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STUDY OBJECTIVE: In 1997, the Georgia General Assembly enacted the Teenage and Adult Drivers Responsibility Act (TADRA), a comprehensive legislative package that attempted to reduce fatal crashes of teenaged drivers by introducing graduated driver's licensing, 'zero tolerance' of underage impaired drivers, and automatic license revocation for speeding greater than 25 miles per hour over the posted limit and other dangerous driving behaviors. To determine whether TADRA reduced teen driving fatalities, we examine fatal crash rates involving various age groups before versus after the law was enacted. METHODS: Data from the Fatal Accident Reporting System were used to calculate annualized fatal crash rates of various age groups of drivers during an 11-year interval 5 1/2 years before TADRA was enacted and 5 1/2 years afterwards. To identify potential historical effects, Georgia's experience was compared to that of Alabama, South Carolina, and Tennessee, states that did not adopt equally comprehensive legislation during the study period. RESULTS: During the preenactment period, 317 Georgia drivers aged 16 were involved in a fatal crash (57/100,000 person-years) compared to 230 in the postenactment period (36/100,000 person-years; risk ratio [RR] 0.63; 95% confidence interval 0.53 to 0.75). Speed-related fatal crashes were cut by 42%, and alcohol-related fatal crashes decreased nearly 60%, without displacing fatal crashes to older age groups. These reductions greatly exceeded those noted in 2 of 3 comparison states and the nation overall. CONCLUSION: TADRA markedly reduced fatal crash rates among 16-year-old Georgia drivers. Fatal crashes were not displaced to older age groups. [ABSTRACT FROM AUTHOR]

Objective: To estimate a causal relationship between mental health staffing and time to initiation of mental health care for new patients., Data Sources and Study Setting: As the largest integrated health care delivery system in the United States, the Veterans Health Administration (VHA) provides a unique setting for isolating the effects of staffing on initiation of mental health care where demand is high and out-of-pocket costs are not a relevant confounder. We use data from the Department of Defense and VHA to obtain patient and facility characteristics and health care use., Study Design: To isolate exogenous variation in mental health staffing, we used an instrumental variables approach-two-stage residual inclusion with a discrete time hazard model. Our outcome is time to initiation of mental health care after separation from active duty (first appointment) and our exposure is mental health staffing (standardized clinic time per 1000 VHA enrollees per pay period)., Data Collection/extraction Methods: Our cohort consists of all Veterans separating from active duty between July 2014 and September 2017, who were enrolled in the VHA, and had at least one diagnosis of post-traumatic stress disorder, major depressive disorder, and/or substance use disorder in the year prior to separation from active duty (N = 54,209)., Principal Findings: An increase of 1 standard deviation in mental health staffing results in a higher likelihood of initiating mental health care (adjusted hazard ratio: 3.17, 95% confidence interval: 2.62, 3.84, p < 0.001). Models stratified by tertile of mental health staffing exhibit decreasing returns to scale., Conclusions: Increases in mental health staffing led to faster initiation of care and are especially beneficial in facilities where staffing is lower, although initiation of care appears capacity-limited everywhere., (© 2024 The Author(s). Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Objective: To investigate whether the Veterans Health Administration's (VA) 2019 Referral Coordination Initiative (RCI) was associated with changes in the proportion of VA specialty referrals completed by community-based care (CC) providers and mean appointment waiting times for VA and CC providers., Data Sources/study Settings: Monthly facility level VA data for 3,097,366 specialty care referrals for eight high-volume specialties (cardiology, dermatology, gastroenterology, neurology, ophthalmology, orthopedics, physical therapy, and podiatry) from October 1, 2019 to May 30, 2022., Study Design: We employed a staggered difference-in-differences approach to evaluate RCI's effects on referral patterns and wait times. Our unit of analysis was facility-month. We dichotomized facilities into high and low RCI use based on the proportion of total referrals for a specialty. We stratified our analysis by specialty and the staffing model that high RCI users adopted: centralized, decentralized, and hybrid., Data Collection/extraction Methods: Administrative data on referrals and waiting times were extracted from the VA's corporate data warehouse. Data on staffing models were provided by the VA's Office of Integrated Veteran Care., Principal Findings: We did not reject the null hypotheses that high RCI use do not change CC referral rates or waiting times in any of the care settings for most specialties. For example, high RCI use for physical therapy-the highest volume specialty studied-was associated with -0.054 (95% confidence interval [CI]: -0.114 to 0.006) and 2.0 days (95% CI: -4.8 to 8.8) change in CC referral rate and waiting time at CC providers, respectively, among centralized staffing model adopters., Conclusions: In the initial years of the RCI program, RCI does not have a measurable effect on waiting times or CC referral rates. Our findings do not support concerns that RCI might be impeding Veterans' access to CC providers. Future evaluations should examine whether RCI facilitates Veterans' ability to receive care in their preferred setting., (© 2024 Health Research and Educational Trust.)

Patients with psychogenic nonepileptic seizure (PNES) who fail performance validity testing (PVT) may appear to produce non-valid cognitive profiles. Consequently, they may not get referred to treatment and events persist, with worsening disability and high resource utilization. As a result, we report pre- and post-treatment neuropsychological evaluation findings in a 59-year-old woman with a confirmed diagnosis of PNES established using video-EEG monitoring. At pre-treatment baseline neuropsychological evaluation, PNES events occurred weekly to daily. Performance was impaired across PVTs and across multiple cognitive domains. After behavioral intervention specific to PNES, these events substantially reduced in frequency to rare stress-induced flares. Post-treatment neuropsychological evaluation revealed marked improvement of most cognitive and behavioral scores from baseline, and valid PVT scores. We review predisposing, precipitating, and perpetuating factors for PNES and cognitive impairment in this case and discuss the patient's outcome from treatment. Effectively managing PNES events and dissociative tendencies while reducing unnecessary pharmacological interventions appears to have allowed this patient to function closer to her optimal state. This case illustrates the complexity of Functional Neurologic Disorder (FND) clinical presentation and challenges the assumption that suboptimal neuropsychological performance predicts poor treatment engagement and outcome. We showcase the reversibility of PNES and cognitive manifestations of FND using targeted psychotherapeutic interventions, which resulted in reduced disability and associated healthcare costs, as well as re-engagement in life.

Background: The MISSION and CHOICE Acts expanded the Veterans Health Administration's (VA) capacity to purchase immunotherapy services for VA patients from community-based providers. Our objective was to identify predictors of community-based immunotherapy treatment, and assess differences in cost and utilization across community treatment settings METHODS: We examined claims for 21,257 patients who started immunotherapy treatment between 2015 and 2020. We assessed growth in VA community-based immunotherapy care, predictors of community-based immunotherapy treatment using multivariable logistic regression based on patients' sociodemographic and clinical characteristics. We compared utilization and costs among those who received community-based immunotherapy services in hospital outpatient departments (HOPDs) versus physician office settings (POs)., Results: The proportion of community-based immunotherapy in the VA increased from 5.3% in 2015 to 32.1% in 2020, with total annual costs of immunotherapy growing from $6.1 million to $187 million. Older, married, and rural patients and those with more comorbidities were more likely than younger, single, or urban patients to be treated in the community. Black patients were more likely to be treated in the VA. Respiratory Cancer was the most common cancer type in both settings. Among community immunotherapy patients, we observed no meaningful differences in the number of units administered, the unit drug costs, or the cost per immunotherapy visit between POs and HOPDs., Conclusion: Drug costs did not differ widely across HOPDs and POs among VA patients who receive community-based immunotherapy., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: Contrary to patients, the psychological impact of functional seizures to caregivers has not been adequately investigated. This study aimed to evaluate the rates and determinants of depression and anxiety in caregivers of patients with functional seizures., Methods: Patients with functional seizures and their caregivers completed surveys about demographic, disease-related, and psychosocial characteristics. Rates and determinants of depression and anxiety were evaluated using the Beck Depression and Anxiety Inventory scores as dependent variables and patient and caregiver characteristics as independent variables., Results: Twenty-nine patients (76% female, mean age of 37 years) and their caregivers (59% female, mean age of 43 years) were recruited. Symptoms of anxiety and/or depression were present in 96% of patients (96% depression, 92% anxiety) and 59% of caregivers (52% depression, 50% anxiety). Specifically, 31% of caregivers manifested mild depression, 14% moderate depression, and 7% severe depression, whereas 48% were not depressed. Similarly, 14% of caregivers manifested mild anxiety, 29% moderate anxiety, and 7% severe anxiety, whereas 50% were not anxious. Patient and caregiver depression levels strongly correlated (r = .73, p < .0001). The presence of anxiety and depression in the caregiver was associated with male patient gender (p = .02), patient depression level (p = .002), the caregiver being a parent or sibling (p = .02), and caregiver burden (p = .0009)., Significance: Caregivers of patients with functional seizures experience high rates of anxiety and depression, explained by specific demographic and psychosocial factors that could act as intervention targets., (© 2023 International League Against Epilepsy.)

Objective: To estimate the effects of changes in Veterans Health Administration (VHA) mental health services staffing levels on suicide-related events among a cohort of Veterans., Data Sources: Data were obtained from the VHA Corporate Data Warehouse, the Department of Defense and Veterans Administration Infrastructure for Clinical Intelligence, the VHA survey of enrollees, and customized VHA databases tracking suicide-related events. Geographic variables were obtained from the Area Health Resources Files and the Centers for Medicare and Medicaid Services., Study Design: We used an instrumental variables (IV) design with a Heckman correction for non-random partial observability of the use of mental health services. The principal predictor was a measure of provider staffing per 10,000 enrollees. The outcome was the probability of a suicide-related event., Data Collection/extraction Methods: Data were obtained for a cohort of Veterans who recently separated from active service., Principal Findings: From 2014 to 2018, the per-pay period probability of a suicide-related event among our cohort was 0.05%. We found that a 1% increase in mental health staffing led to a 1.6 percentage point reduction in suicide-related events. This was driven by the first tertile of staffing, suggesting diminishing returns to scale for mental health staffing., Conclusions: VHA facilities appear to be staffing-constrained when providing mental health care. Targeted increases in mental health staffing would be likely to reduce suicidality., (© 2022 Health Research and Educational Trust.)

Nucleus basalis magnocellularis (NBM) cholinergic projections to the basolateral amygdala (BLA) regulate the acquisition and consolidation of fear-like and anxiety-like behaviors. However, it is unclear whether the alterations in the NBM-BLA circuit promote negative affect during ethanol withdrawal (WD). Therefore, we performed ex vivo whole-cell patch-clamp electrophysiology in both the NBM and the BLA of male Sprague Dawley rats following 10 d of chronic intermittent ethanol (CIE) exposure and 24 h of WD. We found that CIE exposure and withdrawal enhanced the neuronal excitability of NBM putative "cholinergic" neurons. We subsequently used optogenetics to directly manipulate NBM terminal activity within the BLA and measure cholinergic modulation of glutamatergic afferents and BLA pyramidal neurons. Our findings indicate that CIE and withdrawal upregulate NBM cholinergic facilitation of glutamate release via activation of presynaptic nicotinic acetylcholine receptors (AChRs). Ethanol withdrawal-induced increases in NBM terminal activity also enhance BLA pyramidal neuron firing. Collectively, our results provide a novel characterization of the NBM-BLA circuit and suggest that CIE-dependent modifications to NBM afferents enhance BLA pyramidal neuron activity during ethanol withdrawal., Competing Interests: The authors declare no competing financial interests., (Copyright © 2022 Sizer et al.)

Background: Rural residents face more barriers to healthcare access, including challenges in receiving home- and community-based long-term services, compared to urban residents. Self-directed services provide flexibility and choice in care options and may be particularly well suited to help older adults with multiple chronic conditions and functional limitations who reside in rural areas remain independent and live in the community., Methods: We conducted a retrospective observational study to understand whether differences in health outcomes between Veteran-Directed Care (VDC), a self-directed Veterans Health Administration (VHA)-paid care program, and other VHA-paid home- and community-based personal care services vary in rural/urban location. The sample included 37,395 veterans receiving VHA-paid home- and community-based long-term care services in FY17. Our primary outcomes were changes in monthly incidence of VHA or VHA-paid community acute care admissions, nursing home admissions, and emergency department (ED) visits. We used fixed effects logistic regression models on unmatched and coarsened exact matched cohorts, stratified by rural/urban location., Results: Both urban and rural VDC recipients were significantly less likely to be admitted to VHA-paid nursing homes, compared to those receiving other VHA-paid personal care services (rural: incremental effect = -0.22, [-0.30, -0.14]; urban: incremental effect = -0.14, [-0.20, -0.07]). Rural, but not urban, VDC enrollees had significantly fewer VHA-paid acute care admissions and ED visits, relative to recipients of other VHA-paid personal care services (acute care, rural: incremental effect = -0.07, 95% CI = [-0.14, -0.01], urban: incremental effect = -0.01, [-0.06, 0.03]; ED, rural: incremental effect = -0.08, [-0.14, -0.02], urban: incremental effect = 0.01, [-0.03, 0.05])., Conclusions: VDC recipients had fewer incidents of potentially avoidable VHA-paid health care use, compared to similar veterans receiving other VHA-paid personal care services. These differences were more pronounced among rural VDC recipients than urban VDC recipients., (© 2022 The American Geriatrics Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Chronic intermittent ethanol and withdrawal (CIE/WD) produces alcohol dependence, facilitates anxiety-like behavior, and increases post-CIE alcohol intake. The basolateral amygdala (BLA) is one of several brain regions that regulates anxiety-like behavior and alcohol intake through downstream projections to the nucleus accumbens (NAC) and bed nucleus of the stria terminalis (BNST), respectively. Previous studies revealed that CIE/WD induces input- and sex-specific adaptations to glutamatergic function in the BLA. The BLA receives information from two distinct input pathways. Glutamatergic afferents from medial structures like the thalamus and prefrontal cortex enter the BLA through the stria terminalis whereas lateral cortical structures like the anterior insula cortex enter the BLA through the external capsule. CIE/WD increases presynaptic glutamatergic function at stria terminalis synapses and postsynaptic function at external capsule synapses. Previous studies sampled neurons throughout the BLA, but did not distinguish between projection-specific populations. The current study investigated BLA neurons that project to the NAC (BLA-NAC neurons) or the BNST (BLA-BNST neurons) as representative "reward" and "aversion" BLA neurons, and showed that CIE/WD alters glutamatergic function and excitability in a projection- and sex-specific manner. CIE/WD increases glutamate release from stria terminalis inputs only onto BLA-BNST neurons. At external capsule synapses, CIE/WD increases postsynaptic glutamatergic function in male BLA-NAC neurons and female BLA-BNST neurons. Subsequent experiments demonstrated that CIE/WD enhanced the excitability of male BLA-NAC neurons and BLA-BNST neurons in both sexes when glutamatergic but not GABAergic function was intact. Thus, CIE/WD-mediated increased glutamatergic function facilitates hyperexcitability in male BLA-NAC neurons and BLA-BNST neurons of both sexes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Price and McCool.)

The basolateral amygdala (BLA) is intimately involved in the development of neuropsychiatric disorders such as anxiety and alcohol use disorder (AUD). These disorders have clear sex biases, with women more likely to develop an anxiety disorder and men more likely to develop AUD. Preclinical models have largely confirmed these sex-specific vulnerabilities and emphasize the effects of sex hormones on behaviors influenced by the BLA. This review will discuss sex differences in BLA-related behaviors and highlight potential mechanisms mediated by altered BLA structure and function, including the composition of GABAergic interneuron subpopulations, glutamatergic pyramidal neuron morphology, glutamate/GABA neurotransmission, and neuromodulators. Further, sex hormones differentially organize dimorphic circuits during sensitive developmental periods (organizational effects) and initiate more transient effects throughout adulthood (activational effects). Current literature indicates that estradiol and allopregnanolone, a neuroactive progestogen, generally reduce BLA-related behaviors through a variety of mechanisms, including activation of estrogen receptors or facilitation of GABA A -mediated inhibition, respectively. This enhanced GABAergic inhibition may protect BLA pyramidal neurons from the excitability associated with anxiety and alcohol withdrawal. Understanding sex differences and the effects of sex hormones on BLA structure and function may help explain sex-specific vulnerabilities in BLA-related behaviors and ultimately improve treatments for anxiety and AUD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Diet and food choices significantly impact teeth, including enamel quality and development of dental caries. However, studies focusing on diet and its relation to oral care in Latinx children with and without Autism Spectrum Disorders (ASD) have been minimally addressed in research. This qualitative study used an inclusive visual methodology to explore what Latinx caregivers learned about their child's diet preferences and food routines in relation to their oral health. As a secondary aim, the study sought to explore whether notable differences in diet emerged between Latinx children with and without ASD. Participants were 32 Latinx caregivers from 18 families with children with and without Autism ( n = 8 with a typically developing child and n = 10 with a child with ASD) who completed a food journal activity and photo elicitation interview. Interviews were thematically coded for themes pertaining to parents' perceptions of their child's diet and oral health. Findings of this study indicate that the process of taking photos helped Latinx caregivers to better situate the barriers and behaviors influencing everyday food routines in their children within the context of relating to their overall oral health. Via their active participation in the research process, parents were empowered to note strategies they could employ that would directly impact their child's oral health outcomes, such as reducing juice intake and monitoring sugar consumption. Therefore, visual research methodologies are an important strategy for researchers to consider in order to empower participants to be part of the research process and part of the outcomes, and to offer better understanding of the lived experience of populations underrepresented in the literature, such as Latinx children with and without ASD and their families.

Functional neurological disorder (FND) encompasses a complex and heterogeneous group of neuropsychiatric syndromes commonly encountered in clinical practice. Patients with FND may present with a myriad of neurological symptoms and frequently have comorbid medical, neurological, and psychiatric disorders. Over the past decade, important advances have been made in understanding the pathophysiology of FND within a biopsychosocial framework. Many challenges remain in addressing the stigma associated with this diagnosis, refining diagnostic criteria, and providing access to evidence-based treatments. This paper outlines FND treatment approaches, emphasizing the importance of respectful communication and comprehensive explanation of the diagnosis to patients, as critical first step to enhance engagement, adherence, self-agency, and treatment outcomes. We then focus on a brief review of evidence-based treatments for psychogenic non-epileptic seizures and functional movement disorder, a guide for designing future treatment trials for FND, and a proposal for a treatment research agenda, in order to aid in advancing the field to develop and implement treatments for patients with FND.

The opioid epidemic has become a severe public health problem, with approximately 130 opioid-induced deaths occurring each day in the United States. Prescription opioids are responsible for approximately 40% of these deaths. Oxycodone is one of the most commonly abused prescription opioids, but despite its prevalent misuse, the number of preclinical studies investigating oxycodone-seeking behaviors is relatively limited. Furthermore, preclinical oxycodone studies that include female subjects are even more scarce, and it is critical that future work includes both sexes. Additionally, the oral route of administration is one of the most common routes for recreational users, especially in the early stages of drug experimentation. However, currently, only two studies have been published investigating operant oral oxycodone self-administration in rodents. Therefore, the primary goal of the present study was to establish an oral oxycodone operant self-administration model in adult male and female rats, as well as to examine a potential mechanism of stress-primed reinstatement. We found that females consumed significantly more oral oxycodone than males in operant self-administration sessions. We also found that active oxycodone self-administration was reduced by mu opioid receptor antagonism and by substitution of water for oxycodone solution. Lastly, we induced stress-primed reinstatement and found that this behavior was significantly attenuated by antagonism of the neurokinin-1 receptor, consistent with our prior work examining stress-induced reinstatement of alcohol- and cocaine-seeking., (© 2019 Society for the Study of Addiction.)

Background: Health care operations managers need to balance scheduling frequent follow-ups for patients with chronic conditions and fitting in patients requiring care for new complaints., Objective: We quantify how frequency of follow-up visits corresponds with access to care for patients receiving care from the Department of Veterans Affairs (VA)., Design: We use patient data collected between October 2013 and June 2016 by the Survey of Healthcare Experiences of Patients (SHEP). Our sample is comprised of 94,496 patients. We estimate logistic models with 1-month lagged facility-level predictors., Main Measures: We calculate monthly measures characterizing facility-level service provision, including the average time between successive primary care visits, the average primary care visit length, the percentage of primary care appointments that are overbooked, the percent of visits that are unscheduled (i.e., walk-ins), and the ratio of patients to providers. We control for economic factors that are associated with health care supply and demand, including median household income, veteran priority status, the Zillow Housing Price Index, and veteran unemployment rates. We also control for patient demographics., Patients: We restrict the data to patients with at least one in-person primary care visit who have provided information on their ability to access urgent and routine care., Key Results: We find that shorter average follow-up times are associated with better access for patients needing urgent or routine care. A 1-month increase in the average time between successive primary care visits is associated with 10% (p < 0.001) lower odds of reporting being able to access urgent care within 1 day and 13% (p < 0.001) lower odds of reporting usually or always being able to access routine care when needed., Conclusion: Facilities with higher average follow-up times are more likely to have patients report that they are unable to quickly access urgent or routine primary care.

Alcohol exposure is associated with decreased mucociliary clearance, a key innate defense essential to lung immunity. Previously, we identified that prolonged alcohol exposure results in dysfunction of airway cilia that persists at the organelle level. This dysfunction is characterized by a loss of 3',5'-cyclic adenosine monophosphate (cAMP)-mediated cilia stimulation. However, whether or not ciliary dysfunction develops intrinsically at the organelle level has not been explored. We hypothesized that prolonged alcohol exposure directly to isolated demembranated cilia (axonemes) causes ciliary dysfunction. To test this hypothesis, we exposed isolated axonemes to alcohol (100 mM) for 1-24 h and assessed ciliary beat frequency (CBF) in response to cAMP at 1, 3, 4, 6, and 24 h post-exposure. We found that after 1 h of alcohol exposure, cilia axonemes do not increase CBF in response to cAMP. Importantly, by 6 h after the initial exposure to alcohol, cAMP-mediated CBF was restored to control levels. Additionally, we found that thioredoxin reverses ciliary dysfunction in axonemes exposed to alcohol. Finally, we identified, using a combination of a xanthine oxidase oxidant-generating system, direct application of hydrogen peroxide, and electron paramagnetic resonance, that hydrogen peroxide versus superoxide, is likely the key oxidant species driving alcohol-induced ciliary dysfunction in isolated axonemes. These data highlight the role of alcohol to stimulate local production of oxidants in the axoneme to cause ciliary dysfunction. Additionally, these data specifically add hydrogen peroxide as a potential therapeutic target in the treatment or prevention of alcohol-associated ciliary dysfunction and subsequent pneumonia., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Motile cilia on airway cells are necessary for clearance of mucus-trapped particles out of the lung. Ciliated airway epithelial cells are uniquely exposed to oxidants through trapping of particles, debris and pathogens in mucus and the direct exposure to inhaled oxidant gases. Dynein ATPases, the motors driving ciliary motility, are sensitive to the local redox environment within each cilium. Several redox-sensitive cilia-localized proteins modulate dynein activity and include Protein Kinase A, Protein Kinase C, and Protein Phosphatase 1. Moreover, cilia are rich in known redox regulatory proteins and thioredoxin domain-containing proteins that are critical in maintaining a balanced redox environment. Importantly, a nonsense mutation in TXNDC3, which contains a thioredoxin motif, has recently been identified as disease-causing in Primary Ciliary Dyskinesia, a hereditary motile cilia disease resulting in impaired mucociliary clearance. Here we review current understanding of the role(s) oxidant species play in modifying airway ciliary function. We focus on oxidants generated in the airways, cilia redox targets that modulate ciliary beating and imbalances in redox state that impact health and disease. Finally, we review disease models such as smoking, asthma, alcohol drinking, and infections as well as the direct application of oxidants that implicate redox balance as a modulator of cilia motility., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Compulsive ethanol intake, characterized by persistent consumption despite negative consequences, is an addictive behavior identified by the DSM-5 as a central criterion in diagnosing alcohol use disorders (AUD). Epidemiological data suggest that females transition from recreational alcohol use to AUD more rapidly than males. Because of this potential sex difference in the etiology of AUD, it is critical to assess addictive behaviors such as compulsive intake in both males and females in preclinical studies., Methods: We used the model of aversion-resistant ethanol consumption to assess compulsive-like ethanol intake. In these experiments, C57BL6/J mice were first provided with continuous access two-bottle choice between water and ethanol to establish baseline intake. Ethanol solution was then adulterated with increasing concentrations of the bitter tastant quinine hydrochloride. Animals that consume ethanol solution despite its pairing with this negative stimulus are thought to be exhibiting compulsive-like behavior., Results: We found that higher concentrations of quinine were required to suppress ethanol consumption in female mice relative to males. We found no effect of estrous cycle phase on baseline ethanol intake or on quinine-adulterated ethanol intake in females., Conclusions: Collectively, these data suggest that females exhibit a higher degree of aversion-resistance than male mice. Because we observed no effect of estrous cycle phase, it is likely that the presence of threshold levels of estradiol or progesterone, as opposed to their natural fluctuation across the estrous cycle, mediates increased aversion-resistance in females. Alternatively, or in combination, developmental effects of sex hormones could contribute to aversion-resistant ethanol intake., (© The Author(s) 2019. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

What is osteobiography good for? The last generation of archaeologists fought to overcome the traditional assumption that archaeology is merely ancillary to history, a substitute to be used when written sources are defective; it is now widely acknowledged that material histories and textual histories tell equally valid and complementary stories about the past. Yet the traditional assumption hangs on implicitly in biography: osteobiography is used to fill the gaps in the textual record rather than as a primary source in its own right. In this article we compare the textual biographies and material biographies of two thirteenth-century townsfolk from medieval England-Robert Curteis, attested in legal records, and "Feature 958," excavated archaeologically and studied osteobiographically. As the former shows, textual biographies of ordinary people mostly reveal a few traces of financial or legal transactions. Interpreting these traces, in fact, implicitly presumes a history of the body. Osteobiography reveals a different kind of history, the history of the body as a locus of appearance and social identity, work, health and experience. For all but a few textually rich individuals, osteobiography provides a fuller and more human biography. Moreover, textual visibility is deeply biased by class and gender; osteobiography offers particular promise for Marxist and feminist understandings of the past.

Medical countermeasures for acute poisoning by organophosphorus nerve agents are generally assessed over 24h following poisoning and a single administration of treatment. At 24h, the antinicotinic bispyridinium compound MB327 (1,10-(propane-1,3-diyl)bis(4-tert-butylpyridinium)) dimethanesulfonate is as effective as the oxime HI-6 against poisoning by soman, when used as part of a treatment containing atropine and avizafone. In this study, we hypothesised that an earlier endpoint, at 6h, would be more appropriate for the pharmacokinetics and mechanism of action of MB327 and would therefore result in improved protection. MB327 diiodide (33.8mg/kg) or the oxime HI-6 DMS (30mg/kg), in combination with atropine and avizafone (each at 3mg/kg) was administered intramuscularly to guinea pigs 1min following subcutaneous soman and the LD 50 of the nerve agent was determined at 6h after poisoning for each treatment. The treatment containing HI-6 gave a similar level of protection at 6h as previously determined at 24h (protection ratios 3.9 and 2.9, respectively). In contrast, the protection achieved by treatment containing MB327 showed a striking increase at 6h (protection ratio >15.4) compared to the 24h end point (protection ratio 2.8). The treatment gave full protection for at least 5h against doses of soman up to 525μg/kg; in contrast, mortality began in animals treated with HI-6 after 1h. This study demonstrates the importance of using an appropriate end point and has shown that treatment including MB327 was far superior to oxime-based treatment for poisoning by soman, when assessed over a pharmacologically-relevant duration. The improved outcome was seen following a single dose of treatment: it is possible that additional doses to maintain therapeutic plasma concentrations would further increase survival time. Antinicotinic compounds therefore offer a promising addition to treatment, particularly for rapidly aging or oxime-insensitive nerve agents., (Copyright © 2017. Published by Elsevier B.V.)

Post-exposure nerve agent treatment usually includes administration of an oxime, which acts to restore function of the enzyme acetylcholinesterase (AChE). For immediate treatment of military personnel, this is usually administered with an autoinjector device, or devices containing the oxime such as pralidoxime, atropine and diazepam. In addition to the autoinjector, it is likely that personnel exposed to nerve agents, particularly by the percutaneous route, will require further treatment at medical facilities. As such, there is a need to understand the relationship between dose rate, plasma concentration, reactivation of AChE activity and efficacy, to provide supporting evidence for oxime infusions in nerve agent poisoning. Here, it has been demonstrated that intravenous infusion of HI-6, in combination with atropine, is efficacious against a percutaneous VX challenge in the conscious male Dunkin-Hartley guinea-pig. Inclusion of HI-6, in addition to atropine in the treatment, improved survival when compared to atropine alone. Additionally, erythrocyte AChE activity following poisoning was found to be dose dependent, with an increased dose rate of HI-6 (0.48mg/kg/min) resulting in increased AChE activity. As far as we are aware, this is the first study to correlate the pharmacokinetic profile of HI-6 with both its pharmacodynamic action of reactivating nerve agent inhibited AChE and with its efficacy against a persistent nerve agent exposure challenge in the same conscious animal., (Copyright © 2017 Crown Copyright. Published by Elsevier B.V. All rights reserved.)

The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4×LD 50 ). VX-challenged animals received atropine, HI-6 and avizafone on signs of poisoning and 2h later the same combination with or without bioscavenger. Five out of 6 animals which received BChE 2h after the appearance of signs of poisoning survived to the end of the study at 48h, compared with 6 out of 6 which received BChE immediately on signs. All the animals (n=6+6) that received only MedCM, without the addition of BChE, died within 10h of poisoning. The toxicokinetics of a sub-lethal challenge of percutaneous VX were determined in untreated animals. Blood VX concentration peaked at approximately 4h after percutaneous dosing with 0.4×LD 50 ; VX was still detectable at 36h and had declined to levels below the lower limit of quantification (10pg/mL) by 48h in 7 of 8 animals, with the remaining animal having a concentration of 12pg/mL. These studies confirm the persistent systemic exposure to nerve agent following percutaneous poisoning and demonstrate that bioscavenger can be an effective component of treatment even if its administration is delayed., (Copyright © 2017. Published by Elsevier B.V.)

Alcohol use disorder (AUD) is a strong risk factor for development and mortality of pneumonia. Mucociliary clearance, a key innate defense against pneumonia, is perturbed by alcohol use. Specifically, ciliated airway cells lose the ability to increase ciliary beat frequency (CBF) to β-agonist stimulation after prolonged alcohol exposure. We previously found that alcohol activates protein phosphatase 1 (PP1) through a redox mechanism to cause ciliary dysfunction. Therefore, we hypothesized that PP1 activity is enhanced by alcohol exposure through an S-nitrosothiol-dependent mechanism resulting in desensitization of CBF stimulation. Bronchoalveolar S-nitrosothiol (SNO) content and tracheal PP1 activity was increased in wild-type (WT) mice drinking alcohol for 6-weeks compared to control mice. In contrast, alcohol drinking did not increase SNO content or PP1 activity in nitric oxide synthase 3-deficient mice. S-nitrosoglutathione induced PP1-dependent CBF desensitization in mouse tracheal rings, cultured cells and isolated cilia. In vitro expression of mutant PP1 (cysteine 155 to alanine) in primary human airway epithelial cells prevented CBF desensitization after prolonged alcohol exposure compared to cells expressing WT PP1. Thus, redox modulation in the airways by alcohol is an important ciliary regulatory mechanism. Pharmacologic strategies to reduce S-nitrosation may enhance mucociliary clearance and reduce pneumonia prevalence, mortality and morbidity with AUD.

Individuals with alcohol (ethanol)-use disorders are at increased risk for lung infections, in part, due to defective mucociliary clearance driven by motile cilia in the airways. We recently reported that isolated, demembranated bovine cilia (axonemes) are capable of producing nitric oxide ( ∙ NO) when exposed to biologically relevant concentrations of alcohol. This increased presence of ∙ NO can lead to protein S -nitrosylation, a posttranslational modification signaling mechanism involving reversible adduction of nitrosonium cations or ∙ NO to thiolate or thiyl radicals, respectively, of proteins forming S -nitrosothiols (SNOs). We quantified and compared SNO content between isolated, demembranated axonemes extracted from bovine tracheae, with or without in situ alcohol exposure (100 mM × 24 h). We demonstrate that relevant concentrations of alcohol exposure shift the S -nitrosylation status of key cilia regulatory proteins, including 20-fold increases in S -nitrosylation of proteins that include protein phosphatase 1 (PP1). With the use of an ATP-reactivated axoneme motility system, we demonstrate that alcohol-driven S -nitrosylation of PP1 is associated with PP1 activation and dysfunction of axoneme motility. These new data demonstrate that alcohol can shift the S -nitrothiol balance at the level of the cilia organelle and highlight S -nitrosylation as a novel signaling mechanism to regulate PP1 and cilia motility.

The provision of effective Medical Countermeasures (MedCM) for all agents and routes of exposure is a strategic goal of defence research and development. In the case of military autoinjector-based therapies for nerve agent poisoning, current treatment effectiveness is limited by the oxime reactivator being effective against only certain agents, by rapid clearance times of the drugs and because the doses may not be optimal for treatment of severe poisoning. Prolonged poisoning by nerve agents entering the body through the skin is also challenging. Since casualty handling timelines have reduced significantly in recent years, it may be sufficient for first aid therapy to provide protection for only a few hours until further medical treatment is available. Therefore, the traditional evaluation of first aid therapy in animal models of survival at 24 h may not be appropriate. At various echelons of medical care, further therapeutic interventions are possible. The current basis for the medical management of nerve-agent poisoned casualties is derived mainly from clinical experience with pesticide poisoning. Adjunct therapy with a bioscavenger (such as human butyrylcholinesterase (huBChE)), could have utility as a delayed intervention by reducing the toxic load. It has previously been demonstrated that huBChE is an effective post-exposure therapy against percutaneous VX poisoning. It is recommended that the scope of animal models of nerve agent MedCM are extended to cover evaluation of both first aid MedCM over significantly reduced timescales, and subsequent supportive therapeutic and medical management strategies over longer timescales. In addition to bioscavengers, these strategies could include repeated combined and individual therapy drugs to alleviate symptoms, other classes of drugs or ventilatory support. Crown Copyright © [2016] Published by Elsevier Ireland Ltd. This is an open access article under the Open Government Licence (OGL) (http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3/)., (Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.)

Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22μM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision., (Crown Copyright © 2015. Published by Elsevier Ireland Ltd. All rights reserved.)

To support the effort to eliminate the Syrian Arab Republic chemical weapons stockpile safely, there was a requirement to provide scientific advice based on experimentally derived information on both toxicity and medical countermeasures (MedCM) in the event of exposure to VM, VX or VM-VX mixtures. Complementary in vitro and in vivo studies were undertaken to inform that advice. The penetration rate of neat VM was not significantly different from that of neat VX, through either guinea pig or pig skin in vitro . The presence of VX did not affect the penetration rate of VM in mixtures of various proportions. A lethal dose of VM was approximately twice that of VX in guinea pigs poisoned via the percutaneous route. There was no interaction in mixed agent solutions which altered the in vivo toxicity of the agents. Percutaneous poisoning by VM responded to treatment with standard MedCM, although complete protection was not achieved.

Airway mucociliary clearance is a first-line defense of the lung against inhaled particles and debris. Among individuals with alcohol use disorders, there is an increase in lung diseases. We previously identified that prolonged alcohol exposure impairs mucociliary clearance, known as alcohol-induced ciliary dysfunction (AICD). Cilia-localized enzymes, known as the ciliary metabolon, are key to the pathogenesis of AICD. In AICD, cyclic nucleotide-dependent ciliary kinases, which modulate phosphorylation to regulate cilia beat, are desensitized. We hypothesized that alcohol activates cilia-associated protein phosphatase 1 (PP1) activity, driving phosphorylation changes of cilia motility regulatory proteins. To test this hypothesis we identified the effects of prolonged alcohol exposure on phosphatase activity, cilia beat, and kinase responsiveness and cilia-associated phosphorylation targets when stimulated by β-agonist or cAMP. Prolonged alcohol activated PP1 and blocked cAMP-dependent cilia beat and protein kinase A (PKA) responsiveness and phosphorylation of a 29-kDa substrate of PKA. Importantly, prolonged alcohol-induced phosphatase activation was inhibited by the PP1 specific inhibitor, inhibitor-2 (I-2), restoring cAMP-stimulated cilia beat and PKA responsiveness and phosphorylation of the 29-kDa substrate. The I-2 inhibitory effect persisted in tissue, cell, and isolated cilia-organelle models, highlighting the association of ciliary metabolon-localized enzymes to AICD. Prolonged alcohol exposure drives ciliary metabolon-localized PP1 activation. PP1 activation modifies phosphorylation of a 29-kDa protein related to PKA activity. These data reinforce our previous findings that alcohol is acting at the level of the ciliary metabolon to cause ciliary dysfunction and identifies PP1 as a therapeutic target to prevent or reverse AICD.

Ancestrally, relatively attractive individuals and relatively formidable males may have had reduced incentives to be egalitarian (i.e., to act in accordance with norms promoting social equality). If selection calibrated one's egalitarianism to one's attractiveness/formidability, then such people may exhibit reduced egalitarianism ("observed egalitarianism") and be perceived by others as less egalitarian ("perceived egalitarianism") in modern environments. To investigate, we created 3D body models of 125 participants to use both as a source of anthropometric measurements and as stimuli to obtain ratings of bodily attractiveness and perceived egalitarianism. We also measured observed egalitarianism (via an economic "dictator" game) and indices of political egalitarianism (preference for socialism over capitalism) and "equity sensitivity." Results indicated higher egalitarianism levels in women than in men, and moderate-to-strong negative relationships between (a) attractiveness and observed egalitarianism among men, (b) attractiveness and perceived egalitarianism among both sexes, and (c) formidability and perceived egalitarianism among men. We did not find support for two previously-reported findings: that observed egalitarianism and formidability are negatively related in men, and that wealth and formidability interact to explain variance in male egalitarianism. However, this lack of support may have been due to differences in variable measurement between our study and previous studies.

In environments in which female economic dependence on a male mate is higher, male parental investment is more essential. In such environments, therefore, both sexes should value paternity certainty more and thus object more to promiscuity (because promiscuity undermines paternity certainty). We tested this theory of anti-promiscuity morality in two studies (N = 656 and N = 4,626) using U.S. samples. In both, we examined whether opposition to promiscuity was higher among people who perceived greater female economic dependence in their social network. In Study 2, we also tested whether economic indicators of female economic dependence (e.g., female income, welfare availability) predicted anti-promiscuity morality at the state level. Results from both studies supported the proposed theory. At the individual level, perceived female economic dependence explained significant variance in anti-promiscuity morality, even after controlling for variance explained by age, sex, religiosity, political conservatism, and the anti-promiscuity views of geographical neighbors. At the state level, median female income was strongly negatively related to anti-promiscuity morality and this relationship was fully mediated by perceived female economic dependence. These results were consistent with the view that anti-promiscuity beliefs may function to promote paternity certainty in circumstances where male parental investment is particularly important.

We describe the service-for-prestige theory of leadership, which proposes that voluntary leader-follower relations evolved in humans via a process of reciprocal exchange that generated adaptive benefits for both leaders and followers. We propose that although leader-follower relations first emerged in the human lineage to solve problems related to information sharing and social coordination, they ultimately evolved into exchange relationships whereby followers could compensate leaders for services which would otherwise have been prohibitively costly for leaders to provide. In this exchange, leaders incur costs to provide followers with public goods, and in return, followers incur costs to provide leaders with prestige (and associated fitness benefits). Because whole groups of followers tend to gain from leader-provided public goods, and because prestige is costly for followers to produce, the provisioning of prestige to leaders requires solutions to the "free rider" problem of disrespectful followers (who benefit from leader services without sharing the costs of producing prestige). Thus service-for-prestige makes the unique prediction that disrespectful followers of beneficial leaders will be targeted by other followers for punitive sentiment and/or social exclusion. Leader-follower relations should be more reciprocal and mutually beneficial when leaders and followers have more equal social bargaining power. However, as leaders gain more relative power, and their high status becomes less dependent on their willingness to pay the costs of benefitting followers, service-for-prestige predicts that leader-follower relations will become based more on leaders' ability to dominate and exploit rather than benefit followers. We review evidential support for a set of predictions made by service-for-prestige, and discuss how service-for-prestige relates to social neuroscience research on leadership.

Past research suggests that a lower waist-to-chest ratio (WCR) in men (i.e., narrower waist and broader chest) is viewed as attractive by women. However, little work has directly examined why low WCRs are preferred. The current work merged insights from theory and past research to develop a model examining perceived dominance, fitness, and protection ability as mediators of to WCR-attractiveness relationship. These mediators and their link to both short-term (sexual) and long-term (relational) attractiveness were simultaneously tested by having 151 women rate one of 15 avatars, created from 3D body scans. Men with lower WCR were perceived as more physically dominant, physically fit, and better able to protect loved ones; these characteristics differentially mediated the effect of WCR on short-term, long-term, and general attractiveness ratings. Greater understanding of the judgments women form regarding WCR may yield insights into motivations by men to manipulate their body image., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This study sought to identify and quantify complications with local anesthetic administration and reversal on consecutive patients seen for comprehensive dental care in a school-based, portable dental clinic, and includes data on the patients seen by the participating portable dental providers. In 923 dental visits where local anesthetic was administered, a standardized form was used to gain further information and identify any complications; this was accompanied by a questionnaire for the student's teacher, in order to quantify the student's distraction and disruption ratings following the dental visit. After statistical analysis of the 923 consecutive cases, the overall complication rate was 5.3%. All of the complications were considered to be mild or moderate, and there were no severe event reports. The complications encountered most frequently (n = 49) were associated with self-inflicted soft tissue injury. The results of this study indicate that comprehensive care with local anesthesia delivered by a school-based portable dental clinic has a low risk of complications. Whereas safe administration of dental care is achievable with or without phentolamine mesylate as a local anesthetic reversal agent, its use was determined to improve safety outcomes. Three factors appeared to directly increase the incidence of complications: the administration of an inferior alveolar nerve block, attention deficit disorder, and obesity. Teacher evaluations demonstrated that children receiving care by a portable dental team were able to reorient back to classwork and were not disruptive to classmates.

Potent organophosphorous (OP) agents, such as VX, are hazardous by absorption through the skin and are resistant to conventional pharmacological antidotal treatments. The residence time of a stoichiometric bioscavenger, human butyrylcholinesterase (huBuChE), in the plasma more closely matches that of VX than do the residence times of conventional therapy drugs (oxime, anti-muscarinic, anticonvulsant). Intramuscular (i.m.) huBuChE afforded almost complete protection when administered prior to the onset of observable cholinergic signs of VX poisoning, but once signs of poisoning became evident the efficacy of i.m. huBuChE decreased. A combination of nerve agent therapy drugs (oxime, anti-muscarinic, anticonvulsant) with huBuChE (i.m.) protected 100% (8/8) of guinea-pigs from a lethal dose of VX (0.74 mg/kg) to 48 h, even when administered on signs of poisoning. Survival was presumed to be due to immediate alleviation of the cholinergic crisis by the conventional pharmacological treatment drugs, in conjunction with bioscavenger that prevented further absorbed agent reaching the AChE targets. Evidence to support this proposed mechanism of action was obtained from PKPD experiments in which multiple blood samples and microdialysate samples were collected from individual conscious ambulatory animals. Plasma concentrations of intramuscularly-administered atropine, diazepam and HI-6 reached a peak within 15 min and were eliminated rapidly within 4h. Plasma concentrations of huBuChE administered by the i.m. route took approximately 24h to reach a peak, but were well-maintained over the subsequent 7days. Thus, the pharmacological therapy rapidly treated the initial signs of poisoning, whilst the bioscavenger provided prolonged protection by neutralising further nerve agent entering the bloodstream and preventing it from reaching the target organs., (Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Measurement of genome-wide DNA methylation (DNAm) has become an important avenue for investigating potential physiologically-relevant epigenetic changes. Illumina Infinium (Illumina, San Diego, CA, USA) is a commercially available microarray suite used to measure DNAm at many sites throughout the genome. However, it has been suggested that a subset of array probes may give misleading results due to issues related to probe design. To facilitate biologically significant data interpretation, we set out to enhance probe annotation of the newest Infinium array, the HumanMethylation450 BeadChip (450 k), with >485,000 probes covering 99% of Reference Sequence (RefSeq) genes (National Center for Biotechnology Information (NCBI), Bethesda, MD, USA). Annotation that was added or expanded on includes: 1) documented SNPs in the probe target, 2) probe binding specificity, 3) CpG classification of target sites and 4) gene feature classification of target sites., Results: Probes with documented SNPs at the target CpG (4.3% of probes) were associated with increased within-tissue variation in DNAm. An example of a probe with a SNP at the target CpG demonstrated how sample genotype can confound the measurement of DNAm. Additionally, 8.6% of probes mapped to multiple locations in silico. Measurements from these non-specific probes likely represent a combination of DNAm from multiple genomic sites. The expanded biological annotation demonstrated that based on DNAm, grouping probes by an alternative high-density and intermediate-density CpG island classification provided a distinctive pattern of DNAm. Finally, variable enrichment for differentially methylated probes was noted across CpG classes and gene feature groups, dependant on the tissues that were compared., Conclusion: DNAm arrays offer a high-throughput approach for which careful consideration of probe content should be utilized to better understand the biological processes affected. Probes containing SNPs and non-specific probes may affect the assessment of DNAm using the 450 k array. Additionally, probe classification by CpG enrichment classes and to a lesser extent gene feature groups resulted in distinct patterns of DNAm. Thus, we recommend that compromised probes be removed from analyses and that the genomic context of DNAm is considered in studies deciphering the biological meaning of Illumina 450 k array data.

There is accumulating evidence of condition-dependent mate choice in many species, that is, individual preferences varying in strength according to the condition of the chooser. In humans, for example, people with more attractive faces/bodies, and who are higher in sociosexuality, exhibit stronger preferences for attractive traits in opposite-sex faces/bodies. However, previous studies have tended to use only relatively simple, isolated measures of rater attractiveness. Here we use 3D body scanning technology to examine associations between strength of rater preferences for attractive traits in opposite-sex bodies, and raters' body shape, self-perceived attractiveness, and sociosexuality. For 118 raters and 80 stimuli models, we used a 3D scanner to extract body measurements associated with attractiveness (male waist-chest ratio [WCR], female waist-hip ratio [WHR], and volume-height index [VHI] in both sexes) and also measured rater self-perceived attractiveness and sociosexuality. As expected, WHR and VHI were important predictors of female body attractiveness, while WCR and VHI were important predictors of male body attractiveness. Results indicated that male rater sociosexuality scores were positively associated with strength of preference for attractive (low) VHI and attractive (low) WHR in female bodies. Moreover, male rater self-perceived attractiveness was positively associated with strength of preference for low VHI in female bodies. The only evidence of condition-dependent preferences in females was a positive association between attractive VHI in female raters and preferences for attractive (low) WCR in male bodies. No other significant associations were observed in either sex between aspects of rater body shape and strength of preferences for attractive opposite-sex body traits. These results suggest that among male raters, rater self-perceived attractiveness and sociosexuality are important predictors of preference strength for attractive opposite-sex body shapes, and that rater body traits -with the exception of VHI in female raters- may not be good predictors of these preferences in either sex.

The physiological effects of human plasma-derived butyrylcholinesterase (huBuChE) administration and its modulation of the effects of percutaneous VX challenge are poorly understood. Percutaneously administered nerve agents are more slowly absorbed than inhaled agents; consequently, signs of poisoning occur later, with a longer duration. Telemetry was used to monitor heart rate, EEG, temperature and activity in guinea-pigs. Treatment with huBuChE at 30 or 120 min following percutaneous VX challenge ( approximately 2.5 x LD(50)) provided 100% protection from lethality. When huBuChE administration was delayed until the onset of observable signs of poisoning only 1 out of 6 animals survived to the end of the experiment at 7 days. This study adds to the body of evidence demonstrating the efficacy of huBuChE in animals by describing the successful therapeutic use of a protein bioscavenger as a post-exposure treatment against dermal exposure to VX up to 2h post-exposure. This study simultaneously used telemetric methods to show that the efficacy of huBuChE is linked to the prevention of detrimental physiological changes observed in control VX-treated animals. Post-exposure therapy is a promising additional indication for the concept of use of this material, and one that has particular relevance in a civilian exposure scenario., (Crown Copyright (c) 2010. Published by Elsevier Ireland Ltd. All rights reserved.)

For many years in evolutionary science, the consensus view has been that while reciprocal altruism can evolve in dyadic interactions, it is unlikely to evolve in sizable groups. This view had been based on studies which have assumed cooperation to be discrete rather than continuous (i.e., individuals can either fully cooperate or else fully defect, but they cannot continuously vary their level of cooperation). In real world cooperation, however, cooperation is often continuous. In this paper, we re-examine the evolution of reciprocity in sizable groups by presenting a model of the n-person prisoner's dilemma that assumes continuous rather than discrete cooperation. This model shows that continuous reciprocity has a dramatically wider basin of attraction than discrete reciprocity, and that this basin's size increases with efficiency of cooperation (marginal per capita return). Further, we find that assortative interaction interacts synergistically with continuous reciprocity to a much greater extent than it does with discrete reciprocity. These results suggest that previous models may have underestimated reciprocity's adaptiveness in groups. However, we also find that the invasion of continuous reciprocators into a population of unconditional defectors becomes realistic only within a narrow parameter space in which the efficiency of cooperation is close to its maximum bound. Therefore our model suggests that continuous reciprocity can evolve in large groups more easily than discrete reciprocity only under unusual circumstances., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)