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Objectives: The COVID-19 pandemic necessitated rapid transition to telehealth. Telehealth presents challenges for rehabilitation of stroke survivors with moderate-to-severe physical disability, which traditionally relies on physical interactions. The objective was to co-design resources to support delivery of rehabilitation via telehealth for this cohort., Design: Four-stage integrated knowledge translation co-design approach. Stage 1: Research team comprising researchers, clinicians and stroke survivors defined the research question and approach. Stage 2: Workshops and interviews were conducted with knowledge users (participants) to identify essential elements of the program. Stage 3: Resources developed by the research team. Stage 4: Resources reviewed by knowledge users and adapted., Participants: Twenty-one knowledge users (clinicians n = 11, stroke survivors n = 7, caregivers n = 3) RESULTS: All stakeholders emphasised the complexities of telehealth rehabilitation for stroke and the need for individualised programs. Shared decision-making was identified as critical. Potential risks and benefits of telehealth were acknowledged and strategies to ameliorate risks and deliver effective rehabilitation were identified. Four freely available online resources were co-designed; three resources to support clinicians with shared decision-making and risk management and a decision-aid to support stroke survivors and caregivers throughout the process. Over six months, 1129 users have viewed the webpage; clinician resources were downloaded 374 times and the decision-aid was downloaded 570 times., Conclusions: The co-design process identified key elements for delivery of telehealth rehabilitation to stroke survivors with moderate-to-severe physical disability and led to development of resources to support development of an individualised telehealth rehabilitation plan. Future research should evaluate the effectiveness of these resources. CONTRIBUTION OF PAPER., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Health information and resources are often provided in hospital outpatient waiting areas but may not meet the cultural and health literacy needs of older adults from culturally and linguistically diverse (CALD) backgrounds., Objectives: To explore the perspectives and experiences of Cantonese- and Vietnamese-speaking patients and carers in this setting., Methods: This qualitative interview-based study was conducted from December 2019 to March 2020 at a single outpatient rehabilitation service located at a tertiary public hospital. Four adult consumers (two older adult patients, two caregivers) from CALD backgrounds participated in semi-structured interviews with bilingual researchers. Data were transcribed, translated and analysed using reflexive thematic analysis., Results: Five themes were developed which highlighted that older adults' language profiles shaped their health information needs and ability to access resources in waiting areas. Cultural factors such as filial responsibility may also influence health information preferences., Discussion: Older consumers from CALD backgrounds did not have equitable access to health information and resources in the waiting area compared with English-literate older adults., Conclusion: Health information and resources in waiting areas warrant improving to better meet the needs of older patients from CALD backgrounds and their caregivers., (© 2024 The Authors Health Information and Libraries Journal published by John Wiley & Sons Ltd on behalf of Health Libraries Group.)

Introduction: Teaching clinical reasoning to physiotherapy students is essential for preparing them to work effectively with patients., Objective: This qualitative study aimed to explore the experiences and perceptions of clinical supervisors of teaching clinical reasoning in gerontological physiotherapy., Methods: Australian-based clinical supervisors for student placements in gerontological physiotherapy ( n  = 9) participated in individual semi-structured interviews via videoconferencing. Data were analyzed using Braun and Clark's reflexive thematic analysis., Results: Four themes were developed from the data: 1) Preparedness for placement: students and supervisors; 2) Dynamic placement adaptations to meet individual learning needs; 3) Negotiating clinically complex and variable patient needs; and 4) Crafting learning opportunities amidst complexities. Clinical supervisors perceive that teaching clinical reasoning is influenced by student and supervisor preparedness and the complexity of gerontological practice. Supervisors engage in planning prior to placements, adapt tasks, discussions and feedback throughout the placement, and promote multi-disciplinary learning experiences to highlight person-centered and collaborative care., Conclusion: This research enhances physiotherapy academics,' clinical supervisors' and students' understanding of the factors influencing teaching clinical reasoning to students in gerontological settings. The challenges and strategies identified can improve students' and supervisors' preparedness for placements, assist them to negotiate complexity and create opportunities to strengthen the learning experience.

Whilst existing quantitative research identifies outcomes believed to be important by researchers and clinicians, it may neglect outcomes that are meaningful to patients. This study aimed to explore the outcomes of exercise that are important to people with lung cancer and their carers. Data collection involved a qualitative methodology including semi-structured interviews and focus groups. Question guide development was informed by the International Classification of Functioning (ICF) framework. Data were analyzed by two researchers with NVivo (v12) software using a conventional content analysis process, followed by directed content analysis to map outcomes to the ICF. Conduct and reporting adhered to COREQ guidelines. Fifteen participants provided data. Most participants had received their diagnoses 24 months prior to study involvement ( n = 9), and one-third had completed treatment ( n = 5). Important outcomes were reported by participants across all domains of the ICF: activity and participation ( n = 24), body function ( n = 19), body structure ( n = 5), environmental factors ( n = 5), and personal factors ( n = 1). Additional code categories pertained to the impacts of non-cancer factors such as age, frailty, and comorbidities; identifying barriers to exercise; and individualizing outcome measures. Clinicians and researchers should consider selecting outcomes from all relevant domains of the ICF, with a focus on the activity and participation domain, in addition to non-cancer factors such as ageing, frailty, and co-morbidities. Feedback should be provided to patients following outcome measures collection and reassessment.

Health service waiting areas commonly provide health information, resources and supports for consumers; however, the effect on health literacy and related outcomes remains unclear. This scoping review of the literature aimed to explore the use of waiting areas as a place to contribute to the health literacy and related outcomes of consumers attending health appointments. Articles were included if they focussed on health literacy or health literacy responsiveness (concept) in outpatient or primary care health service waiting areas (context) for adult consumers (population) and were published after 2010. Ten bibliographic databases, one full-text archive, dissertation repositories and web sources were searched. The search yielded 5095 records. After duplicate removal, 3942 title/abstract records were screened and 360 full-text records assessed. Data were charted into a standardized data extraction tool. A total of 116 unique articles (published empirical and grey literature) were included. Most articles were set in primary and community care (49%) waiting areas. A diverse range of health topics and resource types were available, but results demonstrated they were not always used by consumers. Outcomes measured in intervention studies were health knowledge, intentions and other psychological factors, self-reported and observed behaviours, clinical outcomes and health service utilization. Intervention studies overall demonstrated positive trends in health literacy-related outcomes, although the benefit declined after 3-6 months. Research on using waiting areas for health literacy purposes is increasing globally. Future research investigating the needs of consumers to inform optimal intervention design is needed., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Physical activity (PA) participation is important for children born extremely preterm or extremely low birthweight as it provides opportunities to improve motor skills and cardiovascular fitness; however there is little evidence on interventions promoting PA participation for this group, particularly at preschool age., Objective: This study aims to explore the acceptability, a critical component of intervention feasibility, of a novel dance participation intervention., Methods: Semi-structured interviews explored the acceptability of Dance PREEMIE, a Dance PaRticipation intervention for Extremely prEterm children with Motor Impairment at prEschool age (trial registration ACTRN12619001266156), from the perspectives of dance teachers delivering the intervention (n = 6), and parents of participating children (n = 6). Data were analyzed using reflexive thematic analysis., Results: Five themes were developed: 1) placing the child center-stage: a shared motivation to promote child wellbeing and development; 2) Dance PREEMIE as a catalyst for participation; 3) child development takes time, practice and exposure; 4) the value of being informed; and 5) dance teachers as architects of the learning environment., Conclusion: Dance PREEMIE was acceptable to both parents of participating children and dance teachers. Findings from this study may inform future interventions aiming to improve PA participation for children with motor impairment at preschool age.

Introduction: Arthroplasty is an effective, yet costly, surgical procedure for end-stage osteoarthritis. Shorter stays in hospital are being piloted in Australia. In some countries, short stay is established practice, associated with improving perioperative care and enhanced recovery after surgery practices. Exploring the acceptability to patients of a short stay care pathway in hospital postarthroplasty is important for informing health policy, adoption and potential scalability of this model of care., Methods: Consecutive patients at one site, at least 3 months post total joint arthroplasty, were invited to participate in theory-informed semi-structured qualitative interviews. The Theoretical Framework of Acceptability (TFA) informed development of the interview guide. Interview data were analysed using the Framework Method., Results: Eighteen patients were invited. Fifteen consented to be contacted and were interviewed. Short-stay post arthroplasty was highly acceptable to patients who had the supports necessary to recover safely at home. Key findings were as follows: flexibility of short-stay care pathway was essential and valued; prior beliefs and expectations informed acceptability; and the absence of out-of-pocket expenses had an incentivizing effect, but was not the primary reason for patients choosing this care pathway. Further themes analysed within the TFA constructs highlighted nuances of acceptability relating to this model of care., Conclusions: A short stay in hospital post arthroplasty appeared to be acceptable to patients who had experienced this care pathway. Our thematic findings identified aspects of the short-stay care pathway that enhanced acceptability and some aspects that limited acceptability. These findings can inform refinement of the short-stay care pathway., Patient or Public Contribution: Patients/people with lived experience were not involved in the study design or conduct of this preliminary work; as this short-stay model of care was recently introduced, only a small group of patients was eligible to participate in this study. This study is the first step towards understanding the experiences of patients about a short-stay model of care post arthroplasty. The findings will help inform future patient and public involvement in expanding the programme., (© 2022 The Authors. Health Expectations published by John Wiley & Sons Ltd.)

Background: The United States medical education system has a vested interest in understanding medical student specialty choice. The purpose of this study is to identify the demographic, educational, lifestyle preference, and other factors associated with matching into surgical specialties., Methods: An annual survey was given to students at the University of Iowa Carver College of Medicine from 2013-2019. 456 medical students were eligible to participate and 374 completed at least one survey. Surveys were distributed 5 times; M1, M2, M3, and M4 years and after the residency match process. Logistic regression was used to estimate the association between various factors and the likelihood of matching into a surgical specialty., Results: Exposure to surgical fields, through a family member practicing surgery (aOR = 3.21), mentorship (aOR = 2.78), or research (aOR = 2.96) increase the likelihood of matching into a surgical specialty. Married students are less likely to pursue surgical specialties (aOR = 0.246). White students interested in surgery in their first two years of medical school were more likely (aOR = 6.472) to match into surgery than non-White students also interested in surgery (aOR = 0.155)., Conclusions: Factors associated with an increased likelihood of matching into surgical specialties include having surgical mentors, performing surgical research, and having family members in surgical specialties. Of the students interested in surgery early in medical school, being of Caucasian ethnicity is associated with higher rates of matching into surgery. Students who are married without children are less likely to enter a surgical field., (Copyright © 2021. Published by Elsevier Inc.)

Aim: The study aim was to (1) investigate the barriers and enablers experienced by consumers to accessing and engaging with health tools in hospital waiting areas and (2) evaluate consumers' ideas for designing a health literacy responsive waiting area., Background: Health information, resources, and supports ("health tools") in waiting areas should be responsive to the health literacy needs of consumers. However, consumers' experiences of using health tools and their ideas for improving them are not known., Methods: Multicenter study was set in hospital waiting areas of outpatient rehabilitation services. Semistructured in-person interviews were conducted with 33 adult consumers attending appointments for various health conditions. Seven stages of the Framework Method were used to analyze data., Results: Six themes were identified which explained barriers and enablers from the perspective of consumers. The barriers were accessibility issues; personal factors-physical condition, emotional state, and preferences; and poorly presented and outdated resources. The enablers were design suits consumer needs and preferences; usable in available time or portable; and compatible environment for engaging and sharing. Consumers shared design ideas which fit within four typologies., Conclusions: A range of barriers and enablers exist which have an impact on consumers' ability to engage with available health information, resources, and supports in hospital outpatient waiting areas. Practical insights from the perspective of consumers can be applied to future health service design. Consumer's design ideas suggest that partnerships with consumers should be formed to design health literacy responsive waiting areas.

In this research, we explore and theorize on the potential of hospital outpatient rehabilitation waiting areas to respond and contribute to the health literacy needs of consumers. Constructivist grounded theory informed the sampling and analytical procedures. Thirty-three consumers attending outpatient rehabilitation for a range of health conditions were recruited to this multi-site study. Semi-structured interview and participant observation data were collected and analyzed concurrently using the constant comparison method. The substantive theory of "seeking choice to fulfill health literacy needs" and five interdependent categories were developed. Results indicated that consumers sought choice reflective of their needs; however, the waiting area offered limited choice. Consumers shared ideas to address the lack of choice. Results provide insight into the health literacy needs of consumers in hospital outpatient waiting areas and how health services can appropriately respond to these needs. Future research should investigate the effect of health service environments on health outcomes.

Aim: To investigate: (1) the types of health information, resources, and supports available to consumers in hospital outpatient waiting areas and (2) whether these are accessed by consumers., Background: Outpatient waiting areas commonly offer health information, resources, and supports to improve the health literacy of waiting consumers. It is not known what is available to or accessed by consumers in hospital outpatient rehabilitation waiting areas., Methods: A multicenter, prospective, observational, cross-sectional study was conducted in the waiting areas of two hospital outpatient rehabilitation services. Direct observations (in person and video recordings) of the waiting areas were used to describe what health information, resources, and supports were available and, if present, what was being accessed and for how long by consumers., Results: Fifteen hours of in-person and video-recorded observations were documented on purpose-designed instruments across the two sites during 18 observation sessions over 8 days. A total of 68 different health information and resources were identified. Approximately half were specifically for consumers (Site 1: 57%; Site 2: 53%). Only seven (10%) were accessed by consumers across both sites. Each resource ( n = 7) was only accessed once. Health resources were used by consumers for 0.8% (3/360 min) of the observation time at each site. Health and social supports and use of other non health resources were also observed., Conclusions: Available health information, resources, and supports were infrequently and briefly accessed by consumers. Further research is required to explore what consumers want and need to improve the health literacy responsiveness of hospital outpatient waiting areas.

The combination of SmI 2 and the conjugate base of triethylurea (TEU - ) has been shown to favor the cyclization of unsaturated halides over direct reduction to a much greater extent than other SmI 2 -based reductants. Aryl, heteroaryl, and alkyl halides (X = Br, Cl, F) readily undergo heterocyclization and carbocyclization in the presence of SmI 2 /TEU - .

Background: Individuals with bipolar disorder (BD) have an increased risk of developing eating disorders (ED) or disordered eating symptoms compared to the general population. Eating pathology characterised by binge and/or purge symptomatology are the most common to develop in BD, yet the underlying aetiological mechanisms are relatively unknown. Theoretical models of BD-ED comorbidity suggest that shared pathophysiological factors, including emotion dysregulation and impulsivity may contribute to the development of binge/purge eating pathology in BD., Method: A systematic search was conducted to assess two research questions: 1. What are the prevalence or incidence rates of different ED in BD? 2. Are clinical correlates hallmarked by emotion dysregulation and/or impulsivity (alcohol/substance use disorders, mood instability and suicidality) significantly elevated in BD with ED (BD-ED) groups compared to BD only?, Results: Any type of lifetime or current ED ranged from 1.9% to 33.3% in BD. Type of BD diagnosis did not appear to significantly impact likelihood of ED development. Alcohol use disorder, mood instability and suicidality were significantly higher in BD-ED compared to BD only., Limitations: Potential biases within the selected studies; impacting generalisability of results and comparability between studies. Varying treatment interventions (including medications) may confound results and comparability between studies. Assessment of binge eating varied, also limiting comparability., Conclusion: Eating pathology may occur comorbidly with BD due to shared underlying pathophysiological features. This could have significant implications for future interventions; both psychopharmacological and psychotherapeutic. More comprehensive investigations are required to identify the functionality of dysregulated emotion and impulsivity in the development of eating pathology in BD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Flaviviruses are a diverse group of arthropod-borne viruses responsible for numerous significant public health threats; therefore, understanding the interactions between these viruses and the human immune response remains vital. West Nile virus (WNV) and Zika virus (ZIKV) infect human dendritic cells (DCs) and can block antiviral immune responses in DCs. Previously, we used mRNA sequencing and weighted gene coexpression network analysis (WGCNA) to define molecular signatures of antiviral DC responses following activation of innate immune signaling (RIG-I, MDA5, or type I interferon [IFN] signaling) or infection with WNV. Using this approach, we found that several genes involved in T cell cosignaling and antigen processing were not enriched in DCs during WNV infection. Using cis -regulatory sequence analysis, STAT5 was identified as a regulator of DC activation and immune responses downstream of innate immune signaling that was not activated during either WNV or ZIKV infection. Mechanistically, WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and interleukin-4 (IL-4), but not granulocyte-macrophage colony-stimulating factor (GM-CSF), signaling. Unexpectedly, dengue virus serotypes 1 to 4 (DENV1 to DENV4) and the yellow fever 17D vaccine strain (YFV-17D) did not antagonize STAT5 phosphorylation. In contrast to WNV, ZIKV inhibited JAK1 and TYK2 phosphorylation following type I IFN treatment, suggesting divergent mechanisms used by these viruses to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert the immune response in infected DCs. IMPORTANCE Flaviviruses are a diverse group of insect-borne viruses responsible for numerous significant public health threats. Previously, we used a computational biology approach to define molecular signatures of antiviral DC responses following activation of innate immune signaling or infection with West Nile virus (WNV). In this work, we identify STAT5 as a regulator of DC activation and antiviral immune responses downstream of innate immune signaling that was not activated during either WNV or Zika virus (ZIKV) infection. WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and IL-4, but not GM-CSF, signaling. However, other related flaviviruses, dengue virus serotypes 1 to 4 and the yellow fever 17D vaccine strain, did not antagonize STAT5 phosphorylation. Mechanistically, WNV and ZIKV showed differential inhibition of Jak kinases upstream of STAT5, suggesting divergent countermeasures to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert antiviral immune responses in human DCs., (Copyright © 2019 American Society for Microbiology.)

West Nile virus (WNV) is a neurotropic flavivirus and the leading cause of mosquito-borne encephalitis in the United States. Recent studies in humans have found that dysfunctional T cell responses strongly correlate with development of severe WNV neuroinvasive disease. However, the contributions of human dendritic cells (DCs) in priming WNV-specific T cell immunity remains poorly understood. Here, we demonstrate that human monocyte derived DCs (moDCs) support productive viral replication following infection with a pathogenic strain of WNV. Antiviral effector gene transcription was strongly induced during the log phase of viral growth, while secretion of type I interferons (IFN) occurred with delayed kinetics. Activation of RIG-I like receptor (RLR) or type I IFN signaling prior to log phase viral growth significantly diminished viral replication, suggesting that early activation of antiviral programs can block WNV infection. In contrast to the induction of antiviral responses, WNV infection did not promote transcription or secretion of proinflammatory (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], CCL3, CCL5, and CXCL9) or T cell modulatory (IL-4, IL-12, and IL-15) cytokines. There was also minimal induction of molecules associated with antigen presentation and T cell priming, including the costimulatory molecules CD80, CD86, and CD40. Functionally, WNV-infected moDCs dampened allogenic CD4 and CD8 T cell activation and proliferation. Combining these observations, we propose a model whereby WNV subverts human DC activation to compromise priming of WNV-specific T cell immunity. IMPORTANCE West Nile virus (WNV) is an encephalitic flavivirus that remains endemic in the United States. Previous studies have found dysfunctional T cell responses correlate to severe disease outcomes during human WNV infection. Here, we sought to better understand the ability of WNV to program human dendritic cells (DCs) to prime WNV-specific T cell responses. While productive infection of monocyte-derived DCs activated antiviral and type I interferon responses, molecules associated with inflammation and programming of T cells were minimally induced. Functionally, WNV-infected DCs dampened T cell activation and proliferation during an allogeneic response. Combined, our data support a model whereby WNV infection of human DCs compromises WNV-specific T cell immunity., (Copyright © 2019 American Society for Microbiology.)

Liquid-chromatography mass spectrometry is commonly used to identify and quantify metabolites from biological samples to gain insight into human physiology and pathology. Metabolites and their abundance in biological samples are labile and sensitive to variations in collection conditions, handling and processing. Variations in sample handling could influence metabolite levels in ways not related to biology, ultimately leading to the misinterpretation of results. For example, anticoagulants and preservatives modulate enzyme activity and metabolite oxidization. Temperature may alter both enzymatic and non-enzymatic chemistry. The potential for variation induced by collection conditions is particularly important when samples are collected in remote locations without immediate access to specimen processing. Data are needed regarding the variation introduced by clinical sample collection processes to avoid introducing artifact biases. In this study, we used metabolomics and lipidomics approaches paired with univariate and multivariate statistical analyses to assess the effects of anticoagulant, temperature, and time on healthy human plasma samples collected to provide guidelines on sample collection, handling, and processing for vaccinology. Principal component analyses demonstrated clustering by sample collection procedure and that anticoagulant type had the greatest effect on sample metabolite variation. Lipids such as glycerophospholipids, acylcarnitines, sphingolipids, diacylglycerols, triacylglycerols, and cholesteryl esters are significantly affected by anticoagulant type as are amino acids such as aspartate, histidine, and glutamine. Most plasma metabolites and lipids were unaffected by storage time and temperature. Based on this study, we recommend samples be collected using a single anticoagulant (preferably EDTA) with sample processing at <24 h at 4 °C.

Purpose: To validate differences in protein levels between good and poor prognosis American Joint Committee on Cancer (AJCC) stage III melanoma patients and compile a protein panel to stratify patient risk., Experimental Design: Protein extracts from melanoma metastases within lymph nodes in patients with stage III disease with good (n = 16, >4 years survival) and poor survival (n = 14, <2 years survival) were analyzed by selected reaction monitoring (SRM). Diagonal Linear Discriminant Analysis (DLDA) was performed to generate a protein biomarker panel., Results: SRM analysis identified ten proteins that were differentially abundant between good and poor prognosis stage III melanoma patients. The ten differential proteins were combined with 22 proteins identified in our previous work. A panel of 14 proteins was selected by DLDA that was able to accurately classify patients into prognostic groups based on levels of these proteins., Conclusions and Clinical Relevance: The ten differential proteins identified by SRM have biological significance in cancer progression. The final signature of 14 proteins identified by SRM could be used to identify AJCC stage III melanoma patients likely to have poor outcomes who may benefit from adjuvant systemic therapy., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model affects neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Oncolytic viruses pose many questions in their use in cancer therapy. In this study, we assessed the potential of mpJX-594 (mouse-prototype JX-594), a replication-competent vaccinia virus administered by intravenous injection, to target the tumor vasculature, produce immune activation and tumor cell killing more widespread than the infection, and suppress invasion and metastasis. These actions were examined in RIP-Tag2 transgenic mice with pancreatic neuroendocrine tumors that developed spontaneously and progressed as in humans. mpJX-594 initially infected tumor vascular endothelial cells, leading to vascular pruning and prolonged leakage in tumors but not in normal organs; parallel effects were observed in U87 gliomas. Viral infection spread to tumor cells, where tumor cell killing was much more widespread than the infection. Widespread tumor cell killing at 5 days was prevented by depletion of CD8 + T lymphocytes and did not require GM-CSF, as mpJX-594 variants that expressed human, mouse, or no GM-CSF produced equivalent amounts of killing. The antivascular, antitumor, and antimetastatic effects of mpJX-594 were amplified by concurrent or sequential administration of sunitinib, a multitargeted receptor tyrosine kinase inhibitor. These effects were not mimicked by selective inhibition of VEGFR2 despite equivalent vascular pruning, but were accompanied by suppression of regulatory T cells and greater influx of activated CD8 + T cells. Together, our results showed that mpJX-594 targets tumor blood vessels, spreads secondarily to tumor cells, and produces widespread CD8 + T-cell-dependent tumor cell killing in primary tumors and metastases, and that these effects can be amplified by coadministration of sunitinib. Significance: These findings reveal multiple unrecognized features of the antitumor properties of oncolytic vaccinia viruses, all of which can be amplified by the multitargeted kinase inhibitor sunitinib. Cancer Res; 78(4); 922-37. ©2017 AACR ., (©2017 American Association for Cancer Research.)

During July 2016-January 2017, two unrelated measles cases were identified in the Denver, Colorado area after patients traveled to countries with endemic measles transmission. Each case resulted in multiple exposures at health care facilities and public venues, and activated an immediate and complex response by local and state public health agencies, with activities led by the Tri-County Health Department (TCHD), which serves Adams, Arapahoe, and Douglas counties. To track the economic burden associated with investigating and responding to single measles cases, personnel hours and supply costs incurred during each investigation were tracked prospectively. No secondary cases of measles were identified in either investigation. Postexposure prophylaxis (PEP) was administered to 31 contacts involving the first case; no contacts of the second case were eligible for PEP because of a delay in diagnosing measles disease. Public health costs of disease investigation in the first and second case were estimated at $49,769 and $18,423, respectively. Single measles cases prompted coordinated public health action and were costly and resource-intensive for local public health agencies.

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that is causally linked to severe neonatal birth defects, including microcephaly, and is associated with Guillain-Barre syndrome in adults. Dendritic cells (DCs) are an important cell type during infection by multiple mosquito-borne flaviviruses, including dengue virus, West Nile virus, Japanese encephalitis virus, and yellow fever virus. Despite this, the interplay between ZIKV and DCs remains poorly defined. Here, we found human DCs supported productive infection by a contemporary Puerto Rican isolate with considerable variability in viral replication, but not viral binding, between DCs from different donors. Historic isolates from Africa and Asia also infected DCs with distinct viral replication kinetics between strains. African lineage viruses displayed more rapid replication kinetics and infection magnitude as compared to Asian lineage viruses, and uniquely induced cell death. Infection of DCs with both contemporary and historic ZIKV isolates led to minimal up-regulation of T cell co-stimulatory and MHC molecules, along with limited secretion of inflammatory cytokines. Inhibition of type I interferon (IFN) protein translation was observed during ZIKV infection, despite strong induction at the RNA transcript level and up-regulation of other host antiviral proteins. Treatment of human DCs with RIG-I agonist potently restricted ZIKV replication, while type I IFN had only modest effects. Mechanistically, we found all strains of ZIKV antagonized type I IFN-mediated phosphorylation of STAT1 and STAT2. Combined, our findings show that ZIKV subverts DC immunogenicity during infection, in part through evasion of type I IFN responses, but that the RLR signaling pathway is still capable of inducing an antiviral state, and therefore may serve as an antiviral therapeutic target., Competing Interests: The authors have declared that no competing interests exist.

A novel mode of SmI2 activation has been developed using ureates as reaction promoters. Several ureates formed by treatment of the corresponding ureas with n-BuLi have been shown to activate SmI2 to a substantial extent toward the reduction of 1-chlorodecane. Complexes formed from SmI2 and various ureates have been shown to be useful for the reduction of a variety of organohalides, including substrates of low reactivity such as aryl fluorides. Because of ease of synthesis and low molecular weight, the conjugate base of triethylurea (TEU(-)) was of primary focus. Visible spectroscopy and reactivity data are consistent with the hypothesis that the same complex is being formed when SmI2 is combined with either 2 or 4 equiv of TEU(-), in spite of the greater reactivity of SmI2/4 TEU(-) with some alkyl halides. We propose that the active reductant is an N,O chelate formed between SmI2 and 2 equiv of TEU(-).

The recent Zika virus (ZIKV) outbreak in Brazil has been directly linked to increased cases of microcephaly in newborns. Current evidence indicates that ZIKV is transmitted vertically from mother to fetus. However, the mechanism of intrauterine transmission and the cell types involved remain unknown. We demonstrate that the contemporary ZIKV strain PRVABC59 (PR 2015) infects and replicates in primary human placental macrophages, called Hofbauer cells, and to a lesser extent in cytotrophoblasts, isolated from villous tissue of full-term placentae. Viral replication coincides with induction of type I interferon (IFN), pro-inflammatory cytokines, and antiviral gene expression, but with minimal cell death. Our results suggest a mechanism for intrauterine transmission in which ZIKV gains access to the fetal compartment by directly infecting placental cells and disrupting the placental barrier., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) is a key downstream effector of mTOR complex 1 (mTORC1) that represses cap-dependent mRNA translation initiation by sequestering the translation initiation factor eIF4E. Reduced mTORC1 signaling is associated with life span extension and improved metabolic homeostasis, yet the downstream targets that mediate these benefits are unclear. Here, we demonstrated that enhanced 4E-BP1 activity in mouse skeletal muscle protects against age- and diet-induced insulin resistance and metabolic rate decline. Transgenic animals displayed increased energy expenditure; altered adipose tissue distribution, including reduced white adipose accumulation and preserved brown adipose mass; and were protected from hepatic steatosis. Skeletal muscle-specific 4E-BP1 mediated metabolic protection directly through increased translation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and enhanced respiratory function. Non-cell autonomous protection was through preservation of brown adipose tissue metabolism, which was increased in 4E-BP1 transgenic animals during normal aging and in a response to diet-induced type 2 diabetes. Adipose phenotypes may derive from enhanced skeletal muscle expression and secretion of the known myokine FGF21. Unlike skeletal muscle, enhanced adipose-specific 4E-BP1 activity was not protective but instead was deleterious in response to the same challenges. These findings indicate that regulation of 4E-BP1 in skeletal muscle may serve as an important conduit through which mTORC1 controls metabolism.

Signal transduction pathways play diverse, context-dependent roles in vertebrate development. In studies of human embryonic stem cells (hESCs), conflicting reports claim Wnt/β-catenin signaling promotes either self-renewal or differentiation. We use a sensitive reporter to establish that Wnt/β-catenin signaling is not active during hESC self-renewal. Inhibiting this pathway over multiple passages has no detrimental effect on hESC maintenance, whereas activating signaling results in loss of self-renewal and induction of mesoderm lineage genes. Following exposure to pathway agonists, hESCs exhibit a delay in activation of β-catenin signaling, which led us to postulate that Wnt/β-catenin signaling is actively repressed during self-renewal. In support of this hypothesis, we demonstrate that OCT4 represses β-catenin signaling during self-renewal and that targeted knockdown of OCT4 activates β-catenin signaling in hESCs. Using a fluorescent reporter of β-catenin signaling in live hESCs, we observe that the reporter is activated in a very heterogeneous manner in response to stimulation with Wnt ligand. Sorting cells on the basis of their fluorescence reveals that hESCs with elevated β-catenin signaling express higher levels of differentiation markers. Together these data support a dominant role for Wnt/β-catenin signaling in the differentiation rather than self-renewal of hESCs.

The electrochemical and spectrophotometric characterization of the complex formed from samarium diiodide and 4 equiv of tripyrrolidinophosphoric acid triamide (TPPA) is presented. Kinetic studies indicate that the SmI(2)/TPPA complex possesses reactivity greater than the complex formed between samarium diiodide and 4 equiv of HMPA. Examples of the use of SmI(2)/TPPA in synthesis are presented.

Recommended treatment for stage Ta T1 bladder cancer is instillation of a chemotherapeutic agent within 6 hours of transurethral resection of bladder tumor based on recent review of literature. This practice has been adopted by the urology department at Westmead Hospital, Sydney, Australia, where epirubicin is instilled intraoperatively. The practical implementation of the process is described.

Langerhans cell histiocytosis (LCH) is a rare disorder which frequently involves the lungs of affected adults. Recent evidence suggests it is a clonal neoplastic disorder. Prognosis in this disease is variable, but in its multisystem form or when associated with progressive respiratory dysfunction, prognosis is poor. Recent case reports and a phase II trial of the antimonocyte drug 2-chlorodeoxy-adenosine (2CDA) have described success in treating LCH. We used 2CDA to treat a young Australian man with LCH involving lungs and bone. A complete symptomatic remission was achieved with no evidence of recurrence some 5 years after completion of chemotherapy.

Objective: Members of the protein kinase C (PKC) family are important mediators of cell signaling underlying multiple aspects of myocardial function. Activation of the betaII isoform of PKC is thought to be involved in the development of congestive heart failure. To investigate the biological effect of PKC-betaII, we measured gene expression of angiotensin converting enzyme (ACE) and angiotensin II (AngII) receptors AT(1A) and AT(1B) in cardiomyocytes overexpressing PKC-betaII., Methods: An adenovirus construct expressing PKC-betaII was introduced into cultured neonatal rat ventricular myocytes (NRVMs). Western blot and in situ kinase assay was used to measure PKC-betaII level and activity in NRVMs. Real time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to measure the mRNA levels of several genes following PMA stimulation of either un-infected or ad-PKC-betaII infected cells., Results: Our data show that activation of PKC-betaII in cardiomyocytes leads to elevated expression of angiotensin-converting enzyme (ACE) gene. Treatment of adeno-PKC-betaII infected cardiomyocytes with phorbol 12-myristate 13-acetate (PMA) resulted in an 8-fold increase of ACE mRNA expression, whereas ACE mRNA levels only increased around 2-fold in uninfected or adeno-GFP (green fluorescent protein) infected cardiomyocytes with similar PMA treatment. The induction of ACE mRNA was blocked by the PKC-beta-specific antagonist LY379196. No significant change of angiotensin II receptors AT1a and AT1b could be detected in the cardiomyocytes expressing PKC-betaII., Conclusion: These data indicate that ACE is a transcription target of PKC-betaII activation in cardiomyocytes, and also suggest a mechanism for the involvement of PKC in cardiac hypertrophy and fibrosis through increased activity of angiotensin converting enzyme in the myocardium.

Administration of the anesthetic gas N2O evoked an antinociceptive effect in two rodent antinociception paradigms. In the mouse abdominal constriction test, pretreatment with the nitric oxide synthase (NOS) inhibitor L-NG-nitroarginine (L-NOARG) caused dose-related antagonism of the antinociceptive effect of N2O but not of either morphine or trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeneacetamide methane sulfonate. This antinociceptive effect was also antagonized by systemic pretreatment with the NOS inhibitors L-NG-nitroarginine methyl ester (L-NAME) and L-NG-monomethylnitroarginine. The antagonism of N2O by L-NOARG and L-NAME was completely reversed by i.c.v. administration of L-arginine but not D-arginine. In the absence of NOS inhibition, N2O antinociception was potentiated by i.c.v. treatment with L-arginine but not D-arginine. The i.c.v. pretreatment with L-NAME also reduced N2O antinociception; this antagonism was also stereospecifically reversed by L-arginine. In the rat hot plate test, the antinociceptive response to 70% N2O was antagonized in dose-related manner by i.c.v. pretreatment with L-NOARG or L-NAME. N2O antinociception was restored by i.c.v. treatment with L-arginine but not D-arginine. However, neither L-arginine nor D-arginine alone affected N2O antinociception. These results implicate a key role for NO in the mediation of the antinociceptive effects of N2O in both mice and rats.