with combat-injured families experiencing distress and disruption may be warranted to support family and child health, regardless of injury severity.

Discrepancy rates of radiology resident interpretations of on-call neuroradiology MR imaging studies.

PURPOSE: To determine the discrepancy rates of radiology residents interpreting emergent neuroradiology magnetic resonance (MR) imaging studies and to assess any adverse clinical outcomes. MATERIALS AND METHODS: Three hundred sixty-one brain and spine MR imaging and MR angiographic examinations that were ordered emergently after hours and given preliminary interpretations by radiology residents were retrospectively reviewed from December 1, 2006 to May 31, 2007 with institutional review board approval. Discrepancies between the interpretations of radiology residents and the final reports of attending neuroradiologists were classified as either false-negative (FN, failure to recognize abnormalities) or false-positive (FP, misinterpreting normal images as abnormal). Discrepancies that could affect patient care or clinical outcome were considered major. RESULTS: Overall, the agreement rate was 92.8%, the overall discrepancy rate was 7.2%, the major disagreement rate was 4.2%, and the minor disagreement rate was 2.2%. Misinterpretations among 1st-year residents on call were significant (P < .04) when compared with more senior-level residents. There were 23 FN interpretations. The most common misses were acute stroke (n = 3), aneurysm (n = 3), vascular occlusion (n = 3), and disk herniation (n = 2). There were only three FP interpretations (misdiagnoses of syrinx, arachnoiditis, and acute infarct). CONCLUSION: There was no adverse clinical outcome as a result of misinterpretations, owing in part to rapid turnaround time for final reporting. Level of residency training has a significant effect on the rate of discrepancy, which may be mitigated by recent changes regarding 1st-year radiology residents' overnight call.

Psychiatric medications for deployment: an update.

OBJECTIVE: This article discusses issues regarding the usage of psychotropic medications during military deployments, with emphasis on Operation Iraqi Freedom. METHOD: The role of psychotropic medications in the Army combat stress control doctrine is reviewed and compared with operational experiences of psychiatrists who have deployed to Iraq, Bosnia, and Egypt. RESULTS: Many issues regarding psychotropic medications experienced by deployed psychiatrists are not discussed in the Army combat stress control doctrine. CONCLUSION: The advent of new psychotropic medications, the changes in the types of conflicts fought, and the role of National Guard and Reserve forces in current conflicts have all had an impact on the role and usage of psychotropic medications during military deployments.

Treatment of the stress casualty during operation Iraqi freedom one.

INTRODUCTION: Service members with mental health issues during Operation Iraqi Freedom receive evaluation and treatment at different echelons of care. Mental health teams consist of professionals and paraprofessionals assigned to Combat Stress Control units, Division Mental Health Sections, and Combat Support Hospitals. METHODS: Army doctrine for mental health care is delineated and examples describing how mental health personnel must be flexible in this challenging environment and are useful mental health tools for commanders in the operational environment are presented. DISCUSSION: Specific treatment issues related to the combat environment during Operation Iraqi Freedom are discussed in relation to each team and in light of doctrine.