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Attention to gender-related issues in immunization programmes goes beyond focusing on coverage discrepancies between girls and boys. There are multiple ways in which gender roles, norms and relations influence resource allocation, decision making, access, and health outcomes, including for immunization programmes. Gender impacts immunization both on the demand side through people's health seeking behaviours, and the supply side through provision of health services. To increase immunization coverage, and in particular to reach zero-dose children, it is necessary to understand and address the many ways in which gender interacts with additional socio-economic, geographic and cultural factors -- such as age, race/ethnicity, religion, marital status, education, wealth, sexual orientation and gender identity, HIV status, disability and migration status -- to influence access to and delivery of vaccines. The Immunization Agenda 2030 (IA2030) commits to addressing gender-related barriers to immunization and advancing gender equality and gender is an important cross-cutting consideration for all seven IA2030 strategic priorities. Gender-responsive strategies are particularly highlighted as an IA2030 key area of focus for Strategic Priority 3: Coverage & Equity. Gender-related barriers and gender inequality can prevent people, both male and female and those of diverse gender identities, from getting vaccinated. These operate at multiple levels from the individual and family/household to community and within institutions/systems and national policies/frameworks and are underpinned by power relations leading to different opportunities, limitations, challenges, needs and vulnerabilities, especially for women and girls. By applying knowledge about gender and taking action to design gender-responsive interventions, it is possible to implement more effective immunization programmes and increase coverage for all., 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 © 2024 World Health Organization. Published by Elsevier Ltd.. All rights reserved.)

Context: Medical interns (interns) find prescribing challenging and many report lacking readiness when commencing work. Errors in prescribing puts patients' safety at risk. Yet error rates remain high, despite education, supervision and pharmacists' contributions. Feedback on prescribing may improve performance. Yet, work-based prescribing feedback practices focus on rectifying errors. We aimed to explore if prescribing can be improved using a theory-informed feedback intervention., Methods: In this pre-post study, we designed and implemented a constructivist-theory informed prescribing feedback intervention, informed by Feedback-Mark 2 Theory. Interns commencing internal medicine terms in two Australian teaching hospitals were invited to engage in the feedback intervention. Their prescribing was evaluated by comparing errors per medication order of at least 30 orders per intern. Pre/baseline (weeks 1-3) were compared with post intervention (weeks 8-9). Interns' baseline prescribing audit findings were analysed and discussed at individualised feedback sessions. These sessions were with a clinical pharmacologist (Site 1) and a pharmacist educator (Site 2)., Results: Eighty eight intern's prescribing over five 10-week terms was analysed from two hospitals. The frequency of prescribing errors significantly reduced at both sites after the intervention, across all five terms (p < 0.001).There were initially 1598 errors in 2750 orders (median [IQR] 0.48 [0.35-0.67] errors per order) and after the intervention 1113 errors in 2694 orders (median [IQR] 0.30 [0.17-0.50] errors per order)., Conclusion: Our findings suggest interns' prescribing practices may improve as a result of constructivist -theory learner centred, informed feedback with an agreed plan. This novel intervention, contributed, to a reduction in interns' prescribing errors. This study suggests new strategies for improving prescribing safety should include the design and implementation of theory-informed feedback interventions., (© 2023. Crown.)

Purpose: To review the current literature on the use of intravitreal methotrexate (IVT MTX) for the treatment and prevention of proliferative vitreoretinopathy (PVR)., Methods: All reports of IVT MTX to treat and prevent PVR published in PubMed, Google Scholar, and EBSCOhost were reviewed. The relevant current studies are included in this report., Results: The literature search yielded 32 articles describing the use of MTX in PVR. These included preclinical studies, 1 case report, and several case series. Early studies found that IVT MTX is a promising medication for the treatment and prevention of PVR. MTX works as a potent anti-inflammatory agent through a new mechanism of action different from that of other medications for use in PVR. Few side effects have been reported and were mostly limited to mild reversible corneal keratopathy. There are 2 current ongoing randomized controlled clinical trials to further evaluate the efficacy of MTX for PVR., Conclusions: MTX is a safe and potentially efficacious medication for the treatment and prevention of PVR. Additional clinical trials are needed to further establish this effect., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Studies show that morningness is positively associated with subjective well-being. Our previous research investigated factors that could underlie this relationship, finding that the association between morningness-eveningness and subjective well-being can be partially attributed to the higher levels of perceived social support received by morning-oriented individuals. In the present study, we examine the longitudinal effects of perceived social support in mediating the relationship between morningness-eveningness and subjective well-being. Our results show that this mediating effect remains significant with respect to changes in well-being over a 6-month period. It seems that the causal effect of morningness on well-being may be partially mediated by the causal effect of social support. The findings provide further support for the conclusion that perceived social support is an important contributing factor to the greater well-being reported by morning-oriented individuals. Additionally, our results provide seminal evidence for the causal effect of morningness on well-being., (© 2022 European Sleep Research Society.)

Objectives: Societal restrictions imposed to prevent transmission of COVID-19 may challenge circadian-driven lifestyle behaviours, particularly amongst those vulnerable to mood disorders. The overarching aim of the present study was to investigate the hypothesis that, in the routine-disrupted environment of the COVID-19, amongst a sample of people living with mood disorders, greater social rhythm disruption would be associated with more severe mood symptoms., Methods: We conducted a two-wave, multinational survey of 997 participants ( M A g e = 39.75 ± 13.39 , F e m a l e = 81.6 % ) who self-reported a mood disorder diagnosis (i.e., major depressive disorder or bipolar disorder). Respondents completed questionnaires assessing demographics, social rhythmicity (The Brief Social Rhythm Scale), depression symptoms (Patient Health Questionnaire-9), sleep quality and diurnal preference (The Sleep, Circadian Rhythms and Mood questionnaire) and stressful life events during the COVID-19 pandemic (The Social Readjustment Rating Scale)., Results: The majority of participants indicated COVID-19-related social disruption had affected the regularity of their daily routines to at least some extent ( n  = 788, 79.1%). As hypothesised, lower social rhythmicity was associated with greater depressive symptoms when tested cross-sectionally (standardised β  = -.25, t  = -7.94, P  = 0.000) and when tested using a 2-level hierarchical linear model across two time points ( b  = -0.14, t  = -3.46, df  = 264, P  ≤ 0.001)., Conclusions: These results are consistent with the social zeitgeber hypothesis proposing that mood disorders are sensitive to life events that disrupt social rhythms.

Objectives: The diversity in the governance of the American Society of Transplant Surgeons has not been described. We aimed to quantify the present state of its leadership as a baseline to inform future research., Materials and Methods: Lists of leaders on the American Society of Transplant Surgeons Council, the COVID-19 Strike Force, and 20 different American Society of Transplant Surgeons committees were obtained from the Society's website. Demographic and training information for the members were compiled through internet searches and analyzed., Results: The American Society of Transplant Surgeons Council included 15 members, with 20% women. It was 93.3% non-Hispanic White. The COVID-19 Strike Force included 12 surgeons, 16.7% of whom were female, with 75% non-Hispanic White. Of the 198 committee members, 23.7% were women, 68.7% were nonHispanic White, 16.6% were Asian, 8.1% were Hispanic, and 6.6% were Black. Among female committee members, underrepresented minorities comprised 23.6%. Committee chairs included 23% women, 23% underrepresented minorities, and 2.3% minority women. International medical graduates were more likely men (P = .02)., Conclusions: Representation of women in the American Society of Transplant Surgeons leadership has kept pace with their membership in the transplant surgery workforce. There is a deficiency of female under - represented minorities in leadership positions at the Society. Further interventions are required to recruit underrepresented minorities to transplant surgery, catalog their footprint in the workforce, and champion their role as leaders within the American Society of Transplant Surgeons.

Poor sleep has significant impacts on both mental and physical well-being. This is especially the case for shift workers who rely on good sleep practices to manage the disruption caused by their working conditions. In recent years there has been a proliferation of sleep-focused mobile phone applications, some of which may be suitable for use by shift workers. There is limited evidence however, on whether these applications are sufficient in managing the sleep needs of the early start shift working population (i.e., those whose work schedules begin pre-dawn). This scoping review aims to identify and discuss peer-reviewed literature on mobile sleep applications used by early start shift workers for sleep-self management. Four databases (Scopus, EBSCOhost, CINAHL and PsycInfo) were searched for relevant literature using a pre-determined search string. The initial search using the term early start shift work returned no papers, however a broadened search on shift work in general found 945 papers for title and abstract screening, of which 21 were deemed eligible for full text screening. Two of these papers met the inclusion criteria for this review. The results highlight, firstly, the paucity of research on the use of mobile phone applications for sleep self-management amongst early start shift workers, and secondly, the need for further research on the effectiveness of mobile applications for sleep self-management amongst shift workers in general. A working definition of early start shift work that can be used to stimulate research in this understudied population of shift workers is also proposed., 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 Bullock, Learmonth, Davis and Al Mahmud.)

Ovarian cancer is the most deadly gynecological cancer, so proper assessment of a pelvic mass is necessary in order to determine which are at high risk for malignancy and should be referred to a gynecologic oncologist. However, in a family medicine setting, evaluation and treatment of these masses can be challenging due to a lack of resources. A number of risk assessment tools are available to family medicine physicians, including imaging techniques, imaging systems, and blood-based biomarker assays each with their respective pros and cons, and varying ability to detect malignancy in pelvic masses. Effective utilization of these assessment tools can inform the care pathway for patients which present with an adnexal mass, such as expectant management for those with a low risk of malignancy, or referral to a gynecologic oncologist for surgery and staging, for those at high risk of malignancy. Triaging patients to the appropriate care pathway improves patient outcomes and satisfaction, and family medicine physicians can play a key role in this decision-making process., Competing Interests: KS has been a consultant for Aspira Women’s Health, Inc., and is currently employed by Einstein Healthcare Network. The remaining 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 Bullock, Larkin, Turker and Stampler.)

Introduction: The diversity among surgical directors for liver, kidney, and pancreas transplant departments has not been previously evaluated. We aim to quantify the sex and racial demographics of transplant department leaders and assess the impact on patient outcomes., Methods: Demographics were collected for 116 liver, 192 kidney, and 113 pancreas transplant directors using Organ Procurement and Transplantation Network (OPTN) directory and program websites. Scientific Registry of Transplant Recipients (SRTR) 5-tier program outcomes rankings were obtained for each program and matched to leader demographics. A retrospective analysis of transplant recipients from 2010 to 2019 was performed using the United Network for Organ Sharing (UNOS) database., Results: 91.5% of transplant surgical directors were male. 55% of departments had a Non-Hispanic White leader. Asian, Hispanic and Black transplant chiefs were at the helm of 23.3%, 9%, and 5% of divisions respectively. Multivariate cox regression analysis did not identify any differences in patient outcomes by transplant director demographics., Conclusion: There is a paucity of female and URM leaders in transplant surgery. Initiatives to promote research, mentorship, and career advancement opportunities for women and URM are necessary to address the current leadership disparity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Studies show that morningness preference and subjective well-being are positively related. However, little is known about potential factors that may underpin this association. In the present study, we explored the mediational role of general social support and its facets (family, friends, and significant other) in the relationship between morningness-eveningness and subjective well-being. The present study was conducted with a sample of 1,067 adults (51% women), with a mean (SD, range) age of 36.41 (9.95, 18-55) years. Our results corroborated earlier findings that morningness was positively associated with both subjective well-being and social support. Controlling for age and gender, we obtained significant mediation effects, showing that the association between morningness-eveningness and subjective well-being might stem, at least in part, from the higher levels of social support received by morning-oriented individuals. This may lead to the conclusion that social support is an important antecedent of the greater well-being reported by morning-oriented individuals., (© 2021 European Sleep Research Society.)

Background: Europe and North America are in the grips of a devastating overdose crisis. People who use substances often feel unsafe to access healthcare due to fears of stigma, blame, judgement, poor treatment, or other repercussions. As a result, they often avoid, delay, or leave care, resulting in premature death and missed opportunities for care. Internationally, there have been concerted efforts to move towards patient-engaged research to enhance the quality of health care systems and services. In Canada, the Canadian Institutes of Health Research (CIHR) Strategy for Patient-Oriented Research (SPOR) initiative promotes engagement of patients as active partners in health care research. As part of a community based patient oriented research project, we critically analyze the SPOR framework to provide insights into what constitutes safer research with people who use(d) substances., Methods: We undertook a two-stage process that began with a review of community based research principles and the SPOR framework. At the second stage, we undertook a qualitative descriptive study employing focus groups to generate description of the adequacy and appropriateness of the SPOR framework for guiding research with people who use(d) substances on four key dimensions (patient engagement, guiding principles, core areas of engagement and benefits). The data were analyzed using qualitative content analysis to identify key issues and insights., Results: While the SPOR framework includes a range of patient roles, principles and areas for engagement, there are issues and gaps related to essential elements of safe patient-oriented research for people who use substances. These include an individualized focus on patients as partners, lack of recognition of community benefits, power imbalances and distrust due to systemic stigma, engagement as one way capacity building and learning, and lack of accountability for taking action on research findings., Conclusions: Given the extent of stigma in health care and the ongoing illicit drug policy crisis, strategies for enhancing equitable Patient-Oriented Research (POR) include shifting language from patient partners to community researchers, recognizing power inequities and adding trust and equity as core POR principles including pay equity. Employing community based participatory research as a POR methodology allows the lead researchers to fully engage community throughout the research process, enhances community benefits and accountability for action., (© 2022. The Author(s).)

Background: The diversity among general surgery residency, HPB and other fellowship program directors has been previously analyzed. However, the diversity in abdominal transplant surgery fellowship program directors remains unknown., Methods: Abdominal transplant fellowship programs and the corresponding program directors were identified from the American Society of Transplant Surgeons website. Demographic and training information for the members was compiled through internet searches and analyzed., Results: 72 program directors were included. 83.33% were male. 63.9% were non-Hispanic White, 25% were Asian, along with 5.56% Hispanic and Black each. Male program directors were more likely to be Associate Professor (p = 0.041), while females were more likely to be Assistant Professor (p = 0.021). 66% of female program directors were non-Hispanic White., Conclusion: Transplant surgery fellowship programs are primarily led by male and non-Hispanic White surgeons. Female representation as leaders is on par with their membership in the transplant surgery workforce. There is a deficiency of both male and female underrepresented minorities in program director positions., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Social distancing/lockdown policies during the coronavirus (COVID-19) pandemic may alter social rhythms of people through imposition of restrictions on normal daily activities. This may in turn challenge circadian function, particularly in people with mood disorders. Although objective data describing the relationship between circadian disturbances and mood disorders exist, data regarding the subjective experience of circadian challenge is sparse, and its association with mood symptoms is unclear. The present qualitative study was one component of a mixed-methods multi-national project, which took advantage of widespread disruption to daily routines due to Government COVID-related lockdowns during 2020. The Behavior Emotion and Timing during COVID-19 (BEATCOVID) survey study included three open questions generating qualitative data on participants' subjective experience of social disruption due to social distancing/lockdown policies, two of which asked about the barriers and opportunities for stabilizing routines. Responses were coded and analyzed using Thematic Analysis. A total of N = 997 participants responded to at least one of the free-text questions. Four themes were identified: 1) loss of daily timed activities, 2) role of social interaction, 3) altered time perception and 4) disruption to motivation and associated psychological effects. Themes were organized into a provisional heuristic map, generating hypotheses for future research centered on the new concept of 'psychological drift.'

The role of CD4+ T cells in HIV infection and the latent reservoir, that is, latently infected cells that harbor replication competent virus, has been rigorously assessed. We have previously reported a quantitative viral outgrowth assay (QVOA) for SIV that demonstrated the frequency of latently infected CD4+ T cells is approximately 1 in a million cells, similar to that of HIV infected individuals on ART. However, the frequency of productively infected monocytes in blood and macrophages in tissues has not been similarly studied. Myeloid cells are infected during acute HIV and SIV infection; however, unlike lymphocytes, they are resistant to the cytopathic effects of the virus. Moreover, tissue-resident macrophages have the ability to self-renew and persist in the body for months to years. Thus, tissue macrophages, once infected, have the characteristics of a stable viral reservoir. A better understanding of the number of productively infected macrophages is critical to understanding the role of infected myeloid cells as a viral reservoir. In order to assess the functional latent reservoir. we have developed specific QVOAs for monocytes in blood, and macrophages in spleen, BAL and brain, which are described in detail in this chapter., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: The effects of impaired sleep on the wellbeing of young adults are profound, and the adverse outcomes for mental health are well documented in the research literature., Objective: This systematic review and meta-analysis aimed to identify, summarize, and synthesize the available evidence from randomized-controlled trials (RCTs) investigating psychological interventions aimed at improving sleep and related secondary outcomes such as anxiety and depression in healthy young adults., Method: Nine electronic databases (Cochrane Central Registry of Controlled Trials [CENTRAL], PubMed, Scopus, PsycNET, CINHAL, INFORMIT, Web of Science [Science and Social Citation Index], OpenSigle and EMBASE) were searched, returning 54 full-text papers for assessment, with 13 studies meeting inclusion criteria for the meta-analysis., Results: A random effects meta-analysis showed that the combined effect of all interventions was moderate (ES = -0.53, 95% CIs [- 0.69, -0.36], p < .01), reflecting the efficacy of psychological interventions at improving sleep scores at post-intervention. Subgroup analyses of individual interventions showed that cognitive-behavioral interventions improved sleep (ES = -0.67, 95% CIs [-0.77, -0.57], p < .01) and secondary outcomes for anxiety (ES = -0.35, 95% CIs [-0.56, -0.15], p < .01) and depression (ES = -0.41, 95% CIs [-0.70, -0.13], p < .01) at post-intervention., Conclusion: The results of the current review support the implementation of cognitive and behavioral interventions for sleep among young adults experiencing both sleep and comorbid mental health problems.

Background: Although social distancing is a key public health response during viral pandemics, psychosocial stressors, such as social isolation, have been implicated in adverse health outcomes in general [1] and in the context of infectious disease, such as human immunodeficiency virus (HIV) [2, 3]. A comprehensive understanding of the direct pathophysiologic effects of psychosocial stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection., Methods: To determine the effect of psychosocial stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly (n = 35) and socially (n = 41) housed simian immunodeficiency virus (SIV)-infected pigtailed macaques (Macaca nemestrina)., Results: Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T-cell declines and more CD4 and CD8 T-cell activation compared with socially housed macaques throughout acute SIV infection., Conclusions: These data demonstrate that psychosocial stress directly impacts the pathogenesis of acute SIV infection and imply that it may act as an integral variable in the progression of HIV infection and potentially of other viral infections., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Competing Interests: The authors declare no funding or conflicts of interest.

Introduction: Kidney transplant (KT) directors are general surgeons or urologists. All KT centers must meet established performance standards. However, it has not been established if general surgery and urology led programs have disparate outcomes., Methods: Transplant outcomes and donor-recipient characteristics by director training were investigated. Organ Procurement and Transplantation Network (OPTN) directory, program websites were analyzed for surgical director demographics. Scientific Registry of Transplant Recipients (SRTR) 1-year kidney survival and deceased donor (DD) wait-time rankings were evaluated. A retrospective analysis of 142 157 KT recipients from 2010 to 2019 was performed using the United Network for Organ Sharing (UNOS) database., Results: One hunderd and seventy three (90.6%) KT programs were led by general surgeons. There were no significant differences in gender, ethnicity, region, credentials, or fellowship completion. Recipients undergoing KT with urology led programs were older (P = .002) and had longer wait-times (P < .001). These centers used higher KDPI (.47 vs. .45, P < .001) and higher HLA mismatch (3.92 vs. 3.89, P = .02) kidneys. Urology led centers utilized living donors less frequently (32.1% vs. 35.8%, P < .001) and had longer CIT (15.44 vs. 12.21, P < .001). Both had similar SRTR ranking of 1-year survival and DD wait-time., Conclusion: Most directors were general surgeon. Patient outcomes did not differ by transplant director training. Urologists represent a viable option for KT leadership and recruitment should be encouraged., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Adhesive small bowel obstruction (ASBO) has classically been managed with nasogastric tube decompression and watchful waiting. Our group developed an evidence-based protocol to manage ASBO utilizing a water-soluble contrast (WSC) agent. We hypothesized the protocol would decrease the length of stay (LOS) for patients admitted with ASBO along with the time interval from admission to surgery., Method: From 2010 to 2018, a retrospective review was performed, including all patients admitted with a diagnosis of ASBO. These patients were divided into two groups: the preprotocol group included years 2010-2013 and the postprotocol group included years 2015-2018. A Student t-test and a two-proportion z-test were used for statistical analysis., Result: We captured 767 patients; 296 in the preprotocol group and 471 in the postprotocol group. We found a significant decrease in overall LOS between the preprotocol and postprotocol groups (6.56 d versus 4.08 d; P < 0.001) along with decreases in LOS for patients managed nonoperatively (5.36 d versus 3.42 d; P < 0.001) and operatively (16.09 d versus 9.47 d; P < 0.001). Time interval from admission to the operation was significantly decreased in the postprotocol group (3.79 d versus 2.10 d; P < 0.050). We identified a trend toward decreased rates of bowel ischemia and resections with our protocol., Conclusions: These results reaffirm previous reports of WSC's impact on overall LOS in ASBO while showing a similar impact on both operative and nonoperative groups. The decreased time interval between admission and operation may impact the incidence of bowel ischemia and resections., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Delayed graft function (DGF) is a manifestation of acute kidney injury uniquely framed within the transplant process and a predictor of poor long-term graft function1. It is less common in the setting of living donor (LD) kidney transplantation. However, the detrimental impact of DGF on graft survival is more pronounced in LD2., Purpose: To study the effects of DGF in the setting of LD kidney transplantation., Methods: We performed a retrospective analysis of LD kidney transplantations performed between 2010 and 2018 in the UNOS/OPTN database for DGF and its effect on graft survival., Results: A total of 42,736 LD recipients were identified, of whom 1115 (2.6%) developed DGF. Recipient dialysis status, male gender, diabetes, end-stage renal disease, donor age, right donor nephrectomy, panel reactive antibodies, HLA mismatch, and cold ischemia time were independent predictors of DGF. Three-year graft survival in patients with and without DGF was 89% and 95%, respectively. DGF was the greatest predictor of graft failure at three years (hazard ratio = 1.766, 95% CI: 1.514-2.059, P = 0.001) and was associated with higher rates of rejection (9% vs. 6.28%, P = 0.0003). Among patients with DGF, the graft survival rates with and without rejection were not different., Conclusion: DGF is a major determinant of poor graft functional outcomes, independent of rejection.

Background: Interest in biological clock pathways in bipolar disorders (BD) continues to grow, but there has yet to be an audit of circadian measurement tools for use in BD research and practice., Procedure: The International Society for Bipolar Disorders Chronobiology Task Force conducted a critical integrative review of circadian methods that have real-world applicability. Consensus discussion led to the selection of three domains to review-melatonin assessment, actigraphy, and self-report., Results: Measurement approaches used to quantify circadian function in BD are described in sufficient detail for researchers and clinicians to make pragmatic decisions about their use. A novel integration of the measurement literature is offered in the form of a provisional taxonomy distinguishing between circadian measures (the instruments and methods used to quantify circadian function, such as dim light melatonin onset) and circadian constructs (the biobehavioral processes to be measured, such as circadian phase)., Conclusions: Circadian variables are an important target of measurement in clinical practice and biomarker research. To improve reproducibility and clinical application of circadian constructs, an informed systematic approach to measurement is required. We trust that this review will decrease ambiguity in the literature and support theory-based consideration of measurement options., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Today, biomedical advancements allow older adults, including those with dementia, to live longer, with most living at home with a lay caregiver. Recent research details the stressful role of caregiving to persons with dementia (PWD). The current qualitative phenomenological study describes the lived experience of caregivers caring for PWD, including their experience with palliative care. A community sample of lay caregivers (N = 11) underwent recorded individual interviews. Interviews were analyzed following van Manen's approach to isolate thematic statements. Most caregivers were older (mean age = 71, SD = 9.6; range = 53 to 84 years) and female (n = 10). Study themes included: (a) Uncertainty: The Slippery Slope, (b) The Sense of Loneliness, (c) Complexities of Frustration, and (d) On the Other Side of the Spectrum. Findings show these caregivers are dealing with a dynamic range of feelings about their experiences. Opportunities exist for health care professionals to discuss such feelings and refer caregivers to supportive services, including palliative care. [Journal of Gerontological Nursing, 46(8), 17-27.]., (Copyright 2020, SLACK Incorporated.)

There is a scarcity of published research describing the impact of a pharmacist on the post-take ward round (PTWR) in addition to ward-based pharmacy services. The aim of this paper was to evaluate the impact of clinical pharmacists' participation on the PTWR on the risk assessment scores of medication-related recommendations with and without a pharmacist. This includes medication-related recommendations occurring on the PTWR and those recommendations made by the ward-based pharmacist on the inpatient ward. A pre-post intervention study was undertaken that compared the impact of adding a pharmacist to the PTWR compared with ward-based pharmacist services alone. A panel reviewed the risk of not acting on medication recommendations that was made on the PTWR and those recorded by the ward-based pharmacist. The relationship between the risk scores and the number and proportion of recommendations that led to action were compared between study groups. There were more medication-related recommendations on the PTWR in the intervention group when a pharmacist was present. Proportionately fewer were in the 'very high and extreme' risk category. Although there was no difference in the number of ward pharmacist recommendations between groups, there was a significantly higher proportion of ward pharmacist recommendations in the "very high and extreme" category in those patients who had been seen on a PTWR attended by a pharmacist than when a pharmacist was not present. There were a greater proportion of "low and medium" risk actionable medication recommendations actioned on the PTWR in the intervention group; and no difference in the risk scores in ward pharmacist recommendations actioned between groups. Overall, the proportion of recommendations that were actioned was higher for those made on the PTWR compared with the ward. The addition of a pharmacist to the PTWR resulted in an increase in low, medium, and high risk recommendations on the PTWR, more very high and extreme risk recommendations made by the ward-based pharmacist, plus an increased number of recommendations being actioned during the patients' admission., Competing Interests: The authors declare no conflict of interest.

Sleep problems are common in childhood and impact cognitive, psychological and physical wellbeing. The current study investigated the association between sleep problems and internalising and externalising behaviour in 114 school-aged children (5-12 years) from four primary schools in Melbourne, Australia. Data were collected using the Sleep Disorder Inventory for Students to measure sleep and the Conners Behavior Rating Scale to assess behaviour, both by parent report. Hierarchical regression analysis, controlling for socioeconomic status and age, identified moderate associations between sleep problems and emotional distress, aggressive behaviour and hyperactivity/impulsivity. Findings suggest screening for sleep problems in children presenting clinically with behavioural issues is a potentially important clinical practice. Additionally, results support the elaboration of transdiagnostic theory, whereby sleep problems are a common process in both internalising and externalising behaviour in children., Competing Interests: Conflicts of InterestThe authors declare no conflict of interest., (© 2019 by the authors.)

Introduction : There is a lack of good quality economic evidence for the inclusion of pharmacists on hospital ward rounds in addition to, or as an alternative to, traditional ward-based clinical pharmacy services. There has been no systematic review of the cost or cost-effectiveness of pharmacists attending and contributing on ward rounds. Areas covered : A literature search was conducted in Medline, Embase, Cochrane, and CINAHL and reported in accordance with the PRISMA guidelines in May 2019. As well, a search using Google Scholar and a targeted hand search were undertaken. Studies that reported any estimate of the cost or cost-effectiveness were included if pharmacist participation on inpatient hospital ward rounds was the predominant focus of the intervention. The identified studies were subsequently screened by three reviewers who extracted data on their clinical and economic design. A bias assessment was completed using the ROBINS-I tool. Expert opinion : Seven studies were identified investigating a clinical pharmacist's inclusion on hospital ward rounds where there was a cost estimated. However, none were deemed to be a full economic evaluation and all were found to be open to a serious risk of bias. Future evaluations should include a comparator group and investigate the cost and cost savings of the service, alongside their clinical outcomes.

Mood states in bipolar disorder appear to be closely linked to changes in sleep and circadian function. It has been suggested that hypersensitivity of the circadian system to light may be a trait vulnerability for bipolar disorder. Healthy persons with emotional-behavioural traits associated with bipolar disorder also appear to exhibit problems with circadian rhythms, which may be associated with individual differences in light sensitivity. This study investigated the melanopsin-driven post-illumination pupil response (PIPR) in relation to emotional-behavioural traits associated with bipolar disorder (measured with the General Behavior Inventory) in a non-clinical group (n = 61). An increased PIPR was associated with increased bipolar disorder-related traits. Specifically, the hypomania scale of the General Behavior Inventory was associated with an increased post-blue PIPR. Further, both the full hypomania and shortened '7 Up' scales were significantly predicted by PIPR, after age, sex and depressive traits were controlled. These findings suggest that increased sensitivity to light may be a risk factor for mood problems in the general population, and support the idea that hypersensitivity to light is a trait vulnerability for, rather than symptom of, bipolar disorder., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Individuals with a circadian preference for mental and physical activity later in the day ("Evening types") are consistently found to fare worse on most facets of well-being than individuals with a circadian preference for mental and physical activity earlier in the day ("Morning types"). Several explanatory hypotheses of this association between chronotype and well-being have been proposed, including shared genetic, biological, developmental, and psychosocial mechanisms. This paper presents a critical summary of these explanatory mechanisms and offers suggestions for their integration in an interdisciplinary biopsychosocial framework.

Background Medication communication and prescribing on the post-take ward round following patient admission to hospital can be suboptimal leading to worse patient outcomes. Objective To evaluate the impact of clinical pharmacist participation on the post-take ward round on the appropriateness of medication prescribing, medication communication, and overall patient health care outcomes. Setting Tertiary referral teaching hospital, Brisbane, Australia. Method A pre-post intervention study was undertaken that compared the addition of a senior clinical pharmacist attending the post-take ward was compared to usual wardbase pharmacist service, with no pharmacist present of the post-take ward round. We assessed the proportion of patients with an improvement in medication appropriateness from admission to discharge, using the START/STOPP checklists. Medication communication was assessed by the mean number of brief and in-depth discussions, with health care outcomes measured by comparing length of stay and 28-day readmission rates. Main outcome measures: Medication appropriateness according to the START/STOPP list, number and type of discussions with team members and length of stay and readmission rate. Results Two hundred and sixty patients were recruited (130 pre- and 130-post-intervention), across 23 and 20 post-take ward rounds, respectively. Post-intervention, there was increase in the proportion of patients who had an improvement medication appropriateness (pre-intervention 25.4%, post-intervention 36.9%; p = 0.004), the number of in-depth discussions about patients' medication (1.9 ± 1.7 per patient pre-intervention, 2.7 ± 1.7 per patient post-, p < 0.001), and the number relating to high-risk medications (0.71 ± 1.1 per patient pre-intervention, to 1.2 ± 1.2 per patient post-, p < 0.05). Length of stay and 28-day mortality were unchanged. Conclusion Clinical pharmacist participation on the post-take ward round leads to improved medication-related communication and improved medication appropriateness but did not significantly improve health care outcomes.

The sleep, circadian rhythms, and mood (SCRAM) questionnaire (Byrne, Bullock et al., 2017) was designed to concurrently measure individual differences in three clinically important functions: diurnal preference, sleep quality, and mood. The 15-item questionnaire consists of three 5-item scales named Morningness, Good Sleep, and Depressed Mood. The overarching aim of the current project was to investigate the validity and reliability of the questionnaire. Here, we report on associations investigated in three data sets. Study 1 (N = 70, 80% females) was used to examine the test-retest reliability of the questionnaire, finding strong test-retest reliability of the three scales over a 2-week period (r's ranging from 0.73 to 0.86). Study 2 (N = 183, 80% females) enabled us to examine the construct validity of the SCRAM scales against well-validated self-report measures of diurnal preference, sleep quality, and depression. Strong correlations were found between each SCRAM scale and their respective measure in bivariate analyses, and associations were robust after the inclusion of the remaining two SCRAM scales as predictors in regression analyses. Data from Study 3 (N = 42, 100% males) were used to measure the extent to which SCRAM scores correlated with objective measures of sleep-wake behavior using actigraphy. Morningness was found to be related to earlier sleep onset and offset times, and Good Sleep was related to higher sleep efficiency but to no other measures of sleep quality; Depressed Mood was not related to actigraphy measures. The findings provide provisional support for construct validity and reliability of the SCRAM questionnaire as a measure of diurnal preference, sleep quality, and depressed mood. Future research into the psychometrics of SCRAM should test the questionnaire's discriminant and predictive validity in clinical samples.

Lung-specific overexpression of prostacyclin synthase (PGIS) decreases tumor initiation in murine lung cancer models. Prostacyclin analogs prevent lung tumor formation in mice and reverse bronchial dysplasia in former smokers. However, the effect of prostacyclin on lung cancer progression has not been well studied. We investigated the effects of pulmonary PGIS overexpression in an orthotopic immunocompetent mouse model of lung cancer using two murine lung cancer cell lines. Pulmonary PGIS overexpression significantly inhibited CMT167 lung tumor growth, increased CXCL9 expression, and increased CD4+ tumor-infiltrating lymphocytes. Immunodepletion of CD4+ T cells abolished the inhibitory effect of pulmonary PGIS overexpression on CMT167 lung tumor growth. In contrast, pulmonary PGIS overexpression failed to inhibit growth of a second murine lung cancer cell line, Lewis Lung Carcinoma (LLC) cells, and failed to increase CXCL9 expression or CD4+ T lymphocytes in LLC lung tumors. Transcriptome profiling of CMT167 cells and LLC cells recovered from tumor-bearing mice demonstrated that in vivo , CMT167 cells but not LLC cells express MHC class II genes and cofactors necessary for MHC class II processing and presentation. These data demonstrate that prostacyclin can inhibit lung cancer progression and suggest that prostacyclin analogs may serve as novel immunomodulatory agents in a subset of lung cancer patients. Moreover, expression of MHC Class II by lung cancer cells may represent a biomarker for response to prostacyclin.

Sleep quality, circadian phase, and mood are highly interdependent processes. Remarkably, there is currently no self-report questionnaire that measures all three of these clinically significant functions: The aim of this project was to address this deficit. In Study 1, 720 participants completed a set of potential items was generated from existing questionnaires in each of the three domains and refined to follow a single presentation format. Study 2 used an independent sample ( N = 498) to interrogate the latent structure. Exploratory factor analysis was used to identify a parsimonious, three-factor latent structure. Following item reduction, the optimal representation of sleep quality, circadian phase, and mood was captured by a questionnaire with three 5-item scales: Depressed Mood, Morningness, and Good Sleep. Confirmatory factor analysis found the three-scale structure provided adequate fit. In both samples, Morningness and Good Sleep were positively associated, and each was negatively associated with the Depressed Mood scale. Further research is now required to quantify the convergent and discriminant validity of its three face-valid and structurally replicated scales. The new sleep, circadian rhythms, and mood (SCRAM) questionnaire is the first instrument to conjointly measure sleep quality, circadian phase, and mood processes, and has significant potential as a clinical tool.

Immune checkpoint inhibitors targeting the interaction between programmed cell death-1 (PD-1) and its ligand PD-L1 induce tumor regression in a subset of non-small cell lung cancer patients. However, clinical response rates are less than 25%. Evaluation of combinations of immunotherapy with existing therapies requires appropriate preclinical animal models. In this study, murine lung cancer cells (CMT167 and LLC) were implanted either orthotopically in the lung or subcutaneously in syngeneic mice, and response to anti-PD-1/PD-L1 therapy was determined. Anti-PD-1/PD-L1 therapy inhibited CMT167 orthotopic lung tumors by 95%. The same treatments inhibited CMT167 subcutaneous tumors by only 30% and LLC orthotopic lung tumors by 35%. CMT167 subcutaneous tumors had more Foxp3 + CD4 + T cells and fewer PD-1 + CD4 + T cells compared with CMT167 orthotopic tumors. Flow cytometric analysis also demonstrated increased abundance of PD-L1 high cells in the tumor microenvironment in CMT167 tumor-bearing lungs compared with CMT167 subcutaneous tumors or LLC tumor-bearing lungs. Silencing PD-L1 expression in CMT167 cells resulted in smaller orthotopic tumors that remained sensitive to anti-PD-L1 therapy, whereas implantation of CMT167 cells into PD-L1 - mice blocked orthotopic tumor growth, indicating a role for PD-L1 in both the cancer cell and the microenvironment. These findings indicate that the response of cancer cells to immunotherapy will be determined by both intrinsic properties of the cancer cells and specific interactions with the microenvironment. Experimental models that accurately recapitulate the lung tumor microenvironment are useful for evaluation of immunotherapeutic agents. Cancer Immunol Res; 5(9); 767-77. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Seasonal variation of manic and depressive symptoms is a controversial topic in bipolar disorder research. Several studies report seasonal patterns of hospital admissions for depression and mania and variation in symptoms that appear to follow a seasonal pattern, whereas others fail to report such patterns. Differences in research methodologies, data analysis strategies, and temporal resolution of data may partly explain the variation in findings between studies. The current study adds a novel perspective to the literature by investigating specific meteorological factors such as atmospheric pressure, hours of sunshine, relative humidity, and daily maximum and minimum temperatures as more proximal predictors of self-reported daily mood change in people diagnosed with bipolar disorder. The results showed that daily maximum temperature was the only meteorological variable to predict clinically-relevant mood change, with increases in temperature associated with greater odds of a transition into manic mood states. The mediating effects of sleep and activity were also investigated and suggest at least partial influence on the prospective relationship between maximum temperature and mood. Limitations include the small sample size and the fact that the number and valence of social interactions and exposure to natural light were not investigated as potentially important mediators of relationships between meteorological factors and mood. The current data make an important contribution to the literature, serving to clarify the specific meteorological factors that influence mood change in bipolar disorder. From a clinical perspective, greater understanding of seasonal patterns of symptoms in bipolar disorder will help mood episode prophylaxis in vulnerable individuals.

Associations among personality, diurnal preference, and circadian phase were investigated using a constant routine laboratory protocol. One hundred and sixty-eight healthy participants aged 18-30 years (Women n = 68) completed either a 30- or 50-hour constant routine under dim-light conditions (<3 lux), during which circadian phase was measured from core body temperature and melatonin. Prior to laboratory admission, self-report measures of personality and diurnal preference were also obtained. The personality trait of Constraint correlated positively with morning diurnal preference and earlier circadian phase, with circadian phase partially mediating the relationship between Constraint and diurnal preference. No other personality variables correlated with circadian phase. Sex was an important covariate in several of the relationships investigated due to lower levels of Constraint and later CBT phase amongst men and was thus controlled for in all relevant analyses. Findings from this highly controlled study are consistent with previous field research in suggesting that earlier circadian phase is associated with the personality trait of Constraint.

Communication between pre- and postsynaptic cells promotes the initial organization of synaptic specializations, but subsequent synaptic stabilization requires transcriptional regulation. Here we show that fibroblast growth factor 22 (FGF22), a target-derived presynaptic organizer in the mouse hippocampus, induces the expression of insulin-like growth factor 2 (IGF2) for the stabilization of presynaptic terminals. FGF22 is released from CA3 pyramidal neurons and organizes the differentiation of excitatory nerve terminals formed onto them. Local application of FGF22 on the axons of dentate granule cells (DGCs), which are presynaptic to CA3 pyramidal neurons, induces IGF2 in the DGCs. IGF2, in turn, localizes to DGC presynaptic terminals and stabilizes them in an activity-dependent manner. IGF2 application rescues presynaptic defects of Fgf22(-/-) cultures. IGF2 is dispensable for the initial presynaptic differentiation, but is required for the following presynaptic stabilization both in vitro and in vivo. These results reveal a novel feedback signal that is critical for the activity-dependent stabilization of presynaptic terminals in the mammalian hippocampus.

Background: Sensitive assays are needed for detection of residual human immunodeficiency virus (HIV) in patients with undetectable plasma viral loads to determine whether eradication strategies are effective. The gold standard quantitative viral outgrowth assay (QVOA) underestimates the magnitude of the viral reservoir. We sought to determine whether xenograft of leukocytes from HIV type 1 (HIV)-infected patients with undetectable plasma viral loads into immunocompromised mice would result in viral amplification., Methods: Peripheral blood mononuclear cells or purified CD4(+) T cells from HIV or simian immunodeficiency virus (SIV)-infected subjects with undetectable plasma viral loads were adoptively transferred into NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. The mice were monitored for viremia following depletion of human CD8(+) T cells to minimize antiviral activity. In some cases, humanized mice were also treated with activating anti-CD3 antibody., Results: With this murine viral outgrowth assay (MVOA), we successfully amplified replication-competent HIV or SIV from all subjects tested, including 5 HIV-positive patients receiving suppressive antiretroviral therapy (ART) and 6 elite controllers or suppressors who were maintaining undetectable viral loads without ART, including an elite suppressor from whom we were unable to recover virus by QVOA., Conclusions: Our results suggest that the MVOA has the potential to serve as a powerful tool to identify residual HIV in patients with undetectable viral loads., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Two functional electron transfer (ET) chains, related by a pseudo-C2 symmetry, are present in the reaction center of photosystem I (PSI). Due to slight differences in the environment around the cofactors of the two branches, there are differences in both the kinetics of ET and the proportion of ET that occurs on the two branches. The strongest evidence that this is indeed the case relied on the observation that the oxidation rates of the reduced phylloquinone (PhQ) cofactor differ by an order of magnitude. Site-directed mutagenesis of residues involved in the respective PhQ-binding sites resulted in a specific alteration of the rates of semiquinone oxidation. Here, we show that the PsaA-F689N mutation results in an ∼100-fold decrease in the observed rate of PhQA(-) oxidation. This is the largest change of PhQA(-) oxidation kinetics observed so far for a single-point mutation, resulting in a lifetime that exceeds that of the terminal electron donor, P700(+). This situation allows a second photochemical charge separation event to be initiated before PhQA(-) has decayed, thereby mimicking in PSI a situation that occurs in type II reaction centers. The results indicate that the presence of PhQA(-) does not impact the overall quantum yield and leads to an almost complete redistribution of the fractional utilization of the two functional ET chains, in favor of the one that does not bear the charged species. The evolutionary implications of these results are also briefly discussed., (Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

The incidence of human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) has rapidly increased over the past 30 years, prompting the suggestion that an epidemic maybe on the horizon. Therefore, there is a clinical need to develop alternate therapeutic strategies to manage the growing number of HPV-positive HNSCC patients. High-risk HPV E6 inactivates p53 through two distinct mechanisms; association with E6AP to degrade p53 and association with p300 to block p300-mediated p53 acetylation and activation. In this study, we determined if targeting the E6-p300 interaction is an effective approach to reactivate p53 in HPV-positive HNSCC. Ectopic expression of the CH1 domain of p300 in HPV-positive HNSCC blocks the association between E6 and p300, increases total and acetylated p53 levels and enhances p53 transcriptional activity. Moreover, expression of p21, miR-34a and miR-200c are increased, demonstrating functional p53 reactivation. CH1 overexpression in HPV-positive HNSCC has a global anticancer effect resulting in a decrease in cell proliferation and clonogenic survival and an increase in apoptosis. The in vivo tumor-initiating ability of HPV-positive HNSCC is severely compromised with CH1 overexpression, in part through a reduction in the cancer-initiating cell population. A novel small-molecule CH1 inhibitor, CH1iB, reactivates p53 and potentiates the anticancer activity of cis-platinum in HPV-positive HNSCC cells. Our work shows that CH1-domain inhibitors represent a novel class of p53-reactivation therapeutics for managing HPV-positive HNSCC patients.

Background: Reduced social rhythmicity is a commonly reported feature of bipolar disorder which may extend to non-clinical populations at risk of bipolar disorder. The aim of the current study was to investigate social rhythms across three groups of participants; a clinical group of bipolar disorder outpatients, and two non-clinical groups with high- and low-vulnerability to bipolar disorder, respectively. It was expected that reduced social rhythmicity would differentiate the clinical group from the low-vulnerability group, but not the high vulnerability group., Methods: Non-clinical participants were selected on the basis of scores derived from the General Behaviour Inventory and allocated to groups of high (n=36) and low (n=36) trait vulnerability to bipolar disorder. The clinical group (n=15) were volunteers recruited from an outpatient clinic. Participants completed a self-report social rhythmicity measure daily for seven consecutive days., Results: One-way analysis of covariance (age) showed a significant overall effect for group, F (2,83)=4.67, p<.05. Post hoc comparisons revealed significant differences in social rhythms between the two nonclinical groups only., Limitations: The cross-sectional design of the study limits the strength of conclusions that can be drawn., Conclusions: The hypothesis was only partially supported. Consistent with expectations, the non-clinical group with higher vulnerability to bipolar disorder recorded lower social rhythmicity than the non-clinical group with lower vulnerability to bipolar disorder. The clinical group however, did not differ in social rhythmicity from the lower vulnerability group. The findings may have consequences for the way in which vulnerability to bipolar disorder is managed., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The human cytomegalovirus (HCMV) IE86 protein is essential for HCMV replication due to its ability to transactivate critical viral early promoters. In the current study, we performed a comprehensive mutational analysis between amino acids (aa) 535 and 545 of IE86 and assessed the impact of these mutations on IE86-mediated transcriptional activation. Using transient assays and complementing analysis with recombinant HCMV clones, we show that single amino acid mutations differentially impair the ability of IE86 to mediate transactivation of essential early gene promoters. The conserved tyrosine at amino acid 544 is critical for activation of the UL54 promoter in vitro and in the context of the viral genome. In contrast, mutation of the proline at position 535 disrupted activation of the UL54 promoter in transient assays but displayed activity similar to that of wild-type (WT) IE86 when assessed in the genomic context. To examine the underlying mechanism of this differential effect, glutathione S-transferase (GST) pulldown assays were performed, revealing that Y544 is critical for binding to the TATA binding protein (TBP), suggesting that this interaction is likely necessary for the ability of IE86 to activate the UL54 promoter. In contrast, mutation of either P535 or Y544 disrupted activation of the UL112-113 promoter both in vitro and in vivo, suggesting that interaction with TBP is not sufficient for IE86-mediated activation of this early promoter. Together, these studies demonstrate that IE86 activates early promoters by distinct mechanisms.

Entry of HIV and SIV into susceptible cells is mediated by CD4 and chemokine receptors, which act as coreceptors. To study cell entry of SIV, we constructed a cell line, xKLuSIV, derived from non-susceptible human K562 cells, that express the firefly luciferase reporter gene under control of a minimal SIV long terminal repeat (LTR). Using these susceptible cells, we studied the entry of a well-characterized molecularly cloned macrophage-tropic SIV. xKLuSIV cells that express rhesus macaque CD4 and/or the rhesus chemokine receptor CCR5 are susceptible to infection with the macrophage-tropic, neurovirulent strain SIV/17E-Fr, but only xKLuSIV cells expressing both CCR5 and CD4 were susceptible to infection by the macrophage-tropic, non-neurovirulent strain SIV/17E-Cl. CCR5-dependent, CD4-independent infection by SIV/17E-Fr was abrogated by pre-incubation of the cells with AOP-RANTES, a ligand for CCR5. In addition to viral entry occurring by a CD4-independent mechanism, neutralization of SIV/17E-Fr with rhesus mAbs from 3 different neutralization groups blocked entry into x KLuSIV cells by both CD4-dependent and -independent mechanisms. Triggering the env glycoprotein of SIV-17 EFr with soluble CD4 had no significant effect in infectivity, but triggering of the same glycoprotein of SIV/17E-Cl allowed it to enter cells in a CD4-independent fashion. Using mutant molecular clones, we studied the determinants for CD4 independence, all of which are confined to the env gene. We report here that truncation of the TM at amino acid 764 and changing a single amino acid (R751G) in the SIV envelope transmembrane protein (TM) conferred the observed CD4-independent phenotype. Our data suggest that the envelope from the neurovirulent SIV/17E-Fr interacts with CCR5 in a CD4-independent manner, and changes in the TM protein of this virus are important components that contribute to neurovirulence in SIV.

Context: The prevalence of human immunodeficiency virus (HIV) central nervous system (CNS) disease has not decreased despite highly active antiretroviral therapy. Current antiretroviral drugs are expensive, have significant adverse effects including neurotoxicity, and few cross the blood-brain barrier., Objective: To examine the ability of minocycline, an antibiotic with potent anti-inflammatory and neuroprotective properties, to protect against encephalitis and neurodegeneration using a rapid, high viral load simian immunodeficiency virus (SIV) model of HIV-associated CNS disease that constitutes a rigorous in vivo test for potential therapeutics., Design and Subjects: Five SIV-infected pigtailed macaques were treated with 4 mg/kg per day of minocycline beginning at early asymptomatic infection (21 days after inoculation). Another 6 macaques were inoculated with SIV but remained untreated. Blood and cerebrospinal fluid (CSF) samples were taken on days 7, 10, 14, 21, 28, 35, 43, 56, 70, 77, and 84, and all macaques were humanely killed at 84 days after inoculation, a time that corresponds to late-stage infection in HIV-infected individuals., Main Outcome Measures: Blood and CSF samples were tested for viral load by real-time reverse transcription-polymerase chain reaction and levels of monocyte chemoattractant protein 1 were quantitated by enzyme-linked immunosorbent assay. The presence and severity of encephalitis was determined by microscopic examination of tissues. Central nervous system inflammation was further assessed by measuring infiltration and activation of macrophages, activation of p38 mitogen-activated protein kinase and expression of amyloid precursor protein by quantitative immunohistochemistry., Results: Minocycline-treated macaques had less severe encephalitis (P = .02), reduced CNS expression of neuroinflammatory markers (major histocompatibility complex class II, P = .03; macrophage marker CD68 , P = .07; T-cell intracytoplasmic antigen 1, P = .03; CSF monocyte chemoattractant protein 1, P = .001), reduced activation of p38 mitogen-activated protein kinase (P<.001), less axonal degeneration (beta-amyloid precursor protein, P = .03), and lower CNS virus replication (viral RNA, P = .04; viral antigen, P = .04). In in vitro analysis, minocycline suppression of HIV and SIV replication in cultured primary macrophages did not correlate with suppression of activation of p38-mitogen-activated protein kinase pathways, whereas suppression in primary lymphocytes correlated with suppression of p38 activation., Conclusions: In this experimental SIV model of HIV CNS disease, minocycline reduced the severity of encephalitis, suppressed viral load in the brain, and decreased the expression of CNS inflammatory markers. In vitro, minocycline inhibited SIV and HIV replication. These findings suggest that minocycline, a safe, inexpensive, and readily available antibiotic should be investigated as an anti-HIV therapeutic.

This study used a simian immunodeficiency virus (SIV)-macaque model to determine whether virus persists in the central nervous system (CNS) of human immunodeficiency virus (HIV)-infected individuals in which plasma viral load has been suppressed by highly active antiretroviral therapy. SIV-infected macaques were treated with two reverse transcriptase inhibitors: PMPA (q- R-(2-phosphonomethoxypropyl)adenine)which does not cross the blood-brain barrier, and FTC (beta-2('),3(')-dideoxy-3 thia-5-fluorocytidine), which does. Viral DNA and RNA were quantitated in the brain after 6 months of suppression of virus replication in blood and cerebrospinal fluid (CSF). Viral DNA was detected in brain from all macaques, including those in which peripheral viral replication had been suppressed either by antiretroviral therapy or host immune responses. Significant neurological lesions were observed only in one untreated macaque that had active virus replication in the CNS. Expression of the inflammatory markers, major histocmopatibility complex (MHC) II and CD68 was significantly lower in macaques treated with PMPA/FTC. Thus, although antiretroviral treatment may suppress virus replication in the periphery and the brain and reduce CNS inflammation, viral DNA persists in the brain despite treatment. This suggests that the brain may serve as a long-term viral reservoir in HIV-infected individuals treated with antiretroviral drugs that suppress virus replication.

Atherogenic response to dietary fat and cholesterol challenge was evaluated in mice lacking both the LDL receptor (LDLr(-/-)) and apoA-I (apoA-I(-/-)) gene, LDLr(-/-)/apoA-I(-/-) or double-knockout mice. Gender- and age-matched LDLr(-/-)/apoA-I(-/-) mice were fed a diet consisting of 0.1% cholesterol and 10% palm oil for 16 weeks and compared to LDLr(-/-) mice or single-knockout mice. The LDLr(-/-) mice showed a 6- to 7-fold increase in total plasma cholesterol (TPC) compared to their chow-fed mice counterparts, while LDLr(-/-)/apoA-I(-/-) mice showed only a 2- to 3-fold increase in TPC compared to their chow-fed controls. This differential response to the atherogenic diet was unanticipated, since chow-fed LDLr(-/-) and LDLr(-/-)/apoA-I(-/-) mice began the study with similar LDL levels and differed primarily in their HDL concentration. The 6-fold diet-induced increase in TPC observed in the LDLr(-/-) mice occurred mainly in VLDL/LDL and not in HDL. Mid-study plasma samples taken after 8 weeks of diet feeding showed that LDLr(-/-) mice had TPC concentrations approximately 60% of their 16-week level, while the LDLr(-/-)/apoA-I(-/-) mice had reached 100% of their 16-week TPC concentration after only 8 weeks of diet. Male LDLr(-/-) mice showed similar aortic cholesterol levels to male LDLr(-/-)/apoA-I(-/-) mice despite a 4-fold higher VLDL/LDL concentration in the LDLr(-/-) mice. A direct comparison of the severity of aortic atherosclerosis between female LDLr(-/-) and LDLr(-/-)/apoA-I(-/-) mice was compromised due to the loss of female LDLr(-/-)/apoA-I(-/-) mice between 10 and 14 weeks into the study. Diet-fed female and, with time, male LDLr(-/-)/apoA-I(-/-) mice suffered from severe ulcerated cutaneous xanthomatosis. This condition, combined with a complete depletion of adrenal cholesterol, manifested in fatal wasting of the affected mice. In conclusion, LDLr(-/-) and LDLr(-/-)/apoA-I(-/-) mice showed dramatic TPC differences in response to dietary fat and cholesterol challenge, while despite these differences both genotypes accumulated similar levels of aortic cholesterol.

Background: Herbal therapies have been widely used in allergic rhinitis (AR), but none have been shown to be effective in controlled scientific clinical trials., Objective: The aim of this study was to test the effects of the Chinese herbal formulation Biminne in patients with moderate to severe perennial AR., Methods: In a randomized, double-blind, placebo-controlled clinical trial, 58 patients were randomized to receive either Biminne capsules (n = 26) or placebo (n = 32) in doses of five capsules twice a day for 12 weeks. Main outcomes were measured by changes in symptom diaries, quality of life scores, patients' evaluations of improvement on visual analog scores, and physicians' overall evaluation. Total serum immunoglobulin E was measured in all patients without knowledge of which group they were in. After 1 year we performed a randomized, double-blind, dose-response study in 22 patients who had previously received placebo., Results: The trial outcomes evaluated by four instruments showed a statistically significant improvement in some of the symptoms of AR, whereas others exhibited a positive trend that did not reach statistical significance. Followup 1 year after completion of the trial suggested that benefit of the treatment persisted. A pilot dose-response study showed both half and full strengths were effective. Total serum immunoglobulin E was reduced after the herbal treatment., Conclusions: Our results suggest the Biminne formulation is effective in treatment of perennial AR. Its mode of action is unknown.

The developing fetus is uniquely sensitive to perturbation with estrogenic chemicals. The carcinogenic effect of prenatal exposure to diethylstilbestrol (DES) is the classic example. Because phytoestrogen use in nutritional and pharmaceutical applications for infants and children is increasing, we investigated the carcinogenic potential of genistein, a naturally occurring plant estrogen in soy, in an experimental animal model previously reported to result in a high incidence of uterine adenocarcinoma after neonatal DES exposure. Outbred female CD-1 mice were treated on days 1-5 with equivalent estrogenic doses of DES (0.001 mg/kg/day) or genistein (50 mg/kg/day). At 18 months, the incidence of uterine adenocarcinoma was 35% for genistein and 31% for DES. These data suggest that genistein is carcinogenic if exposure occurs during critical periods of differentiation. Thus, the use of soy-based infant formulas in the absence of medical necessity and the marketing of soy products designed to appeal to children should be closely examined.

Diabetes is a major health problem of increasing incidence in the United States. Diabetes research has been limited by lack of availability of good animal models, particularly for the study of comorbidities associated with diabetes. We investigated the use of cynomolgus monkeys as an animal model of both type 1 and type 2 diabetes and compared these naturally occurring diseases with streptozotocin-induced diabetes. Both type 1 diabetics and streptozotocin-induced diabetics present with sudden onset of hyperglycemia and are ketosis prone without exogenous insulin. Type 2 diabetics can have a very long period of moderate hyperglycemia and hypertriglyceridemia and only require exogenous insulin therapy if pancreatic islet reserves are depleted. Type 2 diabetes is preceded by a relatively long period of insulin resistance that is associated with obesity and dyslipidemia. As insulin resistance progresses, islet size and insulin content increases initially. However, with sustained periods of insulin resistance, islet amyloid polypeptide (IAPP) is deposited in islets and can replace normal islet architecture, resulting in an insulin-deficient state. Appearance of IAPP also occurs in human type 2 diabetics but not in conventional rodent models. Unlike type 2 diabetes, neither type 1 nor streptozotocin-induced diabetes is associated with IAPP. Rather, islets can appear normal histologically, but have decreased insulin secretion and immunostaining. Further, the amount of insulin present in the islet is correlated with plasma insulin levels following glucose challenge. Studies are ongoing to determine the pathogenic changes associated with the progression of diabetes and to find novel drug treatments for diabetics.