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Background Bariatric surgery can influence the presentation, diagnosis, and management of gastrointestinal cancers. Oesophago-Gastric (OG) malignancies in patients who have had a prior bariatric procedure have not been fully characterised. Objective To characterise OG malignancies after bariatric procedures. Setting University Hospital, United Kingdom. Methods We performed a retrospective, multi-centre observational study of patients with OG malignancies after bariatric surgery to characterise this condition. Results This study includes 170 patients from 75 centres in 25 countries who underwent bariatric procedures between 1985 and 2020. At the time of the bariatric procedure, the mean age was 50.2 ± 10 years and the mean weight 128.8 ± 28.9 kg. Females comprised 57.3% (n=98) of the population. Most (n=64) patients underwent a Roux-en-Y Gastric Bypass (RYGB) followed by Adjustable Gastric Band (AGB) (n = 46) and Sleeve Gastrectomy (SG) (n = 43). Time to cancer diagnosis after bariatric surgery was 9.5 ± 7.4 years and mean weight at diagnosis was 87.4 ± 21.9 kg. The time lag was 5.9 ± 4.1 years after SG compared to 9.4 ± 7.1 years after RYGB and 10.5 ± 5.7 years after AGB. One-third of patients presented with metastatic disease. The majority of tumours were adenocarcinoma (82.9%). Approximately 1 in 5 patients underwent palliative treatment from the outset. Time from diagnosis to mortality was under one year for most patients who died over the intervening period. Conclusions The OGMOS (Oesophago-Gastric Malignancies after Obesity/ Bariatric Surgery) study presents the largest series to date of patients developing OG malignancies after bariatric surgery and attempts to characterise this condition.

Telehealth use has increased in the setting of the COVID-19 pandemic. However, there are disparities in telehealth use based on age, income, race/ethnicity, low health, digital literacy, and limited English proficiency. There are multilevel barriers to telehealth use at the patient, health systems, telehealth portal, and policy levels. To ensure equity in telehealth services and to leverage these services to maximize the reach of health care services, concerted efforts are needed to design telehealth tools and workflows. It should include reimbursement for staff training, patient education, and technical support needed for telehealth use. Furthermore, ongoing monitoring and responsive modifications in the use of telehealth services are needed to promote telehealth equity.

Background Home death is one of the key performance indicators of the quality of palliative care service delivery. Such a measure has direct implications on everyone involved at the end of life of a dying patient, including a patient’s carers and healthcare professionals. There are no studies that focus on the views of the team of integrated inpatient and community palliative care service staff on the issue of preference of place of death of their patients. This study addresses that gap. Methods Thirty-eight participants from five disciplines in two South Australian (SA) public hospitals working within a multidisciplinary inpatient and community integrated specialist palliative care service, participated in audio-recorded focus groups and one-on-one interviews. Data were transcribed and thematically analysed. Results Two major and five minor themes were identified. The first theme focused on the role of healthcare professionals in decisions regarding place of death, and consisted of two minor themes, that healthcare professionals act to: a) mediate conversations between patient and carer; and b) adjust expectations and facilitate informed choice. The second theme, healthcare professionals’ perspectives on the preference of place of death, comprised three minor themes, identifying: a) the characteristics of the preferred place of death; b) home as a romanticised place of death; and c) the implications of idealising home death. Conclusion Healthcare professionals support and actively influence the decision-making of patients and family regarding preference of place of death whilst acting to protect the relationship between the patient and their family/carer. Further, according to healthcare professionals, home is neither always the most preferred nor the ideal place for death. Therefore, branding home death as the ideal and hospital death as a failure sets up families/carers to feel guilty if a home death is not achieved and undermines the need for and appropriateness of death in institutionalised settings.

Background Current international consensus is that ‘early’ referral to palliative care services improves cancer patient and family carer outcomes. In practice, however, these referrals are not routine. An approach which directly addresses identified barriers to early integration of palliative care is required. This protocol details a trial of a standardized model of early palliative care (Care Plus) introduced at key defined, disease-specific times or transition points in the illness for people with cancer. Introduced as a ‘whole of system’ practice change for identified advanced cancers, the key outcomes of interest are population health service use change. The aims of the study are to examine the effect of Care Plus implementation on (1) acute hospitalisation days in the last 3 months of life; (2) timeliness of access to palliative care; (3) quality and (4) costs of end of life care; and (5) the acceptability of services for people with advanced cancer. Methods Multi-site stepped wedge implementation trial testing usual care (control) versus Care Plus (practice change). The design stipulates ‘control’ periods when usual care is observed, and the process of implementing Care Plus which includes phases of planning, engagement, practice change and evaluation. During the practice change phase, all patients with targeted advanced cancers reaching the transition point will, by default, receive Care Plus. Health service utilization and unit costs before and after implementation will be collated from hospital records, and state and national health service administrative datasets. Qualitative data from patients, consumers and clinicians before and after practice change will be gathered through interviews and focus groups. Discussion The study outcomes will detail the impact and acceptability of the standardized integration of palliative care as a practice change, including recommendations for ongoing sustainability and broader implementation. Trial registration Australian New Zealand Clinical Trials Registry ACTRN 12619001703190. Registered 04 December 2019.

Cannabis is well established as possessing immune modulating activity. The objective of this study was to evaluate the anti-inflammatory properties of selected cannabis-derived terpenes and cannabinoids. Based on their activity in cannabis-chemovar studies, α-pinene, trans-nerolidol, D-limonene, linalool and phytol were the selected terpenes evaluated. The cannabinoid compounds evaluated included cannabidivarin, cannabidiol, cannabinol, cannabichromene, cannabigerol and delta-9-tetrahydrocannabinol. Human PBMC were pretreated with each compound, individually, at concentrations extending from 0.001 to 10 μM and then stimulated with CpG (plasmacytoid dendritic cell), LPS (monocytes), or anti-CD3/CD28 (T cells). Proliferation, activation marker expression, cytokine production and phagocytosis, were quantified. Of the 21 responses assayed for each compound, cannabinoids showed the greatest immune modulating activity compared to their vehicle control. Delta-9-tetrahydrocannabinol possessed the greatest activity affecting 11 immune parameters followed by cannabidivarin, cannabigerol, cannabichromene, cannabinol and cannabidiol. α-Pinene showed the greatest immune modulating activity from the selected group of terpenes, followed by linalool, phytol, trans-nerolidol. Limonene had no effect on any of the parameters tested. Overall, these studies suggest that selected cannabis-derived terpenes displayed minimal immunological activity, while cannabinoids exhibited a broader range of activity. Compounds possessing anti-inflammatory effects may be useful in decreasing inflammation associated with a range of disorders, including neurodegenerative disorders.

Urinary tract infections (UTIs) seen in the emergency department are commonly treated as an outpatient with oral antibiotics. Given that antibiotics are available for over-the-counter purchase in Mexico, there is speculation that potential misuse and overuse of antibiotics in United States-Mexico border areas could lead to antibiotic resistance patterns that would render some empiric treatments for UTIs less effective. The purpose of this study was to examine the effectiveness of Infectious Disease Society of America (IDSA) guideline-recommended antibiotics for treatment of outpatient UTI diagnosed in the emergency department. Data were collected from a county hospital on the U.S.-Mexico border with a metropolitan area of over 2 million people. Secondary analysis included frequency of urine culture isolated, resistance rates of urine pathogens, and prescriber habits.This study was a retrospective chart review of adult patients diagnosed and treated for UTI from August 1, 2019, to February 29, 2020. Culture results of included patients were analyzed against in vitro-tested antibiotics. Bacterial isolate frequency, resistance rates, and prescribing habits were collected.A total of 985 patient charts were reviewed, of which 520 patients met inclusion criteria for analysis of prescribing habits. Of these, 329 positive bacterial culture growths were included in the analysis of antibiotic resistance rates. Oral antibiotics with comparatively lower resistance rates were amoxicillin/clavulanate, cefdinir, cefuroxime, and nitrofurantoin. Oral antibiotics with notably high resistance rates included trimethoprim-sulfamethoxazole (TMP-SMX), tetracycline, ciprofloxacin, levofloxacin, and cephalexin. Nitrofurantoin was prescribed most frequently for outpatient treatment of UTI/cystitis (41.6%) while cephalexin was the most commonly prescribed antibiotic for outpatient treatment of pyelonephritis (50%).Our findings suggest that, while part of standard IDSA guidelines, fluoroquinolones and TMP-SMX are not ideal empiric antibiotics for treatment of outpatient UTI in the U.S.-Mexico border region studied due to high resistance rates. Although not listed as first line agents per current IDSA recommendations, 2nd and 3rd generation cephalosporins, and amoxicillin/clavulanate would be acceptable options given resistance patterns demonstrated in accordance with IDSA allowance for tailoring selection to local resistance. Nitrofurantoin appears to be consistent with recommendations and demonstrates a favorable resistance profile for treatment of outpatient UTI within this region.

Innate-like B cells (ILBs) are a heterogeneous population B cells which participate in innate and adaptive immune responses. This diverse subset of B cells is characterized by the expression of CD5 and has been shown to secrete high levels of immunoglobulin M (IgM) in the absence of infection or vaccination. Further, CD5

HIV infection affects an estimated 38 million people. Approximately 50% of HIV patients exhibit neurocognitive dysfunction termed HIV-Associated Neurocognitive Disorder (HAND). HAND is a consequence of chronic low-level neuroinflammation due to HIV entry into the brain. Initially, monocytes become activated in circulation and traffic to the brain. Monocytes, when activated, become susceptible to infection by HIV and can then carry the virus across the blood brain barrier. Once in the brain, activated monocytes secrete chemokines, which recruit virus-specific CD8+ T cells into the brain to further promote neuroinflammation. HAND is closely linked to systemic inflammation driven, in part, by HIV but is also due to persistent translocation of microorganisms across the GI tract. Persistent anti-viral responses in the GI tract compromise microbial barrier integrity. Indeed, HIV patients can exhibit remarkably high levels of activated (CD16+) monocytes in circulation. Recent studies, including our own, show that HIV patients using medical marijuana exhibit lower levels of circulating CD16+ monocytes than non-cannabis using HIV patients. Cannabis is a known immune modulator, including anti-inflammatory properties, mediated, in part, by ∆9-tetrahydrocannabinol (THC), as well as less characterized minor cannabinoids, such as cannabidiol (CBD), terpenes and presumably other cannabis constituents. The immune modulating activity of THC is largely mediated through cannabinoid receptors (CB) 1 and 2, with CB1 also responsible for the psychotropic properties of cannabis. Here we discuss the anti-inflammatory properties of cannabinoids in the context of HIV and propose CB2 as a putative therapeutic target for the treatment of neuroinflammation. Graphical Abstract HIV-associated neurocognitive disorder is a systemic inflammatory disease leading to activation of plasmacytoid dendritic cells, monocytes and T cells. Monocyte and CD8 T cell migration across the BBB and interaction with astrocytes promotes neurotoxic inflammatory mediators release. CB2 ligands are proposed as therapeutics capable of suppressing systemic and localized inflammation.

CD8+ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ9-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8+ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8+ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10+, MCP-1+, and IL-6+ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8+ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8+ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8+ T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8+ T cell-dependent neuroinflammatory processes by inhibiting CD8+ cell differentiation into effector cells, suppressing CD8+ effector cell function, and reducing activation of astrocytes by CD8+ T cell-derived inflammatory cytokines.

Restrictions, social isolation, and uncertainty related to the global COVID-19 pandemic have disrupted the ways that parents and children maintain family routines, health, and wellbeing. Companion animals (pets) can be a critical source of comfort during traumatic experiences, although changes to family routines, such as those caused by COVID-19, can also bring about challenges like managing undesirable pet behaviours or pet-human interactions. We aimed to examine the relationship between pet attachment and mental health for both parents and their children during the COVID-19 pandemic in Australia. A total of 1,034 parents living with a child under 18 years and a cat or dog completed an online cross-sectional survey between July and October 2020. Path analysis using multivariate linear regression was conducted to examine associations between objective COVID-19 impacts, subjective worry about COVID-19, human-pet attachment, and mental health. After adjusting for core demographic factors, stronger pet-child attachment was associated with greater child anxiety (parent-reported, p < .001). Parent-pet attachment was not associated with self-reported psychological distress (p = .42), however, parents who reported a strong emotional closeness with their pet reported greater psychological distress (p = .002). Findings highlight the role of pets during times of change and uncertainty. It is possible that families are turning to animals as a source of comfort, during a time when traditional social supports are less accessible. Alternatively, strong pet attachment is likely to reflect high levels of empathy, which might increase vulnerability to psychological distress. Longitudinal evidence is required to delineate the mechanisms underpinning pet attachment and mental health.

Study objective To determine the sensitivity of a highly sensitive bedside leukocyte esterase reagent strip (RS) for detection of spontaneous bacterial peritonitis (SBP) in emergency department (ED) ascites patients undergoing paracentesis. Methods We conducted a prospective, observational cohort study of ED ascites patients undergoing paracentesis at two academic facilities. Two practitioners, blinded to each other's results, did a bedside RS analysis of the peritoneal fluid in each patient and documented the RS reading at 3-min according to manufacturer-specified colorimetric strip reading as either “negative”, “trace”, “small”, or “large”. The primary outcome measure was sensitivity of the RS strip for SBP (absolute neutrophil count ≥ 250 cells/mm3) at the “trace” threshold (positive equals trace or greater). Results There were 330 cases enrolled, with 635 fluid analyses performed. Of these, 40 fluid samples had SBP (6%). Bedside RS had a sensitivity, specificity, positive predictive value, and negative predictive value of 95% (95% CI 82%–99%), 48% (95% CI 44%–52%), 11% (95% CI 10%–11%), and 99% (95% CI 97%–99%) respectively at the “trace” threshold for the detection of SBP. Conclusion Bedside use of the RS in ED ascites patients demonstrated high sensitivity for SBP. Given the wide confidence intervals, we cannot currently recommend it as a stand-alone test. We recommend further study with a larger number of SBP patients, potentially combining a negative RS result with low clinical suspicion to effectively rule out SBP without formal laboratory analysis.

Purpose To provide evidence-based recommendations on the management of malignant bowel obstruction (MBO) for patients with advanced cancer. Methods The Multinational Association for Supportive Care in Cancer (MASCC) MBO study group conducted a systematic review of databases (inception to March 2021) to identify studies about patients with advanced cancer and MBO that reported on the following outcomes: symptom management, bowel obstruction resolution, prognosis, overall survival, and quality of life. The review was restricted to studies published in English, but no restrictions were placed on publication year, country, and study type. As per the MASCC Guidelines Policy, the findings were synthesized to determine the levels of evidence to support each MBO intervention and, ultimately, the graded recommendations and suggestions. Results The systematic review identified 17,656 published studies and 397 selected for the guidelines. The MASCC study group developed a total of 25 evidence-based suggestions and recommendations about the management of MBO-related nausea and vomiting, bowel movements, pain, inflammation, bowel decompression, and nutrition. Expert consensus-based guidance about advanced care planning and psychosocial support is also provided. Conclusion This MASCC Guideline provides comprehensive, evidence-based recommendations about MBO management for patients with advanced cancer.

BACKGROUND: Management of juxta-renal abdominal aortic aneurysms (JRAAA) remains challenging. Both open surgical and endovascular options are feasible, however, there is lack of level 1 evidence to support one modality over the other. Operative interventions frequently necessitate either open repair with a suprarenal clamp positioning (ORSRC) or complex endovascular repair (EVAR) with fenestrated (fEVAR) or parallel stent grafts (chEVAR). AIM: The aim of this study was to compare the renal function deterioration and mortality between ORSRC and fEVAR in patients who were operated on for unruptured JRAAA at a tertiary centre. DESIGN: This was a retrospective observational study of patients. SETTING: Tertiary vascular unit in the United Kingdom. POPULATION: Patients with unruptured juxta-renal AAA. METHODS: A retrospective review of prospectively collected data was performed on patients who underwent repair for unruptured JRAAA between March 2008 and October 2019. Analysis of short and mid-term outcomes after ORSRC (occlusion of the aorta above at least one of the main renal arteries) and fEVAR was conducted. Patients who underwent open repair of JRAAA with an infrarenal clamp were excluded. Procedural data as well as data regarding complications was noted. Acute kidney injury (AKI) and chronic kidney disease were defined using the KDIGO criteria (Kidney Disease: Improving Global Outcomes). Renal impairment data up to 1 year and mortality up to 5 years was recorded. RESULTS: During the study period, 162 patients who underwent JRAAA repair met the inclusion criteria (60.5% of them having ORSRC). Approximately, 85.8% of the population were males (80.6% in the open group compared to 93.7% in the endovascular group; p=0.019). The mean age for patients in the open group was 74.0 (SD=±5.5) years compared to 76.1 (SD=±7.2) years in the fEVAR group (p=0.035). More patients in the ORSRC group were symptomatic (18.4% versus 6.3% in the fEVAR group; p=0.028) and they also had larger aneurysms compared to the fEVAR group (66.9 (±12.7) mm versus 62.6 (±8.6) mm, respectively; p=0.021). In the ORSRC group, all patients required suprarenal clamping, with clamping above only one of the main renal arteries carried out in 43 patients (44.3%) of cases. At baseline, 37.0% and 44.5% of patients had CKD stage 3 or worse in ORSRC and fEVAR groups, respectively (p=0.759). Approximately 47.6% of patients having ORSRC had evidence of acute renal impairment on post-operative day 3 compared to 12.7% of those in the endovascular group (p

Background Advance care planning involves the discussion and documentation of an individual’s values and preferences to guide their future healthcare should they lose capacity to make or communicate treatment decisions. Advance care planning can involve the individual’s completion of an Advance Care Directive (ACD), a legislated and common-law instrument which may include appointment of a substitute decision-maker and binding refusals of treatment. In South Australia, ACDs intersect in the acute-care context with the Resuscitation Plan 7-Step Pathway (7-SP), an integrated care plan written for and by clinicians, designed to organise and improve patients’ end-of-life care through the use of structured documentation. Here, we examine the perspectives of healthcare professionals (HCPs) within a hospital setting on the practical integration of ACDs and the 7-SP, exploring the perceived role, function, and value of each as they intersect to guide end-of-life care in an Australian hospital setting. Methods Qualitative data were collected via eight focus groups with a total of 74 HCPs (acute care, and oncology specialists; medical intern; general and emergency nurses; social workers) across two hospitals. Audio recordings were transcribed and thematically analysed. Results HCPs viewed ACDs as a potentially valuable means of promoting patient autonomy, but as rarely completed and poorly integrated into hospital systems. Conversely, the process and documentation of the 7-SP was perceived as providing clarity about clinicians’ responsibilities, and as a well-understood, integrated resource. Participants sometimes exhibited uncertainty around which document takes precedence if both were present. Sometimes, the routinisation of the 7-SP meant it was understood as the ‘only way’ to determine patient wishes and provide optimal end-of-life care. When this occurs, the perceived authority of ACDs, or of patients’ choice not to participate in end-of-life discussions, may be undermined. Conclusions The intersection of ACDs and the 7-SP appears problematic within acute care. Clinicians’ uncertainty as to whether an ACD or 7-SP takes precedence, and when it should do so, suggests a need for further clarity and training on the roles of these documents in guiding clinical practice, the legislative context within which specific documentation is embedded, and the dynamics associated with collaborative decision-making in end-of-life care.

Examining and addressing unmet care needs is integral to improving the provision and quality of cancer services. This review explored the prevalence of unmet supportive care needs, and factors associated with unmet need, in adults with advanced cancers (solid and hematological malignancies) and their caregivers. Electronic databases (PubMed, CINAHL, EMBASE) were searched, producing 85 papers representing 81 included studies. People with advanced cancer reported the highest unmet needs in financial, health system and information, psychological, and physical and daily living domains, whereas caregivers reported the highest unmet needs in psychological, and patient care and support domains. Distress, depression, and anxiety were associated with higher unmet needs across all unmet need domains for people with advanced cancer and their caregivers. Substantial heterogeneity in study populations and methods was observed. Findings from this review can inform targeted strategies and interventions to address these unmet needs in people with advanced cancer.

Objective In youth, a preoccupation with weight and the desire to be thinner, or drive for thinness, might persist into adulthood and predict reward-based compulsive eating and greater weight status. Methods A total of 623 women were enrolled from a prospective cohort study starting at 10 years old and assessed up to 20 years later. Drive for thinness was measured five times during adolescence. In adulthood (mean age = 39.5), drive for thinness, reward-based eating drive, and BMI were measured. Results Structural equation modeling found cumulative adolescent drive for thinness predicted higher scores for both adult drive for thinness and reward-based eating drive. Youth drive for thinness was not directly associated with adult BMI but rather indirectly through adult drive for thinness. Reward-based eating drive was not associated with adult BMI. Conclusions Drive for thinness during the critical developmental years may exert long-term effects on adulthood eating behaviors tied to greater weight gain, potentially reflecting an important early target of intervention.

Emergency medicine physicians must receive training in chest tube placement. This life-saving skill must be completed quickly and competently to prevent morbidity and mortality. Training on live patients is no longer an appropriate or acceptable practice. Current training devices have been noted to be costly, may be difficult to store, or may require time-consuming cleanup or setup.Fifteen Chest tube High-feedback Educational Simulation Trainers were created. Frames were made from wood and PVC, and soft tissue layers were designed using silicone and polyurethane foam. Nine training sites volunteered to test the model and provided feedback on the acceptability of the task trainer for skill training.Survey findings demonstrated that the model was realistic for teaching, portable, and was easy to use and maintain. In our model, the outer skin was noted to tear easily, thus limiting its use for suture training. Overall programs reported that they would use this model if it was available for the same or lower cost than current models.An inexpensive task trainer was created that was easy to store, quick to set up, durable, easy to clean, and rated as effective at training the skill of chest tube insertion.

BACKGROUND Health professionals' bereavement practices, including funeral attendance, have attracted relatively little attention from researchers. There may be a number of motivations and perceived benefits for health professionals to attend patient funerals. There are no published data comparing different groups of health professionals' perceptions of and practices in attending the funerals of their patients. OBJECTIVE To understand the attitudes and practices of health professionals toward attendance at patient funerals. DESIGN Cross-sectional nationwide online survey of attitudes and practices toward attendance at patient funerals based upon data from interviews with health professionals. PARTICIPANTS Australian health practitioners from medicine, nursing, psychology, social work, and other allied health professions (n = 1098). RESULTS Attendance at patient funerals was predicted by age, telling colleagues about own funeral attendance practices, having discussions with colleagues about funeral attendance, having long relationships with patients, and having a majority of patients at the end of life. Nonattendance was predicted by believing that if they cannot attend all funerals, they prefer not to attend any, feeling that colleagues disapprove of funeral attendance, believing that attending funerals is crossing the line between the personal and the professional, and being a psychologist. CONCLUSIONS Our findings emphasize the need for more open discussions and reflection among individuals and groups of health practitioners regarding attendance at funerals. Understanding the motivations of physicians, nurses, social workers, and other allied health practitioners to attend or not attend patient funerals is an important first step in working toward policies, protocols, and guidelines to support best practice.

Plasmacytoid dendritic cells (pDC) compose 0.2–0.5% of circulating leukocytes but play a significant role in mounting host immune responses. Elevated and chronic activation of pDC are implicated in autoimmune disease like systemic lupus erythematosus and rheumatoid arthritis. Δ(9)-tetrahydrocannabinol (THC) is a well characterized cannabinoid with potent anti-inflammatory activity, but acceptance of THC as a treatment for autoimmune disorders has been hindered due to psychotropic activity. The psychotropic effects of THC are mediated through cannabinoid receptor 1 (CB1) expressed in the central nervous system while the immunomodulatory effects of THC result from THC binding to CB1 and CB2 on immune cells. Synthetic CB2-selective agonists have been developed to explore immune modulation by cannabinoids in the absence of psychotropic effects. The goal of these studies was to determine if the CB2-selective agonists, JWH-015 and JWH-133, have comparable efficacy to THC in modulating IFNα and TNFα responses by primary human pDC. Treatment with JWH-133 and JWH-015 inhibited CpG-induced IFNα and TNFα responses by pDC. Further, the phosphorylation of IRF7, TBK1, NFκB, and IKKγ, key events in pDC activation, were suppressed by THC, JWH-133, and JWH-015. Likewise, the phosphorylation of AKT at the S473 and T308 residues were differentially modulated by treatment with THC and both JWH compounds. Collectively, these results demonstrate the potential for CB2 targeted therapeutics for treatment of inflammatory conditions involving aberrant pDC activity.

Background The Accreditation Council for Graduate Medical Education expects residents to attain competency in systems-based practice by advocating for quality patient care, working in interprofessional teams, and implementing system solutions to prevent errors. Diabetes in pregnancy was identified as an area for improvement through comprehensive interdisciplinary and interprofessional care. Objective An interdisciplinary and interprofessional workshop was created by 3 regional academic institutions to improve collaborative practice, clinical knowledge, and clinical judgment of residents. Methods A workshop consisting of 4 clinical simulation stations for ultrasound assessment, glycemic control, hyperglycemic emergencies, and macrosomia complications was designed to address gaps in quality of care. Workshop participants were residents from 6 programs and students in nursing, pharmacy, and sonography. Attitude and clinical knowledge were measured preworkshop and postworkshop, and at 3-month and 6- to 7-month follow-up. Results There were increases in average clinical knowledge scores across time points from residents: 56.4% preworkshop, 64.8% postworkshop, 66.0% at 3-month follow-up, and 68.1% at 6- to 7-month follow-up. Additionally, participants reported positive attitudes toward interprofessional education and indicated high overall satisfaction. Conclusions Residents demonstrated improved knowledge and attitudes toward interprofessional training after participating in a large-scale simulation workshop focused on the care of patients with diabetes in pregnancy.

Current advances in combined antiretroviral therapy have rendered HIV infection a chronic, manageable disease; however, the problem of persistent immune activation still remains despite treatment. The immune cell receptor SLAMF7 has been shown to be upregulated in diseases characterized by chronic immune activation. In this study, we studied the function of the SLAMF7 receptor in immune cells of HIV patients and the impacts of SLAMF7 signaling on peripheral immune activation. We observed increased frequencies of SLAMF7+ PBMCs in HIV+ individuals in a clinical phenotype-dependent manner, with discordant and long-term nonprogressor patients showing elevated SLAMF7 levels, and elite controllers showing levels comparable to healthy controls. We also noted that SLAMF7 was sensitive to IFN-⍺ stimulation, a factor elevated during HIV infection. Further studies revealed SLAMF7 to be a potent inhibitor of the monocyte-derived proinflammatory chemokine CXCL10 (IP-10) and other CXCR3 ligands, except in a subset of HIV+ patients termed SLAMF7 silent (SF7S). Studies utilizing small molecule inhibitors revealed that the mechanism of CXCL10 inhibition is independent of known SLAMF7 binding partners. Furthermore, we determined that SLAMF7 activation on monocytes is able to decrease their susceptibility to HIV-1 infection in vitro via downregulation of CCR5 and upregulation of the CCL3L1 chemokine. Finally, we discovered that neutrophils do not express SLAMF7, are CXCL10+ at baseline, are able to secrete CXCL10 in response to IFN-⍺ and LPS, and are nonresponsive to SLAMF7 signaling. These findings implicate the SLAMF7 receptor as an important regulator of IFN-⍺–driven innate immune responses during HIV infection.

Each herpesvirus family establishes latency in a unique cell type. Since herpesviruses genomes are maintained as episomes, the viruses need to devise mechanisms to retain the latent genome during cell division., Human cytomegalovirus (HCMV) microRNAs play essential roles in latency and reactivation in CD34+ hematopoietic progenitor cells (HPCs) via regulation of viral and cellular gene expression. In the present study, we show that HCMV miR-US25-1 targets RhoA, a small GTPase required for CD34+ HPC self-renewal, proliferation, and hematopoiesis. Expression of miR-US25-1 impairs signaling through the nonmuscle myosin II light chain, which leads to a block in cytokinesis and an inhibition of proliferation. Moreover, infection with an HCMV mutant lacking miR-US25-1 resulted in increased proliferation of CD34+ HPCs and a decrease in the proportion of genome-containing cells at the end of latency culture. These observations provide a mechanism by which HCMV limits proliferation to maintain latent viral genomes in CD34+ HPCs.

Xenobiotic-mediated activation of the aryl hydrocarbon receptor (AHR) is immunotoxic in a number of immune cell types, with the B cell being a well-established sensitive target. Recent advances have provided evidence that the B cell repertoire is a heterogeneous population, with subpopulations exhibiting vastly different cellular and functional phenotypes. Recent work from our laboratory identified the T cell specific kinase lck as being differentially regulated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a potent activator of AHR. While LCK is primarily expressed in T cells, a subset of CD5+ B cells also express LCK. CD5 positivity describes a broad class of B lymphocytes termed innate-like B cells (ILBs) that are critical mediators of innate immunity through constitutive secretion of polyvalent natural immunoglobulin M (IgM). We hypothesized that CD5+ ILBs may be sensitive to AHR-mediated immunotoxicity. Indeed, when CD5+ B cells were isolated from the CD19+ pool and treated with TCDD, they showed increased suppression of the CD40 ligand-induced IgM response compared to CD5- B cells. Further, characterization of the CD5+ population indicated increased basal expression of AHR, AHR repressor (AHRR), and cytochrome p450 family 1 member a1 (CYP1A1). Indeed the levels of AHR-mediated suppression of the IgM response from individual donors strongly correlated with the percentage of the B cell pool that was CD5+, suggesting that CD5+ B cells are more sensitive to AHR-mediated impairment. Together these data highlight the sensitive nature of CD5+ ILBs to AHR activation and provide insight into mechanisms associated with AHR activation in human B cells.

Importance Annually, US schools screen millions of students’ body mass index (BMI) and report the results to parents, with little experimental evidence on potential benefits and harms. Objective To determine the impact of school-based BMI reporting on weight status and adverse outcomes (weight stigmatization and weight-related perceptions and behaviors) among a diverse student population. Design, Setting, and Participants Cluster randomized clinical trial. The Fit Study (2014-2017) randomized 79 California schools to BMI screening and reporting (group 1), BMI screening only (group 2), or control (no BMI screening or reporting [group 3]) in grades 3 to 8. The setting was California elementary and middle schools. Students in grades 3 to 7 at baseline participated for up to 3 years. A modified intent-to-treat protocol was used. Data analysis was conducted from April 13, 2017, to March 26, 2020. Interventions School staff assessed BMI each spring among students in groups 1 and 2. Parents of students in group 1 were sent a BMI report each fall for up to 2 years. Main Outcomes and Measures Changes in BMIzscore and in adverse outcomes (based on surveys conducted each fall among students in grades 4 to 8) from baseline to 1 and 2 years of follow-up. Results A total of 28 641 students (14 645 [51.1%] male) in grades 3 to 7 at baseline participated in the study for up to 3 years. Among 6534 of 16 622 students with a baseline BMI in the 85th percentile or higher (39.3%), BMI reporting had no effect on BMIzscore change (−0.003; 95% CI, −0.02 to 0.01 at 1 year and 0.01; 95% CI, −0.02 to 0.03 at 2 years). Weight dissatisfaction increased more among students having BMI screened at school (8694 students in groups 1 and 2) than among control participants (5674 students in group 3). Results of the effect of BMI reporting on other adverse outcomes were mixed: compared with the control (group 3), among students weighed at school (groups 1 and 2), weight satisfaction declined more after 2 years (−0.11; 95% CI, −0.18 to −0.05), and peer weight talk increased more after 1 year (0.05; 95% CI, 0.01-0.09); however, concerning weight control behaviors declined more after 1 year (−0.06; 95% CI, −0.10 to −0.02). Conclusions and Relevance Body mass index reports alone do not improve children’s weight status and may decrease weight satisfaction. To improve student health, schools should consider investing resources in evidence-based interventions. Trial Registration ClinicalTrials.gov Identifier:NCT02088086

Immunodeficient mice engrafted with human tissues provide a robust model for the in vivo investigation of human-restricted viruses such as human cytomegalovirus (HCMV). Several humanized mouse models have been developed and improved over the last 30 years. Here, we describe a protocol for the transplant of human hematopoietic stem cells with autologous fetal liver and thymic tissues into NOD.Cg-Prkdc

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level by binding to sites within the 3' untranslated regions of messenger RNA (mRNA) transcripts. The discovery of this completely new mechanism of gene regulation necessitated the development of a variety of techniques to further characterize miRNAs, their expression, and function. In this chapter, we will discuss techniques currently used in the miRNA field to detect, express and inhibit miRNAs, as well as methods used to identify and validate their targets, specifically with respect to the miRNAs encoded by human cytomegalovirus.

Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals and is a significant problem during transplantation. The virus can establish a latent infection in CD34+ hematopoietic progenitor cells (HPCs) and periodically reactivate to cause disease in the absence of an intact immune system., Human cytomegalovirus (HCMV) infection of myeloid lineage cells, such as CD34+ hematopoietic progenitor cells (HPCs) or monocytes, results in the upregulation of antiapoptotic cellular proteins that protect the newly infected cells from programmed cell death. The mechanisms used by HCMV to regulate proapoptotic cellular proteins upon infection of CD34+ HPCs have not been fully explored. Here, we show that HCMV utilizes pUL7, a secreted protein that signals through the FLT3 receptor, and miR-US5-1 and miR-UL112-3p to reduce the abundance and activity of the proapoptotic transcription factor FOXO3a at early times after infection of CD34+ HPCs. Regulation of FOXO3a by pUL7, miR-US5-1, and miR-UL112 results in reduced expression of the proapoptotic BCL2L11 transcript and protection of CD34+ HPCs from virus-induced apoptosis. These data highlight the importance of both viral proteins and microRNAs (miRNAs) in protecting CD34+ HPCs from apoptosis at early times postinfection, allowing for the establishment of latency and maintenance of viral genome-containing cells. IMPORTANCE Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals and is a significant problem during transplantation. The virus can establish a latent infection in CD34+ hematopoietic progenitor cells (HPCs) and periodically reactivate to cause disease in the absence of an intact immune system. What viral gene products are required for successful establishment of latency is still not fully understood. Here, we show that both a viral protein and viral miRNAs are required to prevent apoptosis after infection of CD34+ HPCs. HCMV pUL7 and miRNAs miR-US5-1 and miR-UL112-3p act to limit the expression and activation of the transcription factor FOXO3a, which in turn reduces expression of proapoptotic gene BCL2L11 and prevents virus-induced apoptosis in CD34+ HPCs.

In human cytomegalovirus (HCMV)-seropositive patients, CD34(+) hematopoietic progenitor cells (HPCs) provide an important source of latent virus that reactivates following cellular differentiation into tissue macrophages. Multiple groups have used primary CD34(+) HPCs to investigate mechanisms of viral latency. However, analyses of mechanisms of HCMV latency have been hampered by the genetic variability of CD34(+) HPCs from different donors, availability of cells, and low frequency of reactivation. In addition, multiple progenitor cell types express surface CD34, and the frequencies of these populations differ depending on the tissue source of the cells and culture conditions in vitro. In this study, we generated CD34(+) progenitor cells from two different embryonic stem cell (ESC) lines, WA01 and WA09, to circumvent limitations associated with primary CD34(+) HPCs. HCMV infection of CD34(+) HPCs derived from either WA01 or WA09 ESCs supported HCMV latency and induced myelosuppression similar to infection of primary CD34(+) HPCs. Analysis of HCMV-infected primary or ESC-derived CD34(+) HPC subpopulations indicated that HCMV was able to establish latency and reactivate in CD38(+) CD90(+) and CD38(+/low) CD90(−) HPCs but persistently infected CD38(−) CD90(+) cells to produce infectious virus. These results indicate that ESC-derived CD34(+) HPCs can be used as a model for HCMV latency and that the virus either latently or persistently infects specific subpopulations of CD34(+) cells. IMPORTANCE Human cytomegalovirus infection is associated with severe disease in transplant patients and understanding how latency and reactivation occur in stem cell populations is essential to understand disease. CD34(+) hematopoietic progenitor cells (HPCs) are a critical viral reservoir; however, these cells are a heterogeneous pool with donor-to-donor variation in functional, genetic, and phenotypic characteristics. We generated a novel system using embryonic stem cell lines to model HCMV latency and reactivation in HPCs with a consistent cellular background. Our study defined three key stem cell subsets with differentially regulated latent and replicative states, which provide cellular candidates for isolation and treatment of transplant-mediated disease. This work provides a direction toward developing strategies to control the switch between latency and reactivation.

This scoping review examines the strength of evidence for the effectiveness of public policy-led place-based initiatives designed to improve outcomes for disadvantaged children, their families and the communities in which they live. Study designs and methods for evaluating such place-based initiatives were assessed, along with the contexts in which initiatives were implemented and evaluated. Thirty-two reports relating to 12 initiatives were included. Eleven initiatives used a quasi-experimental evaluation to assess impact, although there were considerable design variations within this. The remaining initiative used a pre- and post- evaluation design. Place-based initiatives by definition aim to improve multiple and interrelated outcomes. We examined initiatives to determine what outcomes were measured and coded them within the five domains of pregnancy and birth, child, parent, family and community. Across the 83 outcomes reported in the 11 studies with a comparison group, 30 (36.4%) demonstrated a positive outcome, and all but one initiative demonstrated a positive outcome in at least one outcome measure. Of the six studies that examined outcomes more than once post baseline, 10 from 38 outcomes (26.3%) demonstrated positive sustained results. Many initiatives were affected by external factors such as policy and funding changes, with unknown impact on their effectiveness. Despite the growth of place-based initiatives to improve outcomes for disadvantaged children, the evidence for their effectiveness remains inconclusive.

Background Of almost 5.7 million Americans with heart failure, 80% are 65 years and older. Empowerment approaches facilitating recognition of personal and social contextual resources may improve well-being in this vulnerable population. Objective This research evaluated the feasibility of the Health Empowerment Intervention (HEI) in older adults with heart failure, including effects on health empowerment, purposeful participation, self-management, functional health, and well-being. Methods Twenty older adults with heart failure were randomly assigned to HEI or Attention Control conditions. The HEI consisted of 6 weekly sessions based on the Health Empowerment Theory. Outcomes were measured at baseline and at 6 weeks. Results Feasibility of the HEI was supported; participants realized significant improvement in health empowerment and purposeful participation in goal attainment.ConclusionsThis research supports the feasibility of the HEI and provides a basis for continued evaluation.

Background: Despite the increasing number of people requiring palliative care at home, there is limited evidence on how home-based palliative care is best practised. Aim: The aim of this participatory qualitative study is to determine the characteristics that contribute to brilliant home-based palliative care. Design: This study was inspired by the brilliance project – an initiative to explore how positive organisational scholarship in healthcare can be used to study brilliant health service management from the viewpoint of patients, families, and clinicians. The methodology of positive organisational scholarship in healthcare was combined with video-reflexive ethnography. Setting/participants: Home-based specialist palliative care services across two Australian states participated in the study. Clinicians were able to take part in the study at different levels. Pending their preference, this could involve video-recording of palliative care, facilitating and/or participating in reflexive sessions to analyse and critique the recordings, identifying the characteristics that contribute to brilliant home-based palliative care, and/or sharing the findings with others. Results: Brilliance in home-based palliative care is contingent on context and is conceptualised as a variety of actions, people, and processes. Care is more likely to be framed as brilliant when it is epitomised: anticipatory aptitude and action; a weave of commitment; flexible adaptability; and/or team capacity-building. Conclusion: This study is important because it verifies the characteristics of brilliant home-based palliative care. Furthermore, these characteristics can be adapted for use within other services.

BACKGROUND Our objective was to examine the association between school wellness committees and implementation of nutrition wellness policies and children's weight status and obesity-related dietary outcomes. METHODS A cross-sectional study was conducted of 4790 children aged 4-15 years recruited from 130 communities in the Healthy Communities Study. Multilevel statistical models assessed associations between school wellness policies and anthropometric (body mass index z-score [BMIz]) and nutrition measures, adjusting for child and community-level covariates. RESULTS Children had lower BMI z-scores (-0.11, 95% confidence interval [CI]: -0.19, -0.03) and ate breakfast more frequently (0.14 days/week, 95% CI: 0.02-0.25) if attending a school with a wellness committee that met once or more in the past year compared to attending a school with a wellness committee that did not meet/did not exist. Children had lower added sugar (p < .0001), lower energy-dense foods (p = .0004), lower sugar intake from sugar-sweetened beverages (p = .0002), and lower dairy consumption (p = .001) if attending a school with similar or stronger implementation of the nutrition components of the school wellness policies compared to other schools in the district. CONCLUSIONS A more active wellness committee was associated with lower BMI z-scores in US schoolchildren. Active school engagement in wellness policy implementation appears to play a positive role in efforts to reduce childhood obesity.

The risk of chronic disease is widespread. In the United States, nearly 60% of the population has at least 1 chronic health condition. Among the most common are cardiovascular disease, obesity, and type 2 diabetes, all of which are associated with poor diet quality. At these levels, strategies are needed that can effectively impact widespread dietary practices and population nutrition and health. Increasingly, the food environment has been recognized as a powerful influencer of the quality of diets of community members. Local nutrition policies can effectively change the food environment in ways that increase access and affordability to healthful food and beverage choices and reduce access to and affordability of less healthful food and beverage choices. While much of the effort to change dietary practices is focused on education, this paper discusses 3 strategies by which nutrition policy can improve the dietary practices of individuals: (1) promoting healthy food purchases in the retail food environment, (2) improving access to healthy foods and beverages in food assistance programs, and (3) reducing access to less healthy foods and beverages through the use of taxes. Often enhanced by educational efforts, these strategies, used by government, business, and voluntary organizations, together make it easier for the public to make healthful dietary choices and thereby reduce the risk of chronic disease.

The aryl hydrocarbon receptor (AHR) is a cytosolic ligand-activated transcription factor involved in xenobiotic sensing, cell cycle regulation, and cell development. In humans, the activation of AHR by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AHR-ligand, impairs the secretion of immunoglobulin M (IgM) to suppress humoral immunity. However, the mechanisms bridging the activation of AHR and the impairment of IgM secretion by human primary B cells remain poorly understood. Recent transcriptomic analysis revealed upregulation of lymphocyte-specific protein tyrosine kinase (LCK) in AHR-activated human primary B cells. LCK is a well-characterized tyrosine kinase that phosphorylates critical signaling proteins involved in activation and cytokine production in T cells. Conversely, the role of LCK in human primary B cells is not well understood. In the current studies, we have verified the transcriptomic finding by detecting AHR-mediated upregulation of LCK protein in human primary B cells. We also confirmed the role of AHR in the upregulation of LCK by using a specific AHR antagonist, which abolished the AHR-mediated increase of LCK. Furthermore, we have confirmed the role of LCK in the AHR-mediated suppression of IgM by using LCK specific inhibitors, which restored the IgM secretion by human B cells in the presence of TCDD. Collectively, the current studies demonstrate a novel role of LCK in IgM response and provide new insights into the mechanism for AHR-mediated impairment of immunoglobulin secretion by human primary B cells.

ObjectiveTo assess produce availability, quality and price in a large sample of food stores in low-income neighbourhoods in California.DesignCross-sectional statewide survey.SettingBetween 2011 and 2015, local health departments assessed store type, WIC (Supplemental Nutrition Program for Women, Infants, and Children)/SNAP (Supplemental Nutrition Assistance Program) participation, produce availability, quality and price of selected items in stores in low-income neighbourhoods. Secondary data provided reference chain supermarket produce prices matched by county and month.tTests and ANOVA examined differences by store type; regression models examined factors associated with price.SubjectsLarge grocery stores (n231), small markets (n621) and convenience stores (n622) in 225 neighbourhoods.ResultsProduce in most large groceries was rated high quality (97 % of fruits, 98 % of vegetables), but not in convenience stores (25 % fruits, 14 % vegetables). Small markets and convenience stores participating in WIC and/or SNAP had better produce availability, variety and quality than non-participating stores. Produce prices across store types were, on average, higher than reference prices from matched chain supermarkets (27 % higher in large groceries, 37 % higher in small markets, 102 % higher in convenience stores). Price was significantly inversely associated with produce variety, adjusting for quality, store type, and SNAP and WIC participation.ConclusionsThe study finds that fresh produce is more expensive in low-income neighbourhoods and that convenience stores offer more expensive, poorer-quality produce than other stores. Variety is associated with price and most limited in convenience stores, suggesting more work is needed to determine how convenience stores can provide low-income consumers with access to affordable, high-quality produce. WIC and SNAP can contribute to the solution.

OBJECTIVE. The purposes of this article are to detail the experience of a single-center academic institution in applying the patient-centered approach to a lung cancer screening program and to examine how this approach can expand to other aspects of follow-up imaging of lung nodules. CONCLUSION. As the practice of patient-centered radiology gains attention, diagnostic radiologists are findings new ways to become more involved in patient care. A lung cancer screening program is one opportunity for radiologists to consult with and educate patients.

Following increased interest in and use of new public management (NPM), greater regulation has been introduced into many Western health systems. Yet, the effects have revealed the negative aspects of NPM. Positive organizational scholars have argued that adversity can give rise to positive deviance. Yet as a form of noncompliance, positive deviance can be difficult to examine. This methodological article demonstrates how the combined methodologies of positive organizational scholarship in healthcare (POSH) and video reflexive ethnography (VRE) can help examine positive deviance. This study illustrates the methodological utility of POSH VRE to respectfully study the impact of NPM-inspired expectations on public health clinicians, positively reframe how clinicians constructively respond to and manage obstruction, and reveal the unintended effects of NPM-inspired expectations. As a participatory methodology, POSH VRE can promote trust between researchers and clinicians, thereby unveiling instances of positive deviance to NPM in healthcare.

OBJECTIVE: Chronic immune activation and elevated numbers of circulating activated monocytes (CD16(+)) are implicated in HIV-associated neuroinflammation. The objective was to compare the level of circulating CD16(+) monocytes and interferon-γ-inducible protein 10 (IP-10) between HIV-infected cannabis users (HIV+MJ+) and non-cannabis users (HIV+MJ−), and determine whether in vitro Δ(9)-Tetrahydrocannabinol (THC), a constituent of cannabis, affected CD16 expression as well as IP-10 production by monocytes. DESIGN: The levels of circulating CD16(+) monocytes and IP-10 from HIV+MJ− and HIV+MJ+ donors were examined. In vitro experimentation using THC was performed on primary leukocytes isolated from HIV-MJ-, HIV+MJ− and HIV+MJ+ donors to determine if THC has an impact on CD16(+) monocyte and IP-10 levels. METHODS: Flow cytometry was used to measure the number of blood CD16(+) monocytes and serum IP-10 from HIV+MJ− and HIV+MJ+ donors. Peripheral blood mononuclear cells (PBMC) were isolated from HIV-MJ− and HIV+ (MJ− and MJ+) donors for in vitro THC and IFNα treatment, and CD16(+) monocytes and supernatant IP-10 were quantified. RESULTS: HIV+MJ+ donors possessed a lower level of circulating CD16(+) monocytes and serum IP-10, compared to HIV+MJ− donors. Further, monocytes from HIV+MJ+ donors were unable to induce CD16 expression when treated with in vitro IFNα, while HIV-MJ− and HIV+MJ− donors displayed pronounced CD16 induction, suggesting anti-inflammatory effects by cannabis. Lastly, in vitro THC treatment impaired CD16(−) monocyte transition to CD16(+) and monocyte-derived IP-10. CONCLUSIONS: Components of cannabis, including THC, may decelerate peripheral monocyte processes that are implicated in HIV-associated neuroinflammation.

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates biological responses to endogenous and environmental chemical cues. Increasing evidence shows that the AHR plays physiological roles in regulating development, homeostasis, and function of a variety of cell lineages in the immune system. However, the role of AHR in human B cell development has not been investigated. Toward this end, an in vitro feeder-free human B cell developmental model system was employed using human cord blood CD34+ hematopoietic stem/progenitor cells. Using this model, we found that AHR activation by the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin significantly suppressed the generation of early B cells and pro-B cells from hematopoietic stem/progenitor cells, indicating the impairment of B cell lineage specification and commitment. Addition of an AHR antagonist reversed 2,3,7,8-tetrachlorodibenzo-p-dioxin–elicited suppression of early B and pro-B cells, suggesting a role of AHR in regulating B lymphopoiesis. Gene expression analysis revealed a significant decrease in the messenger RNA level of early B cell factor 1 (EBF1) and paired box 5, two critical transcription factors directing B cell lineage specification and commitment. Additionally, binding of the ligand-activated AHR to the putative dioxin response elements in the EBF1 promoter was demonstrated by EMSAs and chromatin immunoprecipitation analysis, suggesting transcriptional regulation of EBF1 by AHR. Taken together, this study demonstrates a role for the AHR in regulating human B cell development, and it suggests that transcriptional alterations of EBF1 by the AHR are involved in the underlying mechanism.

Wait times for access to care have been of increasing interest to public health care officials, health care providers, and the public. There is a paucity of data determining whether extended wait times for melanoma surgery influence patient outcomes. This study measured the association of wait times to surgical treatment with overall survival in patients with melanoma. Population-based health administrative databases were used to identify all Ontario adults diagnosed with melanoma between 2004 and 2011, time to various treatment modalities, and death dates. Proportional hazards modeling using time-dependent covariates was used to determine the adjusted association of time from melanoma diagnosis to various post-diagnostic surgical interventions with overall survival. A total of 2573 patients were included. The 5-year overall survival was 81.1% [95% confidence interval (CI) 79.1–83.0]. Of all patients, 82.9% underwent a wide local excision (WLE) with a median wait time of 43 days [interquartile range (IQR) 24–64], 29.1% underwent a sentinel lymph node biopsy (SNB) with a median wait time of 59 days (IQR 41–81), and 35.0% underwent a lymph node dissection (LND) with a median wait time of 63 days (IQR 43–91). After adjusting for age, sex, rural residence, and risk of mortality from comorbidities, wait times to WLE [hazard ratio (HR) 0.97; 95% CI 0.87–1.08; p = 0.62], SNB [HR 1.04; 95% CI 0.68–1.59; p = 0.86], and LND [HR 0.99; 95% CI 0.89–1.11; p = 0.92] were not associated with overall survival. Overall survival for patients with melanoma was not influenced by wait times to WLE, SNB, and LND.

Introduction Delirium has a high mortality rate. Understanding predictors of prognosis in patients with delirium will aid treatment decisions and communication. This study aimed to explore variables associated with death during an established episode of delirium in palliative care when haloperidol treatment had been commenced. Methods A consecutive cohort of palliative care patients, from 14 centers across four countries, is reported. The outcome of interest was death within 14 days from commencement of haloperidol treatment for delirium. Clinicodemographic variables explored were delirium severity, age, gender, primary life limiting illness, body mass index (BMI), total daily haloperidol dose at baseline (mg), functional status, and comorbidities. Results One hundred and sixteen palliative care patients where vital status was known were included in the analysis; 45% (n = 52) died within 10 days, and 56% (n = 65) died within 14 days. In multivariate analyses no clinical or demographic variables predicted death, apart from lower BMI in noncancer patients. Conclusion This study has shown a very high mortality rate within two weeks of commencing haloperidol for delirium in palliative care, with no clear clinical predictors for those with a higher chance of dying. Having a higher BMI offered some benefit in survival, but only in noncancer patients. When delirium occurs in advanced illness, discussion should be initiated about the gravity of the clinical situation.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is a strong AHR agonist, causes significant suppression of human B cell activation and differentiation. The current studies describe the identification of Src homology phosphatase 1 (SHP-1) encoded by the gene PTPN6 as a putative regulator of TCDD-mediated suppression of B cell activation. Shp-1 was initially identified through a genome-wide analysis of AHR binding in mouse B cells in the presence of TCDD. The binding of AHR to the PTPN6 promoter was further confirmed using electrophoretic mobility shift assays in which, specific binding of AHR was detected at four putative DRE sites within PTPN6 promoter. Time-course measurements performed in human B cells highlighted a significant increase in SHP-1 mRNA and protein levels in the presence of TCDD. The changes in the protein levels of SHP-1 were also observed in a TCDD concentration-dependent manner. The increase in SHP-1 levels was also seen to occur due to a change in early signaling events in the presence of TCDD. We have shown that BCL-6 regulates B cell activation by repressing activation marker CD80 in the presence of TCDD. TCDD-treatment led to a significant increase in the double positive (SHP-1hi BCL-6hi) population. Interestingly, treatment of naive human B cells with SHP-1 inhibitor decreased BCL-6 protein levels suggesting possible regulation of BCL-6 by SHP-1 for the first time. Collectively, these results suggest that SHP-1 is regulated by AHR in the presence of TCDD and may, in part through BCL-6, regulate TCDD-mediated suppression of human B cell activation.

Vaccines based on cytomegalovirus (CMV) demonstrate protection in animal models of infectious disease and cancer. Vaccine efficacy is associated with the ability of CMV to elicit and indefinitely maintain high frequencies of circulating effector memory T cells (TEM) providing continuous, life-long anti-pathogen immune activity. To allow for the clinical testing of human CMV (HCMV)-based vaccines we constructed and characterized as a vector backbone the recombinant molecular clone TR3 representing a wildtype genome. We demonstrate that TR3 can be stably propagated in vitro and that, despite species incompatibility, recombinant TR3 vectors elicit high frequencies of TEM to inserted antigens in rhesus macaques (RM). Live-attenuated versions of TR3 were generated by deleting viral genes required to counteract intrinsic and innate immune responses. In addition, we eliminated subunits of a viral pentameric glycoprotein complex thus limiting cell tropism. We show in a humanized mouse model that such modified vectors were able to establish persistent infection but lost their ability to reactivate from latency. Nevertheless, attenuated TR3 vectors preserved the ability to elicit and maintain TEM to inserted antigens in RM. We further demonstrate that attenuated TR3 can be grown in approved cell lines upon elimination of an anti-viral host factor using small interfering RNA, thus obviating the need for a complementing cell line. In sum, we have established a versatile platform for the clinical development of live attenuated HCMV-vectored vaccines and immunotherapies.

Cannabis is widely used in the United States, with an estimated prevalence of 9.5%. Certain cannabinoids in Cannabis sativa, Δ(9)-tetrahydrocannabinol (THC) in particular, possess immune-modulating and anti-inflammatory activity. Depending on the context, the anti-inflammatory activity of cannabinoids may be beneficial (e.g., in treating inflammatory diseases) or detrimental to normal immune defense against pathogens. The potential beneficial effect of cannabinoids on chronic neuroinflammation has gained recent attention. Monocyte migration to the brain has been implicated as a key event in chronic neuroinflammation and in the etiology of central nervous system diseases including viral infection (e.g., human immunodeficiency virus–associated neurocognitive disorder). In the brain, monocytes can contribute to neuroinflammation through interactions with astrocytes, including inducing astrocyte secretion of cytokines and chemokines. In a human coculture system, monocyte-derived interleukin (IL)-1β due to Toll-like receptor 7 (TLR7) activation has been identified to promote astrocyte production of monocyte chemoattractant protein (MCP)-1 and IL-6. THC treatment of the TLR7-stimulated coculture suppressed monocyte secretion of IL-1β, resulting in decreased astrocyte production of MCP-1 and IL-6. Furthermore, THC displayed direct inhibition of monocytes, as TLR7-stimulated monocyte monocultures treated with THC also showed suppressed IL-1β production. The cannabinoid receptor 2 (CB2) agonist, JWH-015, impaired monocyte IL-1β production similar to that of THC, suggesting that THC acts, in part, through CB2. THC also suppressed key elements of the IL-1β production pathway, including IL1B mRNA levels and caspase-1 activity. Collectively, this study demonstrates that the anti-inflammatory properties of THC suppress TLR7-induced monocyte secretion of IL-1β through CB2, which results in decreased astrocyte secretion of MCP-1 and IL-6. SIGNIFICANCE STATEMENT: Because cannabis use is highly prevalent in the United States and has putative anti-inflammatory properties, it is important to investigate the effect of cannabinoids on immune cell function. Furthermore, cannabinoids have garnered particular interest due to their potential beneficial effects on attenuating viral-induced chronic neuroinflammation. This study utilized a primary human coculture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ(9)-tetrahydrocannabinol, and a cannabinoid receptor-2 selective agonist suppress specific monocyte-mediated astrocyte inflammatory responses.

Reactivation of latent Human Cytomegalovirus (HCMV) in CD34+ hematopoietic progenitor cells (HPCs) is closely linked to hematopoiesis. Viral latency requires maintenance of the progenitor cell quiescence, while reactivation initiates following mobilization of HPCs to the periphery and differentiation into CD14+ macrophages. Early growth response gene 1 (EGR-1) is a transcription factor activated by Epidermal growth factor receptor (EGFR) signaling that is essential for the maintenance of CD34+ HPC self-renewal in the bone marrow niche. Down-regulation of EGR-1 results in mobilization and differentiation of CD34+ HPC from the bone marrow to the periphery. In the current study we demonstrate that the transcription factor EGR-1 is directly targeted for down-regulation by HCMV miR-US22 that results in decreased proliferation of CD34+ HPCs and a decrease in total hematopoietic colony formation. We also show that an HCMV miR-US22 mutant fails to reactivate in CD34+ HPCs, indicating that expression of EGR-1 inhibits viral reactivation. Since EGR-1 promotes CD34+ HPC self-renewal in the bone marrow niche, HCMV miR-US22 down-regulation of EGR-1 is a necessary step to block HPC self-renewal and proliferation to induce a cellular differentiation pathway necessary to promote reactivation of virus., Author summary Human cytomegalovirus (HCMV) is a widespread herpesvirus that persists in the host and remains a significant cause of morbidity and mortality in solid organ and stem cell transplant patients. HCMV latency is complex, and the molecular mechanisms for establishment, maintenance, and reactivation from latency are poorly understood. Quiescent stem cells in the bone marrow represent a critical reservoir of latent HCMV, and the mobilization and differentiation of these cells is closely linked to viral reactivation from latency. HCMV encodes small regulatory RNAs, called miRNAs that play important roles in the regulation of viral and cellular gene expression. In this study, we show that HCMV miR-US22 targets Early growth response gene 1 (EGR-1) a host transcription factor that is necessary for stem cell quiescence and self-renewal in the bone marrow. Expression of this miR-US22 down-regulates expression of EGR-1 that reduces CD34+ HPCs proliferation and total hematopoietic colony formation. An HCMV miR-US22 mutant is unable to reactivate from latency suggesting that the ability of the miRNA to disrupt CD34+ HPC renewal in the bone marrow niche to initiate a differentiation pathway is critical for viral reactivation.

Toll-like receptor 7 (TLR7)-activation has been implicated as a significant mechanism of neuroinflammation triggered by ssRNA viruses. Infiltration of monocytes into the brain and astrocyte activation occurs during in vivo TLR7-mediated neuroinflammation. The objective here was to determine whether the TLR7 agonist, imiquimod, and interferon-alpha (IFN-α), promote monocyte-mediated astrocyte secretion of pro-inflammatory factors. Using a human primary co-culture system, we demonstrate that monocytes, together with imiquimod and IFN-α, promote astrocyte secretion of MCP-1, IL-6 and IP-10. Furthermore, TLR7-induced monocyte-derived IL-1β is critical for promoting the astrocyte response. Overall, this study provides a potential mechanism for TLR7-mediated neuroinflammation.

Objective: The purpose of this study was to determine if providing mass casualty training, utilizing the Bleeding Control for the Injured (B-Con) course would allow participants to feel more confident to provide bystander aid to wounded victims in a mass casualty incident (MCI). Design: Quasi-experimental pre-post intervention study. Setting: Participants were healthcare providers attending a trauma research conference hosted by a medical university. Interventions: Participants were given a group lecture in each of the three B-Con skill areas. These include: bleeding control with a tourniquet, bleeding control with gauze, and airway control with a jaw thrust. Participants were then divided into three groups and practiced each skill with instruction from B-Con certified trainers. Main outcomes measures: The primary outcome was scores from pre- to post-intervention in the categories of self-efficacy, perceived benefit, perceived susceptibility, perceived barriers, and perceived severity related to involvement in an MCI. Results: The study included 67 participants, all identifying as medical providers. Means in the categories of self-efficacy, perceived benefit, perceived susceptibility, perceived barriers, and perceived severity significantly increased from pre-intervention to postintervention among the paired variables. Conclusions: This study demonstrates the effectiveness of B-Con training in improving the confidence of participants. By increasing the number of persons who are trained for an MCI, there will be an increased probability that triage and immediate care will be rendered when needed. Future research needs to be completed evaluating the effect of training on a layperson study sample.