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Importance: Several coronaviruses (CoVs) have been detected in domesticated, farmed, and wild meso-carnivores, causing a wide range of diseases and infecting diverse species, highlighting their important but understudied role in the epidemiology of these viruses. Assessing the viral diversity hosted in wildlife species is essential to understand their significance in the cross-species transmission of CoVs. Our focus here was on CoV discovery in meso-carnivores in the Northeast United States as a potential "hotspot" area with high density of humans and urban wildlife. This study identifies novel alphacoronaviruses circulating in multiple free-ranging wild and domestic species in this area and explores their potential epidemiological importance based on regions of the Spike gene, which are relevant for virus-host interactions., Competing Interests: The authors declare no conflict of interest.

Aims: To describe patterns of multiple symptom illness (MSI) in New Zealand military veterans, defined as clusters of "medically unexplained" symptoms not fitting within a specific medical diagnosis, and to investigate the relationship with exposure to traumatic events., Methods: We designed an online cross-sectional survey. The participants of interest were the 3,874 currently serving veterans who had been deployed to a conflict zone, but all veterans were eligible to participate. A modified Centers for Disease Control (CDC) 54-item symptom checklist identified MSI, the post-traumatic checklist-military version (PCL-M) identified symptoms of post-traumatic stress disorder (PTSD) and the brief trauma scale assessed "war zone" service. Factor analysis was used to identify unobserved "latent factors" in the data, factor severity scores and the number of symptoms being calculated for each respondent., Results: The CDC questionnaire was completed by 1,819 veterans, with 1,672 completing the PCL-M. The factor analysis revealed three factors, explaining 86% of the variation in the data. Factor 1 symptoms were of an arthro-neuromuscular nature, Factor 2 cognitive and Factor 3 psycho-physiological. Discriminant function analysis showed that the factors could discriminate between those with and without PTSD but could not discriminate between those who did and did not serve in a war zone., Conclusions: In veterans, multiple symptoms including pain, sleep disorders, cognitive problems and avoidance, especially when severe, may be worthy of further investigation by health professionals because of the possible association with PTSD., Competing Interests: Nil., (© PMA.)

Aim: This study aims to examine opportunities for subsequent injury prevention from the perspectives of people who have recently experienced subsequent injury events., Methods: This qualitative study involved individual semi-structured interviews with people who had >2 injury events in the previous 12 months. Interviews were audio-recorded, transcribed verbatim and thematic analysis undertaken., Results: Sixteen interviews were completed with participants who had experienced a range of index and subsequent injury types. Potential opportunities raised were wide-ranging. Some related to individuals, e.g., motivation to carry out prevention strategies. Other opportunities were related to healthcare providers and the health system. For instance, increasing consultation times to allow a focus on subsequent injury prevention, building rapport and tailoring their approach to the individual, proactively referring people to a range of healthcare providers, and ensuring people are aware of resources and supports available following injury. Broader environmental and societal opportunities were also suggested, such as ensuring adequate social support following injury, ensuring accessibility to rehabilitation and community facilities and the modification of built environments., Conclusion: A broad range of potential opportunities to prevent subsequent injuries were raised. These opportunities are promising and future research to trial interventions raised in this study is warranted to determine their feasibility and effectiveness., Competing Interests: Nil, (© PMA.)

We present the first ancient DNA data from the Pre-Pottery Neolithic of Mesopotamia (Southeastern Turkey and Northern Iraq), Cyprus, and the Northwestern Zagros, along with the first data from Neolithic Armenia. We show that these and neighboring populations were formed through admixture of pre-Neolithic sources related to Anatolian, Caucasus, and Levantine hunter-gatherers, forming a Neolithic continuum of ancestry mirroring the geography of West Asia. By analyzing Pre-Pottery and Pottery Neolithic populations of Anatolia, we show that the former were derived from admixture between Mesopotamian-related and local Epipaleolithic-related sources, but the latter experienced additional Levantine-related gene flow, thus documenting at least two pulses of migration from the Fertile Crescent heartland to the early farmers of Anatolia.

Literary and archaeological sources have preserved a rich history of Southern Europe and West Asia since the Bronze Age that can be complemented by genetics. Mycenaean period elites in Greece did not differ from the general population and included both people with some steppe ancestry and others, like the Griffin Warrior, without it. Similarly, people in the central area of the Urartian Kingdom around Lake Van lacked the steppe ancestry characteristic of the kingdom's northern provinces. Anatolia exhibited extraordinary continuity down to the Roman and Byzantine periods, with its people serving as the demographic core of much of the Roman Empire, including the city of Rome itself. During medieval times, migrations associated with Slavic and Turkic speakers profoundly affected the region.

By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra-West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe.

Objective: To identify factors associated with better or poorer self-reported health status in New Zealand military Veterans., Design: A cross-sectional survey., Participants: The participants of interest were the 3874 currently serving Veterans who had been deployed to a conflict zone, but all Veterans were eligible to participate., Study Variables: The EQ-5D-5L, asking about problems across five dimensions (mobility, self-care, usual activities, pain or discomfort and anxiety or depression), with five levels of severity (eg, no, slight, moderate, severe or extreme problems), also containing a Visual Analogue Scale (EQ-VAS) to self-assess health state, scaled from 0 (worst) to 100 (best) imagined health.Hypothetical relationships with better health were positive social support, sleep and psychological flexibility; with poorer health, post-traumatic stress, exposure to psychological trauma, distress and hazardous drinking., Results: The EQ5-D-5L was completed by 1767 Veterans, 1009 serving, a response rate of 26% from that group, 1767 completing the EQ5-D, 1458 who had deployed, 288 who had not and the 21 who did not provide deployment data. Of these, 247 were not used in the analysis due to missing values in one or more variables, leaving 1520 for analysis.A significantly higher proportion of Veterans reported 'any problems' rather than 'no problems' with four EQ-5D dimensions: mobility, self-care, usual activities and pain or discomfort, but no difference in anxiety or depression. Age, length of service, deployment, psychological flexibility and better sleep quality were associated with higher EQ-VAS scores; distress with lower EQ-VAS scores., Conclusion: In this sample of New Zealand Veterans, psychological flexibility and good sleep are associated with better self-rated health, and distress and poor sleep with diminished health. These factors might be used as sentinel health indicators in assessing Veteran health status, and cognitive-behavioural therapy encompassing these domains may be useful in improving the health of New Zealand Veterans., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Kv3 potassium currents mediate rapid repolarisation of action potentials (APs), supporting fast spikes and high repetition rates. Of the four Kv3 gene family members, Kv3.1 and Kv3.3 are highly expressed in the auditory brainstem and we exploited this to test for subunit-specific roles at the calyx of Held presynaptic terminal in the mouse. Deletion of Kv3.3 (but not Kv3.1) reduced presynaptic Kv3 channel immunolabelling, increased presynaptic AP duration and facilitated excitatory transmitter release; which in turn enhanced short-term depression during high-frequency transmission. The response to sound was delayed in the Kv3.3KO, with higher spontaneous and lower evoked firing, thereby reducing signal-to-noise ratio. Computational modelling showed that the enhanced EPSC and short-term depression in the Kv3.3KO reflected increased vesicle release probability and accelerated activity-dependent vesicle replenishment. We conclude that Kv3.3 mediates fast repolarisation for short precise APs, conserving transmission during sustained high-frequency activity at this glutamatergic excitatory synapse., Competing Interests: AR, VC, MS, KB, SN, JS, BG, CK, IF No competing interests declared, NP This author is employed by Autifony Therapeutics Ltd, (© 2022, Richardson et al.)

Sexual violence (SV) is a pernicious issue that disproportionally impacts girls and women. Although few initiatives have demonstrated effectiveness in leading to reductions in SV, global health organizations have identified empowerment-based programs as a promising approach to SV prevention. The purpose of this article is to discuss the Girls Leadership Academy (GLA), a program of the Nebraska's Women's Center for Advancement, which is a "homegrown," theoretically grounded, practice-based SV prevention program for adolescent girls. More specifically, we discuss previous research relevant to the GLA; the theoretical underpinnings of the GLA; and the history, context, and content of the GLA.

Introduction: Many individuals who experience an injury go on to have subsequent injuries. This study examined the views of health professionals about potential opportunities to prevent subsequent injuries., Methods: Semi-structured individual interviews were held with a range of health professionals involved in treating injuries. Interviews examined opportunities for the prevention of subsequent injuries, particularly opportunities that may be implemented by health professionals. A thematic analysis of the data was undertaken., Results: Thirteen health professionals were interviewed, including physiotherapists, occupational therapists, and emergency department staff. Opportunities to prevent subsequent injuries aligned with the Dahlgren-Whitehead model of health determinants, representing opportunities to focus on demographic factors (e.g. older adults), individual lifestyle factors (e.g. alcohol consumption), social and community networks (e.g. social isolation), living and working conditions (e.g. access to preventive healthcare), and general socioeconomic, cultural, and environmental conditions (e.g. changes in legislation)., Conclusions: Health professionals identified a number of opportunities for subsequent injury prevention, ranging from individually oriented interventions to broader societal interventions. Within their roles, health professionals highlighted potential opportunities to provide education, modify attitudes, engage in multi-disciplinary teamwork, and serve as advocates. Use of these strategies could help to reduce the disability burden presented by subsequent injuries., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Research examining psychological distress in people who have experienced an injury has focused on those with serious injuries or specific injury types, and has not involved long-term follow up. The aims of this investigation were to describe the prevalence of, and factors contributing to, psychological distress in a cohort of people with a broad range of injuries., Methods: The Prospective Outcomes of Injury Study (POIS) is a longitudinal cohort study of 2856 injured New Zealanders recruited from a national insurance entitlement claims register between 2007 and 2009. Participants were interviewed approximately 3, 12, and 24 months after their injury. The Kessler Psychological Distress Scale (K6) was used to measure psychological distress at each interview., Results: 25% of participants reported clinically relevant distress (K6 ≥ 8) 3 months post-injury, 15% reported distress at 12 months, and 16% reported distress at 24 months. Being 45 years or older, Māori or Pacific ethnicity, experiencing pre-injury mental health conditions, having inadequate pre-injury income, reporting poor pre-injury health or trouble accessing healthcare, having a severe injury or an injury resulting from assault, and reporting clinically relevant distress 3 months post-injury were independently associated with an increased risk of distress 12 months post-injury. The majority of these associations were also evident with respect to distress 24 months post-injury., Conclusions: Distress is common after injury among people with a broad range of injury types and severities. Screening for distress early after injury is important to identify individuals in need of targeted support.

Injury is a leading cause of disability and is costly. This prospective cohort study extension aims to improve disability, health, and wellbeing outcomes for injured New Zealanders, including for Māori. We will identify predictors and modifiable risk factors of long-term outcomes (positive and negative), and develop an Injury Early Care Tool (INJECT) to inform the implementation of effective interventions to improve outcomes. In the Prospective Outcomes of Injury Study (POIS), 2856 people participated following an injury (occurring between 2007 and 2009) registered with New Zealand's no-fault accident compensation scheme (ACC). POIS-10 will invite 2121 people (including 358 Māori) who completed a 24-month POIS interview and agreed to follow-up, anticipating 75% participation ( n = 1591). Interviews will collect sociodemographic characteristics, life events, comorbidities, and new injuries since participants' 24-month interview, as well as key disability, health, and wellbeing outcomes 12 years post-injury. Injury-related data will be collected from ACC and hospitalisation records 12 years post-injury. Regression models for the main outcomes will examine the direct effects of predictor variables after adjustment for a wide range of confounders. POIS-10 is enhanced by our partnership with ACC, and expert advisors and will benefit injured people, including Māori, through increased understanding of mechanisms and interventions to improve long-term post-injury outcomes.

Virtual reality simulation (VRS) has become progressively popular as a training tool in ophthalmology. However, debate continues as to whether VRS has resulted in better outcomes for patients after cataract surgery. Accordingly, a qualitative systematic literature review was conducted to identify whether VRS training results in a reduced complication rate after real-life cataract surgery. Included studies measured the effect of VRS on real-life patient outcomes after cataract surgery. Databases searched included MEDLINE (Ovid), The Cochrane Library, Web of Science, PubMed, and CINAHL. A total of 1917 studies were identified, of which 10 studies were included, spanning from 2011 to 2020. The studies comprised 471 ophthalmological residents, with their complication rates assessed after 30 462 cataract surgery procedures. This systematic literature review indicates that VRS seems to be most helpful in reducing the rate of posterior capsular rupture or errant curvilinear capsulorrhexis and had limited evidence in reducing the rate of other complications., (Copyright © 2020 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Objective: To examine how secondary health conditions (SHCs) that develop early after a spinal cord injury (SCI) are related to disability over time. Design: Prospective cohort study. Setting: Two spinal units in New Zealand (Burwood Spinal Unit and Auckland Spinal Rehabilitation Unit). Participants: Between 2007 and 2009, 91 people participated in three telephone interviews approximately 6, 18, and 30 months after the occurrence of a SCI. Outcome measures : SHCs were measured using 14 items derived from the Secondary Complications Survey. Disability was measured using the 12-item World Health Organization Disability Assessment Schedule 2.0. Linear regression analyses were performed to investigate associations between SHCs at 6 months and disability at each assessment point. Results: The most prevalent SHCs were leg spasms, constipation, back pain, pain below the level of SCI, and shoulder pain. Constipation, urinary tract infection, and headaches at 6 months post-SCI were associated with significantly higher levels of disability at each subsequent follow-up, independent of age, sex and SCI impairment. Back pain, and pain below the SCI, at 6 months were associated with significantly greater disability at 18 months, and difficulty coughing at 6 months was associated with significantly greater disability at 30 months. Conclusion: The experience of specific SHCs in the first 6 months after an SCI is related to greater long-term disability. In order to reduce the disability burden of people with SCI, efforts should be directed toward early prevention of these SHCs.

Paraoxonase-1 (PON-1) activity is a new inflammatory and oxidative marker. Technical effects and biological factors could affect the accuracy of PON-1 activity measurement. We investigated the effects of storage at different temperatures, repeated freeze-thaw cycles, interferences from hemolytic, lipemic, and icteric samples, and seasonal effects on PON-1 activity in horses. We evaluated 2 substrates with an automated spectrophotometer. Ten equine serum samples were stored under different conditions. Although storage at room (21°C) or refrigeration (4°C) temperature induced a statistically significant decrease ( p < 0.05) in PON-1 activity, this is not diagnostically relevant. PON-1 activity in frozen samples (-20°C) was stable for short-term storage; diagnostically significant ( p < 0.01) fluctuations were observed after 1 mo. Four repeated freeze-thaw cycles were assessed, and all cycles affected PON-1 activity ( p < 0.01); however, this was diagnostically significant only after the 4th cycle. Hemolysis induced an overestimation of PON-1 activity; lipemia and hyperbilirubinemia did not change PON-1 activity. Thirty-four horses were sampled monthly for 1 y, and PON-1 activity was higher in autumn ( p < 0.05) and winter ( p < 0.05) than in spring and summer.

Integrated care approaches have been recommended to remove barriers to healthcare and improve the physical health outcomes of people living with serious mental illness (SMI) and/or substance use disorders (SUDs). The aim of this systematic scoping review was to describe empirical investigations of interventions designed to integrate physical, mental, and addiction healthcare for this population. An iterative and systematic search of five electronic databases (Medline (Ovid), PsycINFO, CINAHL, Embase (Ovid) and Scopus) was conducted to identify peer-reviewed articles published between January 2000 and April 2019. Two reviewers independently screened publications in two successive stages of title and abstract screening, followed by full-text screening of eligible publications. Data from each included publication were extracted independently by two reviewers using a standardised spreadsheet. A total of 28 eligible publications were identified, representing 25 unique studies. Over half of the included studies investigated the use of case managers to provide self-management skills or to coordinate mental and physical healthcare (n = 14). Other interventions examined the co-location of services (n = 9) and the implementation of screening and referral pathways to specialist treatment (n = 2). Less than half of the included studies described a framework, theory or model that was underpinning the intervention tested. While some aspects of integrated care have been identified and addressed by interventions, other key dimensions have not been considered, such as shared decision-making. Identification of a comprehensive model of integrated care is recommended to inform the development and evaluation of future interventions for people with SMI/SUDs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-β signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-β signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets., Competing Interests: Competing interest statement: D.C.H. reports US Patent No. US 9,803,200 B2 “Inhibition of microRNA-134 for the treatment of seizure-related disorders and neurologic injuries.”, (Copyright © 2020 the Author(s). Published by PNAS.)

Key Points: Kv3.1 and Kv3.3 subunits are highly expressed in the auditory brainstem, with little or no mRNA for Kv3.2 or Kv3.4. Changes in Kv3 currents and action potential (AP) firing were analysed from wild-type, Kv3.1 and Kv3.3 knockout (KO) mice. Both Kv3.1 and Kv3.3 immunostaining was present and western blots confirmed loss of subunit protein in the respective KO. Medial nucleus of the trapezoid body (MNTB) AP repolarization utilized Kv3.1 and/or Kv3.3; while in the lateral superior olive (LSO) Kv3.3 was essential. Voltage-gated calcium currents were unchanged between the genotypes. But APs evoked higher [Ca 2+ ] i in LSO than MNTB neurons; and were highest in the Kv3.3KO, consistent with longer AP durations. High frequency stimulation increased AP failure rates and AP latency in LSO neurons from the Kv3.3KO, underlining the physiological consequences for binaural integration. LSO neurons require Kv3.3 for functional Kv3 channels, while MNTB neurons can utilize either Kv3.1 or Kv3.3 subunits., Abstract: Kv3 voltage-gated potassium channels mediate action potential (AP) repolarization. The relative importance of Kv3.1 and Kv3.3 subunits for assembly of functional channels in neurons of the auditory brainstem was examined from the physiological perspective that speed and precision of AP firing are crucial for sound source localization. High levels of Kv3.1 and Kv3.3 mRNA and protein were measured, with no evidence of compensation by Kv3.2 or Kv3.4 in the respective knockout (KO) mouse. Using the KOs, composition of Kv3 channels was constrained to either Kv3.1 or Kv3.3 subunits in principal neurons of the medial nucleus of the trapezoid body (MNTB) and lateral superior olive (LSO); while TEA (1 mm) was employed to block Kv3-mediated outward potassium currents in voltage- and current clamp experiments. MNTB neuron APs (half-width 0.31 ± 0.08 ms, n = 25) were fast, reliable, and showed no distinction between channels assembled from Kv3.1 or Kv3.3 subunits (in the respective KO). LSO AP half-widths were also fast, but absolutely required Kv3.3 subunits for fast repolarization (half-widths: 0.25 ± 0.08 ms, n = 19 wild-type, 0.60 ± 0.17 ms, n = 21 Kv3.3KO, p = 0.0001). The longer AP duration increased LSO calcium influx and AP failure rates, and increased AP latency and jitter during high frequency repetitive firing. Both Kv3.1 and Kv3.3 subunits contribute to Kv3 channels in the MNTB (and compensate for each other in each KO); in contrast, LSO neurons require Kv3.3 subunits for fast repolarization and to sustain AP firing during high frequency stimulation. In conclusion, Kv3 channels exhibit both redundancy and Kv3.3 dominance between the brainstem nuclei involved in sound localization., (© 2020 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Studies examining the impact of injury on health-related quality of life (HRQL) over time are necessary to understand the short- and long-term consequences of injury for population health. The aim of this systematic review was to provide an evidence update on studies that have measured HRQL over time in general injury populations using a generic (general) health state measure., Methods: Studies conducted between 2010 and 2018 that assessed HRQL at more than one time point among general injury populations were eligible for inclusion. Two reviewers independently extracted information from each study on design, HRQL measure used, method of HRQL measure administration, timing of assessment(s), predictive variables, ability to detect change, and findings. Quality appraisals of each study were also completed by two reviewers using items from the RTI Item Bank on Risk of Bias and Precision of Observational Studies and the Guidelines for the Conduction of Follow-up Studies Measuring Injury-Related Disability., Results: Twenty-nine studies (44 articles) that met the inclusion criteria were identified. HRQL was measured using 14 different generic measures; the SF-36, SF-12, and EQ-5D were used most frequently. A varying number of follow-up assessments were undertaken, ranging from one to five. Follow-up often occurred 12 months post-injury. Fewer studies (n = 11) examined outcomes two or more years post-injury, and only one to 10 years post-injury. While most studies documented improvements in HRQL over time since the injury event, study populations had not returned to pre-injury status or reached general population norm HRQL values at post-injury follow-ups., Conclusions: Since 2010 there has been a substantial increase in the number of studies evaluating the HRQL of general injury populations. However, significant variability in study design continues to impede quantification of the impact of injury on population health over time. Variation between studies is particularly evident with respect to timing and number of follow-up assessments, and selection of instruments to evaluate HRQL.

Background: Post-traumatic stress (PTS) is prevalent among military personnel. Knowledge of the risk and protective factors associated with PTS in this population may assist with identifying personnel who would benefit from increased or targeted support., Aims: To examine factors associated with PTS among New Zealand military personnel., Methods: For this cross-sectional study, currently serving and retired military personnel were invited to complete a questionnaire. The questionnaire included a measure of PTS (the Military Post-traumatic Stress Disorder Checklist; PCL-M), where scores ≥30 indicate the experience of significant PTS symptoms and scores ≥45 indicate a presumptive clinical diagnosis of post-traumatic stress. Potential risk and protective factors associated with PTS were examined using logistic regression modelling., Results: 1817 military personnel completed the questionnaire. PCL-M scores were ≥30 for 549 (30%) participants and ≥45 for 179 (10%) participants. Factors associated with higher PCL-M scores were trauma exposure, older age, male sex, and Māori ethnicity. Factors associated with lower PCL-M scores were greater length of service, psychological flexibility, and better quality sleep., Conclusions: PTS was found to be prevalent among New Zealand military personnel. The experience of trauma was strongly associated with PTS. However, factors such as psychological flexibility (the ability to adapt to changes in circumstances) and good sleep were protective, suggesting that these factors could be key targets for interventions designed to reduce PTS among military personnel in New Zealand., Competing Interests: The authors have declared that no competing interests exist.

Background: Patient and public engagement in paediatric health-care decision making is under-researched, and there is a lack of systematically reviewed literature in this area., Objective: To examine the extent, range and nature of published research investigating the engagement of children/youth, families and the public in paediatric service improvement, to summarize key aspects of the research identified and to identify gaps to help inform future research needs., Methods: Literature was sought in MEDLINE, EMBASE, PsycINFO and CINAHL. Eligible articles presented research focused on patient, family and public engagement strategies in the paediatric health-care setting. Two reviewers extracted and charted data and analysed findings using a descriptive numerical summary analysis and a thematic analysis., Results: From 4331 articles, 21 were eligible. Most were from the United States. The majority of studies were undertaken in hospital settings and used quantitative methods. Various patient and public engagement strategies/interventions were examined, including shared decision-making tools, questionnaires, youth councils/family advisory groups, patient portals and online networks. Most of the studies examined child/youth/parent satisfaction, with fewer investigating treatment outcomes or service improvement. The majority of studies investigated an engagement strategy at the 'individual treatment' level of engagement. Regarding the continuum of engagement, most of the studies were at either the 'consultation' or 'involvement' stage., Conclusion: Future research needs to focus on the investigation of engagement strategies delivered in primary care, and the use of more qualitative and mixed methods approaches is recommended. There is a gap in the area of engagement strategies directed towards 'service design and resources' and 'macro/policy' levels., (© 2019 The Authors Health Expectations published by John Wiley & Sons Ltd.)

Introduction: People with serious mental illness (SMI) and/or substance use disorders (SUDs) have an elevated risk of premature mortality compared with the general population. This has been attributed to higher rates of chronic illness among these individuals, but also to inequities in healthcare access and treatment. Integrated care has the potential to improve the health of people with SMI/SUDs. The aims of this scoping review are to: (1) identify empirical investigations of interventions designed to integrate care for people with SMI/SUDs; (2) describe the underlying theories, models and frameworks of integrated care that informed their development; and (3) determine the degree to which interventions address dimensions of a comprehensive and validated framework of integrated care., Methods and Analysis: Guidelines for best practice and reporting of scoping reviews will be followed using the framework of Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping review checklist. An iterative and systematic search of peer-reviewed publications reporting empirical research findings will be conducted. This literature will be identified by searching five databases: Medline (Ovid), PsycINFO, CINAHL, Embase (Ovid) and Scopus. The search will be restricted to articles published between January 2000 and April 2019. Two reviewers will independently screen publications in two successive stages of title and abstract screening, followed by full-text screening of eligible publications. A tabular summary and narrative synthesis will be completed using data extracted from each included study. A framework synthesis will also be conducted, with descriptions of interventions mapped against a theoretical framework of integrated care., Ethics and Dissemination: This review will identify the extent and nature of empirical investigations evaluating interventions to integrate care for people with SMI/SUDs. Ethical approval was not required. A team of relevant stakeholders, including people with lived experience of mental health conditions, has been established. This team will be engaged throughout the review and will ensure that the findings are widely disseminated. Dissemination will include publication of the review in a peer-reviewed journal. The review protocol has been registered through Open Science Framework and can be accessed at https://osf.io/njkph/., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: The purpose of this systematic review is to identify psychological interventions that have been effective at improving quality of life and reducing psychological distress (depression and anxiety) in patients with head and neck cancer., Methods: All relevant peer-reviewed articles published between March 1980 and March 2017 were identified through an electronic search of five databases: Medline, Embase, PsycINFO, Scopus, and Academic Search Complete. Risk of bias was independently assessed by two reviewers using the Crowe Critical Appraisal Tool (CCAT). Following this, a narrative synthesis of the findings was completed., Results: Twenty-one unique intervention studies were identified. Interventions tested included cognitive behavioural therapy (CBT), psychoeducation, meditation/mindfulness, group therapy, and telehealth initiatives. Ten studies utilised a randomised controlled design. Five of these investigated CBT and three examined psychoeducation, with the greatest empirical support found for these intervention types. However, the majority of studies were underpowered to detect significant effects and did not examine whether improvements in quality of life and psychological well-being were sustained over time., Conclusions: Further research is needed to investigate the effects of psychological interventions among patients with head and neck cancer, using randomised controlled designs, adequately powered samples, and long-term follow-up. This would allow evidence-based recommendations to be made regarding the most appropriate interventions to implement in clinical practice., Trial Registration: CRD42017069851.

Aims and Objectives: To explore the perspectives of nursing and physiotherapy academics regarding techniques designed to prevent musculoskeletal pain and injury in nurses., Background: High rates of musculoskeletal injuries are evident in nurses, yet there is an absence of research identifying effective interventions to address this problem. Exploring the perspectives of individuals with specialist knowledge in the area could help identify barriers to musculoskeletal injury prevention, and innovative strategies to investigate in future studies., Design: Cross-sectional qualitative descriptive study., Methods: Between October-December 2017, group and individual face-to-face semi-structured interviews were used to collect data. All interviews were audio-recorded. A thematic analysis was performed, with two researchers coding audio files using NVivo software. The Consolidated Criteria for Reporting Qualitative Research Checklist was consulted to ensure complete reporting of all methods and findings., Results: Nursing and physiotherapy academics ( N  = 10) were aware of a range of techniques to prevent musculoskeletal injuries in nurses, including education, equipment, health and safety policy and multi-disciplinary collaboration. However, several barriers to using these techniques were identified, including age, knowledge and availability of equipment, personal and contextual factors, staffing and time pressures. Several strategies were recommended for further investigation and implementation in clinical practice, such as the sharing of personal experiences, orthopaedic assessments and changes to workplaces that foster a culture of safety., Conclusions: Further research is required to reduce musculoskeletal pain and injury among nurses. This research should account for the barriers to current prevention strategies and consider investigating novel interventions., Relevance to Clinical Practice: These findings highlight strategies for preventing musculoskeletal injuries among nurses that are likely to be most effective in clinical practice., Competing Interests: No conflict of interest has been declared by the authors.

Background: Musculoskeletal injuries and musculoskeletal pain are prevalent among nurses compared to many other occupational groups., Objective: To identify interventions that may be effective at reducing the prevalence and impact of musculoskeletal injuries and pain in registered nurses., Design: Systematic review., Data Sources: Seven databases were systematically searched, including MEDLINE, CINAHL, EMBASE, PsycInfo, Academic Search Complete, Health Source Nursing, and the Cochrane Database of Systematic Reviews., Review Methods: Peer-reviewed journal articles reporting interventions designed to reduce the occurrence of musculoskeletal injuries and pain among registered nurses, published between January 2004 and June 2016, were eligible for inclusion. Randomised and non-randomised controlled trials, as well as studies implementing before-after designs were included. Studies investigating interventions in samples predominately comprised of nursing aides or non-nursing personnel were excluded. Relevant articles were collected and critically analysed using the Effective Public Health Practice Project methodology. Two reviewers independently extracted data and performed quality appraisals for each study. A narrative synthesis of study findings was performed., Results: Twenty studies met criteria for inclusion in the review. Types of interventions reported included: patient lift systems (N = 8), patient handling training (N = 3), multi-component interventions (N = 7), cognitive behavioural therapy (N = 1), and unstable shoes (N = 1). Only two studies received a 'strong' quality rating according to quality assessment criteria. One of these found no evidence for the effectiveness of patient handling training; the other found preliminary support for unstable shoes reducing self-reported pain and disability among nurses. Overall, evidence for each intervention type was limited., Conclusions: There is an absence of high quality published studies investigating interventions to protect nurses from musculoskeletal injuries and pain. Further research (including randomised controlled trials) is needed to identify interventions that may reduce the high rates of injury and pain among nurses., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Research is yet to investigate whether psychological interventions delivered early after diagnosis can benefit patients with head and neck cancer (HNC)., Purpose: The aim of this study was to investigate the effectiveness of a brief self-regulatory intervention (targeting illness perceptions and coping) at improving HNC patient health-related quality of life (HRQL)., Methods: A pilot randomized controlled trial was conducted, in which 64 patients were assigned to receive three sessions with a health psychologist in addition to standard care or standard care alone. Participants completed questionnaires assessing HRQL, general distress, and illness perceptions at baseline and again 3 and 6 months later., Results: Compared to the control group, patients who received the intervention had increased treatment control perceptions at 3 months (p = .01), and increased social quality of life at 6 months (p = .01). The intervention was particularly helpful for patients exhibiting distress at baseline., Conclusion: A brief psychological intervention following HNC diagnosis can improve patient perceptions of treatment and social quality of life over time. Such interventions could be targeted to patients who are distressed in order to confer the greatest benefit., Trial Registration Number: 12614000813684.

The effects of noncontingent reinforcement (NCR) without extinction during treatment of problem behavior maintained by social positive reinforcement were evaluated for five individuals diagnosed with autism spectrum disorder. A continuous NCR schedule was gradually thinned to a fixed-time 5-min schedule. If problem behavior increased during NCR schedule thinning, a continuous NCR schedule was reinstated and NCR schedule thinning was repeated with differential reinforcement of alternative behavior (DRA) included. Results showed an immediate decrease in all participants' problem behavior during continuous NCR, and problem behavior maintained at low levels during NCR schedule thinning for three participants. Problem behavior increased and maintained at higher rates during NCR schedule thinning for two other participants; however, the addition of DRA to the intervention resulted in decreased problem behavior and increased mands., (© 2017 Society for the Experimental Analysis of Behavior.)

Background: The liner is an integral part of a transtibial prosthesis designed to protect the residual limb, enhance comfort and provide suspension. Literature is difficult to interpret and use given the variety of interventions, outcome measures and method designs. Critical appraisal and synthesis of the evidence is needed to help inform decisions about liner prescription based on the user experience., Objectives: To critically appraise and synthesise research describing the user experience of transtibial prosthetic liners., Study Design: Systematic review., Methods: A comprehensive suite of databases were searched using terms related to amputation level, liner type and user experience. Included studies were in English and measured the first-person experience of using a transtibial liner. Studies were appraised using the McMaster University Critical Review Forms., Results: A total of 18 articles met the inclusion criteria. While the quality of the evidence has improved over time, a number of common issues (e.g. sampling bias, validity of outcome measures, incorrect inferential analysis) reduce our ability to differentiate between the user experience of different transtibial liners., Conclusion: There is insufficient research to differentiate between the user experience of different transtibial liners. High-quality research is needed to inform decisions about liner prescription based on the user experience. Clinical relevance The available evidence suggests that the user experience of commonly reported problems (e.g. sweating) may be very similar between different liners. Aspects of the user experience that differ most between liners (e.g. unwanted noises, rotation within the socket) can help focus attention on what matters most when discussing prescription.

Sight-word instruction can be a useful supplement to phonics-based methods under some circumstances. Nonetheless, few studies have evaluated the conditions under which pictures may be used successfully to teach sight-word reading. In this study, we extended prior research by examining two potential strategies for reducing the effects of overshadowing when using picture prompts. Five children with developmental disabilities and two typically developing children participated. In the first experiment, the therapist embedded sight words within pictures but gradually faded in the pictures as needed using a least-to-most prompting hierarchy. In the second experiment, the therapist embedded text-to-picture matching within the sight-word reading sessions. Results suggested that these strategies reduced the interference typically observed with picture prompts and enhanced performance during teaching sessions for the majority of participants. Text-to-picture matching also accelerated mastery of the sight words relative to a condition under which the therapist presented text without pictures., (© 2016 Society for the Experimental Analysis of Behavior.)

In both observational studies and randomized trials with noncompliance, unmeasured confounding may exist which may bias treatment effect estimates. Instrumental variables (IV) are a popular technique for addressing such confounding, enabling consistent estimation of causal effects. This paper proposes nonparametric IV estimators for censored time to event data that may be subject to competing risks. A simple, plug-in estimator is introduced using nonparametric estimators of the cumulative incidence function, with confidence intervals derived using asymptotic theory. To provide an overall test of the treatment effect, an integrated weighted difference statistic is suggested, which is applicable to data with and without competing risks. Simulation studies demonstrate that the methods perform well with realistic samples sizes. The methods are applied to assess the effect of infant or maternal antiretroviral therapy on transmission of HIV from mother to child via breastfeeding using data from a large, recently completed randomized trial in Malawi where noncompliance with assigned treatment may confound treatment effect estimates., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: There is evidence to suggest that caregivers of patients with head and neck cancer (HNC) are susceptible to post-traumatic stress disorder (PTSD) symptoms. The aim of this study was to investigate whether illness perceptions and coping strategies contribute to the development of these symptoms., Methods: Seventy-eight caregivers completed questionnaires to assess distress, illness perceptions, and coping at diagnosis. Six months later, PTSD symptoms were assessed. Correlation and regression analyses were performed to examine relationships between illness perceptions and coping at diagnosis and PTSD symptoms at 6 months in 48 caregivers., Results: Nineteen percent of caregivers met criteria for estimated PTSD caseness at 6-month follow-up. A regression analysis demonstrated that caregiver perceptions of low treatment benefit and many cancer symptoms, as well as use of avoidant coping techniques, predicted subsequent PTSD., Conclusions: This preliminary study suggests that caregivers who have perceptions of low benefits from treatment and many patient symptoms, and those using avoidant coping strategies, are at increased risk of experiencing symptoms of PTSD. Psychological interventions that target illness perceptions and coping may help to reduce the prevalence of PTSD in caregivers of patients with HNC.

Objective: This study investigated changes in illness perceptions from diagnosis to six months later in patients with head and neck cancer (HNC) and their caregivers. The study also examined whether discrepancy in patient and caregiver perceptions at diagnosis predicted patient health-related quality of life (HRQL) at six months., Design: Forty-two patient-caregiver dyads completed the Brief Illness Perception Questionnaire (Brief IPQ) at diagnosis and again six months later. Patients also completed a HRQL questionnaire at both time points. Analyses were performed using the Actor-Partner Interdependence Model., Main Outcome Measure: Total patient HRQL assessed by the Functional Assessment of Cancer Therapy (FACT-H&N)., Results: Perceptions of emotional impact and illness concern reduced over time in patients and caregivers. Perceptions of treatment control and identity increased in caregivers only. After controlling for the effects of baseline HRQL, and the individual contribution of patient and caregiver illness perceptions, greater discrepancy in perceptions of timeline, personal control, and illness identity among dyads at diagnosis predicted lower patient HRQL at six-month follow-up., Conclusion: Patients' and their caregivers' perceptions of HNC are dynamic over time. Greater discrepancy between patients' and caregivers' illness perceptions at diagnosis predict poorer subsequent patient HRQL.

Evidence suggests that patients with head and neck cancer (HNC) are susceptible to post-traumatic stress disorder (PTSD). However, research is yet to examine predictors of PTSD symptoms in this patient group. The objective of this study was to investigate whether coping strategies at HNC diagnosis were related to outcomes of post-traumatic stress and health-related quality of life (HRQL) 6 months later. Sixty-five patients with HNC completed an assessment of coping, distress, and health-related quality of life at diagnosis and again 6 months later, and an assessment of post-traumatic stress at 6 months. Correlations and regression analyses were performed to examine relationships between coping and outcomes over time. Regression analyses showed that denial, behavioural disengagement and self-blame at diagnosis predicted post-traumatic stress symptoms. Self-blame at diagnosis also predicted poor HRQL. Results have implications for the development of psychological interventions that provide alternative coping strategies to potentially reduce PTSD symptoms and improve HRQL.

Introduction: Approximately 1 in 5 hospitalized COPD patients are readmitted within 30 days of discharge. CHF coexists in more than 20% of patients with COPD, and is associated with early readmission for COPD. Reducing 30-day hospital readmissions for COPD is of intense current interest., Methodology: A retrospective chart review was performed to identify patients discharged with COPD exacerbation and HFrEF. The primary objective was to evaluate if discharge medication prescribing following guidelines for both COPD and HFrEF correlates with reduced 30-day readmission rates., Results: The study included 281 admissions with 39.1% prescribed appropriate discharge medications for both COPD and HFrEF; 30-day readmission rate was 24.5% for these patients compared to 31.1% that were not prescribed appropriate medications (p = 0.24). Beta blockers, ACE inhibitors or ARBS, and aldosterone antagonists were under-prescribed, but this did not significantly associate with increased readmission (p = 0.51, p = 0.23 or 0.99, and p = 0.18, respectively). Those prescribed hydralazine or nitrates were more likely to readmit (both p = 0.01). Diabetes and hyperlipidemia were associated with increased readmission (p = 0.01 and 0.05)., Conclusions: This study did not show a significant difference in 30-day readmission rate based on appropriate discharge medications for both COPD and HFrEF. The comorbidities diabetes and hyperlipidemia and prescription of hydralazine or nitrates were significantly associated with increased readmission rate. Larger patient populations may be needed to assess if guideline based discharge medication prescribing is associated with reduced 30-day readmissions for COPD., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The recently completed HIV prevention trials network study 052 is a landmark collaboration demonstrating that HIV transmission in discordant couples can be dramatically reduced by treating the infected individual with antiretroviral therapy (ART). However, the cellular and virological events that occur in the female reproductive tract (FRT) during ART that result in such a drastic decrease in transmission were not studied and remain unknown. Here, we implemented an in vivo model of ART in BM/liver/thymus (BLT) humanized mice in order to better understand the ability of ART to prevent secondary HIV transmission. We demonstrated that the entire FRT of BLT mice is reconstituted with human CD4+ cells that are shed into cervicovaginal secretions (CVS). A high percentage of the CD4+ T cells in the FRT and CVS expressed CCR5 and therefore are potential HIV target cells. Infection with HIV increased the numbers of CD4+ and CD8+ T cells in CVS of BLT mice. Furthermore, HIV was present in CVS during infection. Finally, we evaluated the effect of ART on HIV levels in the FRT and CVS and demonstrated that ART can efficiently suppress cell-free HIV-RNA in CVS, despite residual levels of HIV-RNA+ cells in both the FRT and CVS.

This study investigated the contribution of patient and caregiver illness perceptions to the quality of life of head and neck cancer (HNC) patients. Ninety-eight patients and their caregivers (n = 80) completed questionnaires at diagnosis. Caregivers' illness perceptions were significantly more negative than patients with respect to consequences, timeline, treatment, concern, and the emotional impact of HNC. The interaction between some patient and caregiver illness perceptions explained additional variance in patient quality of life, above and beyond patients' own illness perceptions. These findings suggest that caregivers should be included in psychological interventions to improve HNC patient quality of life.

The effect of directly observed therapy (DOT) versus self-administered therapy (SAT) on antiretroviral (ART) adherence and virological outcomes in prison has never been assessed in a randomized, controlled trial. Prisoners were randomized to receive ART by DOT or SAT. The primary outcome was medication adherence [percent of ART doses measured by the medication event monitoring system (MEMS) and pill counts] at the end of 24 weeks. The changes in the plasma viral loads from baseline and proportion of participants virological suppressed (<400 copies/mL) at the end of 24 weeks were assessed. Sixty-six percent (90/136) of eligible prisoners declined participation. Participants in the DOT arm (n = 20) had higher viral loads than participants in the SAT (n = 23) arm (p = 0.23). Participants, with complete data at 24 weeks, were analyzed as randomized. There were no significant differences in median ART adherence between the DOT (n = 16, 99% MEMS [IQR 93.9, 100], 97.1 % pill count [IQR 95.1, 99.3]) and SAT (n = 21, 98.3 % MEMS [IQR 96.0, 100], 98.5 % pill count [95.8, 100]) arms (p = 0.82 MEMS, p = 0.40 Pill Count) at 24 weeks. Participants in the DOT arm had a greater reduction in viral load of approximately -1 log 10 copies/mL [IQR -1.75, -0.05] compared to -0.05 [IQR -0.45, 0.51] in the SAT arm (p value = 0.02) at 24 weeks. The proportion of participants achieving virological suppression in the DOT vs SAT arms was not statistically different at 24 weeks (53 % vs 32 %, p = 0.21). These findings suggest that DOT ART programs in prison settings may not offer any additional benefit on adherence than SAT programs.

Objective: The aim of this study was to explore the psychological support needs of patients with head and neck cancer (HNC) and their caregivers. The appropriate timing, length, format and content of sessions were also investigated., Design: Eighty-three patients with HNC and 73 of their caregivers completed questionnaires at diagnosis. Follow-up questionnaires were mailed to patients six months later., Main Outcome Measures: Free text-comments to open-ended questions in the questionnaires were analysed using an inductive thematic approach with coding and theme development directed by the content of responses. This was used to determine psychological support needs both at diagnosis and at six month follow-up., Results: Patients described 'just being there', empathy, maintaining normality and practical support as helpful from family/friends. They desired information, honesty, positivity and empathy from clinical staff. Formal psychological support was desired by approximately 40% of patients and caregivers, particularly early after diagnosis and during treatment. Most participants desired face to face sessions, providing individualised information and coping strategies., Conclusion: The results of this study suggest that psychological interventions for patients with HNC and their caregivers should be delivered early after diagnosis in face to face sessions, presenting honest and factual information about the disease and coping strategies.

Numerous factors affect the response to vitamin K antagonists (VKA) including age, dietary vitamin K, other drugs, pharmacogenetics, and disease states. In antithrombotic guidelines, fever is mentioned as a factor that may increase response to VKA. The purpose of this article is to review the available evidence regarding the effect of fever on response to VKA, and to discuss possible mechanisms of this effect. We performed a search of the English literature from 1943 to June 2014, using the key words fever AND warfarin, acenocoumarol, phenprocoumon, coumarin anticoagulants and VKA; fever AND vitamin K dependent clotting factors II, VII, IX, and X. One animal investigation and 6 studies in humans suggest fever increases response to VKA, but one study did not find a significant effect. The magnitude of this effect is variable. Possible mechanisms for the increased effect of VKA associated with fever are increased catabolism of vitamin K dependent clotting factors, decreased vitamin K intake, and inhibition of VKA metabolism. More rigorous studies are needed to confirm that fever increases response to warfarin and other VKA., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

This paper considers conducting inference about the effect of a treatment (or exposure) on an outcome of interest. In the ideal setting where treatment is assigned randomly, under certain assumptions the treatment effect is identifiable from the observable data and inference is straightforward. However, in other settings such as observational studies or randomized trials with noncompliance, the treatment effect is no longer identifiable without relying on untestable assumptions. Nonetheless, the observable data often do provide some information about the effect of treatment, that is, the parameter of interest is partially identifiable. Two approaches are often employed in this setting: (i) bounds are derived for the treatment effect under minimal assumptions, or (ii) additional untestable assumptions are invoked that render the treatment effect identifiable and then sensitivity analysis is conducted to assess how inference about the treatment effect changes as the untestable assumptions are varied. Approaches (i) and (ii) are considered in various settings, including assessing principal strata effects, direct and indirect effects and effects of time-varying exposures. Methods for drawing formal inference about partially identified parameters are also discussed.

Background: Recent research suggests that pregnancy is a potentially safe option for couples with at least one HIV-infected adult. Data regarding provider discussion of fertility intentions with women living with HIV (WLWH) or in serodiscordant relationships is limited., Methods: We conducted a cross-sectional self-administered survey of health professionals who provide HIV services to women in order to assess knowledge and behaviors regarding family planning options for HIV-infected women and serodiscordant couples., Results: Of 77 respondents, 47(61%) met the inclusion criteria (health care provider who cares for WLWH). Approximately half (57%) of the participants indicated that they always or usually discuss contraception or fertility intentions with their HIV+ female patients of reproductive age. When asked to indicate their awareness of techniques to decrease HIV transmission risk among serodiscordant couples attempting pregnancy, most participants reported awareness of multiple options. Discussion of contraception or fertility intentions was not associated with provider gender, age, and experience in caring for HIV-infected patients, previous training in women's health or provider's awareness of options to decrease transmission risk., Conclusions: HIV providers in this study were knowledgeable of practices that can lead to safer conception and prevent HIV transmission among individuals in serodiscordant relationships but did not always discuss this information with their patients. Further research is needed to explore optimal methods for encouraging such conversations.

Human immunodeficiency virus (HIV) is characterized by immune activation, while chronic malaria is associated with elevated interleukin-10 (IL-10) levels. How these apparently antagonizing forces interact in the coinfected host is poorly understood. Using a rhesus macaque model of simian immunodeficiency virus (SIV)-Plasmodium fragile coinfection, we evaluated how innate immune effector cells affect the balance between immune activation and regulation. In vitro Toll-like receptor (TLR) responses of peripheral blood myeloid dendritic cells (mDC) and monocytes were temporarily associated with acute parasitemic episodes and elevated plasma IL-10 levels. Prolonged infection resulted in a decline of mDC function. Monocytes maintained TLR responsiveness but, in addition to IL-12 and tumor necrosis factor alpha, also produced IL-10. Consistent with the role of spleen in the clearance of parasite-infected red blood cells, coinfected animals also had increased splenic IL-10 mRNA levels. The main cellular source of IL-10 in the spleens of coinfected animals, however, was not splenic macrophages but T cells, suggesting an impairment of adaptive immunity. In contrast to those in spleen, IL-10-positive cells in axillary lymph nodes of coinfected animals were predominantly mDC, reminiscent of the immunosuppressive phenotype of peripheral blood mDC. Concurrent with IL-10 induction, however, SIV infection promoted elevated systemic IL-12 levels. The continuously increasing ratio of plasma IL-12 to IL-10 suggested that the overall host response in SIV-P. fragile-coinfected animals was shifted toward immune activation versus immune regulation. Therefore, SIV-P. fragile coinfection might be characterized by earlier manifestation of immune dysfunction and exhaustion than that of single-pathogen infections. This could translate into increased morbidity in HIV-malaria-coinfected individuals.

Racial differences in antiretroviral treatment responses remain incompletely explained and may be a consequence of differential pharmacokinetics (PK) associated with race. Raltegravir, an inhibitor of HIV-1 integrase, is commonly used in the treatment of HIV-infected patients, many of whom are African-American. However, there are few data regarding the PK of raltegravir in African-Americans. HIV-infected men and women, self-described as African-American and naive to antiretroviral therapy were treated with raltegravir (RAL) at 400 mg twice a day, plus a fixed dose of tenofovir-emtricitabine (TDF/FTC) at 300 mg/200 mg once daily. Intensive PK sampling was conducted over 24 h at week 4. Drug concentrations at two trough values of 12 and 24 h after dosing (C(12) and C(24)), area under the concentration-curve values (AUC), maximum drug concentration (C(max)), and the time at which this concentration occurred (T(max)) in plasma were estimated with noncompartmental pharmacokinetic methods and compared to data from a subset of white subjects randomized to the RAL twice a day (plus TDF/FTC) arm of the QDMRK study, a phase III study of the safety and efficacy of once daily versus twice daily RAL in treatment naive patients. A total of 38 African-American participants were enrolled (90% male) into the REAL cohort with the following median baseline characteristics: age of 36 years, body mass index (BMI) of 23 kg/m(2), and a CD4 cell count of 339/ml. Plasma HIV RNA levels were below 200 copies/ml in 95% of participants at week 4. The characteristics of the 16 white QDMRK study participants were similar, although fewer (69%) were male, the median age was higher (45 years), and BMI was lower (19 kg/m(2)). There was considerable interindividual variability in RAL concentrations in both cohorts. Median C(12) in REAL was 91 ng/ml (range, 10 to 1,386) and in QDMRK participants was 128 ng/ml (range, 15 to 1,074). The C(max) median concentration was 1,042 ng/ml (range, 196 to 10,092) for REAL and 1,360 ng/ml (range, 218 to 9,701) for QDMRK. There were no significant differences in any RAL PK parameter between these cohorts of African-American and white individuals. Based on plasma PK, and with similar adherence rates, the performance of RAL among HIV-infected African-Americans should be no different than that of infected patients who are white.

Purpose: Since 2001, many military families have experienced multiple and extended deployments. Little is known about the effect of parental deployment on the well-being of children, and few, if any, studies to date have engaged school staff to understand whether and how parental deployments affect the behavioral, social, and emotional outcomes of youth in the school setting., Methods: Focus groups and semi-structured interviews were conducted with teachers, counselors, and administrative staff at schools serving children from U.S. Army families (N=148 staff). Participants were queried about the academic, behavioral, and emotional issues faced by children of deployed soldiers. Data were analyzed for themes in these areas, with attention to differences by service component (Active Component vs. Army Reserve and National Guard)., Results: Although some children seem to be coping well with deployment, school staff felt that children's anxiety related to parental absence, increased responsibilities at home, poor mental health of some nondeployed parents, and difficulty accessing mental health services affected the ability of other students to function well in school., Conclusions: School staff felt that parental deployment negatively affected social and emotional functioning for some children and youth, although they felt others were coping well. Future research should examine factors related to youth outcomes during parental deployment (e.g., mental health of the non-deployed parent) and assess the effects of deployment on other measures of behavior such as school engagement and academic performance.