Supervised learning events: direct observation of procedural skills pilot.

BACKGROUND: Workplace-based assessment (WBA) is the assessment of specialist competence based on what a trainee doctor actually does in the workplace. Between January 2014 and January 2015, all UK occupational medicine (OM) trainees were invited to test a suite of direct observation of procedural skills (DOPS) tools designed in a supervised learning event (SLE) format. The Faculty of Occupational Medicine (FOM) Workplace-Based Assessment Advisory Group (WBAAG) studied feedback on the new format. AIMS: To assess the utility of the redesigned tools, including their acceptability, feasibility, usability and key aspects of their reliability and validity. METHODS: The face and content validity of the new forms were assessed by a comprehension trial (CT), inter-rater reliability by a video scoring exercise and usability and acceptability by an electronic survey of trainees and trainers. RESULTS: The CT of trainees and trainers indicated that the face and content validity of the revised tools were acceptable. Inter-rater reliability video assessments indicated there was consistency of grading among trainers. Sixty-eight per cent of trainees and 95% of trainers agreed that the redesigned tools were an improvement on the current WBA DOPS tools and 83% of trainees indicated the new tools encouraged them to reflect on their performance. CONCLUSIONS: The results from this pilot study provided evidence to support a request to the General Medical Council (GMC) for the new SLE-DOPS forms to be used for WBA in OM. These changes were accepted by the GMC in January 2016 for implementation in April 2016.

Is community treatment best? a randomised trial comparing delivery of cancer treatment in the hospital, home and GP surgery.

BACKGROUND: Care closer to home is being explored as a means of improving patient experience as well as efficiency in terms of cost savings. Evidence that community cancer services improve care quality and/or generate cost savings is currently limited. A randomised study was undertaken to compare delivery of cancer treatment in the hospital with two different community settings. METHODS: Ninety-seven patients being offered outpatient-based cancer treatment were randomised to treatment delivered in a hospital day unit, at the patient's home or in local general practice (GP) surgeries. The primary outcome was patient-perceived benefits, using the emotional function domain of the EORTC quality of life (QOL) QLQC30 questionnaire evaluated after 12 weeks. Secondary outcomes included additional QOL measures, patient satisfaction, safety and health economics. RESULTS: There was no statistically significant QOL difference between treatment in the combined community locations relative to hospital (difference of -7.2, 95% confidence interval: -19·5 to +5·2, P=0.25). There was a significant difference between the two community locations in favour of home (+15·2, 1·3 to 29·1, P=0.033). Hospital anxiety and depression scale scores were consistent with the primary outcome measure. There was no evidence that community treatment compromised patient safety and no significant difference between treatment arms in terms of overall costs or Quality Adjusted Life Year. Seventy-eight percent of patients expressed satisfaction with their treatment whatever their location, whereas 57% of patients preferred future treatment to continue at the hospital, 81% at GP surgeries and 90% at home. Although initial pre-trial interviews revealed concerns among health-care professionals and some patients regarding community treatment, opinions were largely more favourable in post-trial interviews. INTERPRETATION: Patient QOL favours delivering cancer treatment in the home rather than GP surgeries. Nevertheless, both community settings were acceptable to and preferred by patients compared with hospital, were safe, with no detrimental impact on overall health-care costs.

Glucocorticoids upregulate decreased IL-7 receptor expression in asthmatic patients and simian immunodeficiency virus-infected non-human primates.

Signaling through interleukin-7 receptor (IL-7R) is essential for regulation of T-cell homeostasis and survival. Previously, we and others have found diminished IL-7R levels in simian immunodeficiency virus (SIV) - infected non-human primates and human immunodeficiency virus (HIV) - infected patients. To date, it remains unknown whether changes in IL-7R expression could also be linked to non-infectious inflammatory diseases such as asthma or anti-inflammatory drug use. Here, we investigated through flow cytometry the levels of IL-7R expression on CD4+ and CD4- T-cells in asthmatic patients in relation to disease severity, immune status and glucocorticoid (GC) use. In addition, we sought to evaluate the effects of in vivo and in vitro GC treatment on IL-7R expression in both asthmatic patients and SIV-infected non-human primates. We demonstrated that expression of IL-7R on peripheral blood CD4+ T-cells was significantly decreased in clinically stable GC-naive mild and moderate asthmatic patients. Accordingly, the development of asthmatic reaction following bronchial allergen challenge performed in sensitized subjects was associated with a significant drop in levels of IL-7R on circulating CD4+ T-cells. In contrast, CD4+ T-cells from both, mild and moderate, but not severe asthmatics, treated with inhaled GC displayed levels of IL-7R similar to that seen in healthy controls. We did not find significant differences with serum or sputum interleukin-7 levels among healthy controls and GC-naïve and GC-treated asthmatic patients. Furthermore, both in vitro GC treatment and short-term oral GC administration to asthmatic patients resulted in a significant enhancement of IL-7R. Similarly, we demonstrated that GC-stimulated T-cells from SIV-infected non-human primates up-regulated IL-7R expression. Accordingly, experimental short-term systemic in vivo administration of GC to SIV-infected macaques led to enhancement of IL-7R expression on circulating T-cells. Our data indicate that GC bear potential to recover diminished IL-7R expression, as well in asthma as in lentiviral infection.

Outbreak of zoonotic cutaneous leishmaniasis with local dissemination in Balkh, Afghanistan.

OBJECTIVES: In Afghanistan zoonotic cutaneous leishmaniasis (CL) due to Leishmania major has been less widely reported than anthroponotic CL due to L. tropica. However, an outbreak of zoonotic CL occurred amongst a group of British soldiers at a military camp near Mazar-e-Sharif in the Balkh province of northern Afghanistan in 2004. METHODS: A study was performed to assess the epidemiology, clinical features, parasitology results, treatment outcomes and environmental health measures associated with this incident. RESULTS: Twenty (17%) of 120 soldiers developed CL due to L. major and the risk of infection increased with the proximity of their accommodation to an area of recently cleared scrub, where many wild rodents were observed. Most cases had features of local dissemination, including secondary lesions from the pseudo-Koebner phenomenon, sporotrichoid lymphatic spread, lymphadenopathy and satellite papules or milia formation around healing lesions. Several cases responded poorly to fluconazole and low dose (10 mg/kg) sodium stibogluconate, which were considered suitable treatments at the time. Environmental health measures at the military camp were found to be deficient. CONCLUSIONS: Zoonotic CL due to L. major is a significant threat for foreign troops based in Balkh, Afghanistan and may present with unusually severe clinical features and be resistant to previously recommended treatments.

Expansion of CD133(+) colon cancer cultures retaining stem cell properties to enable cancer stem cell target discovery.

BACKGROUND: Despite earlier studies demonstrating in vitro propagation of solid tumour cancer stem cells (CSCs) as non-adherent tumour spheres, it remains controversial as to whether CSCs can be maintained in vitro. Additional validation of the CSC properties of tumour spheres would support their use as CSC models and provide an opportunity to discover additional CSC cell surface markers to aid in CSC detection and potential elimination. METHODS: Primary tumour cells isolated from 13 surgically resected colon tumour specimens were propagated using serum-free CSC-selective conditions. The CSC properties of long-term cultured tumour spheres were established and mass spectrometry-based proteomics performed. RESULTS: Freshly isolated CD133(+) colorectal cancer cells gave rise to long-term tumour sphere (or spheroids) cultures maintaining CD133 expression. These spheroid cells were able to self-renew and differentiate into adherent epithelial lineages and recapitulate the phenotype of the original tumour. Relative to their differentiated progeny, tumour spheroid cells were more resistant to the chemotherapeutic irinotecan. Finally, CD44, CD166, CD29, CEACAM5, cadherin 17, and biglycan were identified by mass spectrometry to be enriched in CD133(+) tumour spheroid cells. CONCLUSION: Our data suggest that ex vivo-expanded colon CSCs isolated from clinical specimens can be maintained in culture enabling the identification of CSC cell surface-associated proteins.

Acupuncture for systemic lupus erythematosus: a pilot RCT feasibility and safety study.

The objective of this study was to determine the feasibility of studying acupuncture in patients with systemic lupus erythematosus (SLE), and to pilot test the safety and explore benefits of a standardized acupuncture protocol designed to reduce pain and fatigue. Twenty-four patients with SLE were randomly assigned to receive 10 sessions of either acupuncture, minimal needling or usual care. Pain, fatigue and SLE disease activity were assessed at baseline and following the last sessions. Safety was assessed at each session. Fifty-two patients were screened to enroll 24 eligible and interested persons. Although transient side effects, such as brief needling pain and lightheadedness, were reported, no serious adverse events were associated with either the acupuncture or minimal needling procedures. Twenty-two participants completed the study, and the majority (85%) of acupuncture and minimal needling participants were able to complete their sessions within the specified time period of 5-6 weeks. 40% of patients who received acupuncture or minimal needling had >/=30% improvement on standard measures of pain, but no usual care patients showed improvement in pain. A ten-session course of acupuncture appears feasible and safe for patients with SLE. Benefits were similar for acupuncture and minimal needling.

Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance.

BACKGROUND: The state of tolerance allows long term graft survival without immunosuppressants. Lung transplantation tolerance has not been consistently achieved in either small or large animal models. METHODS: The mechanisms and effectiveness of a tolerance induction protocol consisting of donor specific transfusion (DST; day 0) and a short course of co-stimulatory blockade (anti-CD154 antibody; days -7, -4, 0 and +4) were studied in the mouse heterotopic tracheal transplant model of chronic lung rejection. C57BL/6 mice received BALB/c tracheal grafts (day 0) and were treated with DST alone, anti-CD154 alone, the combination (DST/anti-CD154), or no treatment. No non-specific immunosuppressants were used. RESULTS: DST/anti-CD154 in combination, but neither treatment alone, markedly prolonged the lumen patency and survival (>100 days) of fully histo-incompatible allografts (p<0.05 versus control allografts at every time point studied up to 16 weeks) without immunosuppression. This protocol was donor antigen specific as third party grafts (C3H) were promptly rejected. In addition, DST/anti-CD154 did not result in mixed chimerism but induced transplantation tolerance via a peripheral mechanism(s), which included significantly reduced cytotoxic T cell activity (p<0.001) and a significantly increased percentage of CD4+CD25+ cells (p = 0.03). CONCLUSIONS: The DST/anti-CD154 protocol successfully induced and maintained long term, donor specific tolerance in the mouse heterotopic airway graft model of chronic lung rejection. This finding may lead us closer to successful tolerance induction in lung transplantation.

HIV/AIDS preparedness in mental health care agencies with high and low substance use disorder caseloads.

PURPOSE: The Columbia University HIV Mental Health Training Project, created to improve the mental health workforce's AIDS preparedness in New York and neighboring states, sought to compare the perceived HIV-related needs and capacities of mental health care providers in settings where clients with substance use disorders predominated versus those where clients with substance use disorders were the minority of the agencies' caseload. METHODS: The first consecutive 67 mental health care agencies that requested HIV/AIDS training between March 2000 and January 2001 completed a written needs assessment describing their HIV-related services and training needs. RESULTS: Agencies with higher substance abuse caseloads were significantly more likely than others to have large HIV/AIDS caseloads, to be currently providing condoms to clients, and to rate staff comfort with sexual identity issues as well as drug-related issues as good. Overall, agencies that had received previous training in specific topic areas (e.g., HIV risk assessment) were significantly more likely than others to provide those services. Even so, in all settings, significant gaps in service provision were found. IMPLICATIONS: Two decades into the AIDS epidemic, mental health care agencies, especially those treating smaller caseloads of patients with substance use disorders, may not be providing sufficient services to meet their clients' HIV-related needs.

Severe mental illness and HIV-AIDS.

This chapter reviews the high rates of HIV infection and the risky sex and drug use practices of psychiatric patients, examines the role in HIV risk of psychiatric symptoms and of the contexts in which patients live, provides guidelines for taking sexually transmitted disease and risk histories from patients, presents recommendations for making HIV-testing decisions with patients, and describes the range of HIV-related services available to psychiatric outpatients.

Reduced NFAT1 protein expression in human umbilical cord blood T lymphocytes.

Umbilical cord blood (UCB) stem cells from related and unrelated allogeneic donors have emerged as novel treatment for patients with hematologic malignancies. The incidence and severity of acute graft-versus-host disease (GVHD) after UCB transplantation compares favorably with that observed in recipients of matched unrelated donor allogeneic grafts, but remains a major cause of morbidity and mortality. It has been shown that stimulated lymphocytes from UCB have reduced production of cytokines including interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), which play a role in GVHD pathophysiology. We investigated the molecular mechanisms underlying this reduced cytokine production by analyzing expression of nuclear factor of activated T cells-1 (NFAT1) in UCB T cells. We detected no constitutive expression of NFAT1 protein in unstimulated UCB T cells compared with adult T cells. Moreover, although NFAT1 expression in UCB T cells was upregulated after prolonged (40 hours) T-cell stimulation, it was only partially upregulated when compared with adult controls. Our observation of minimal NFAT1 expression after stimulation correlated with reduced cytoplasmic IFN-gamma and TNF-alpha production in UCB T cells studied simultaneously. Reduced NFAT1 expression may blunt amplification of donor UCB T-cell alloresponsiveness against recipient antigens, thereby potentially limiting GVHD incidence and severity after allogeneic UCB transplantation.

AIDS-related services and training in outpatient mental health care agencies in New York.

Directors of 471 outpatient mental health settings in New York State (82.1 percent of 574 settings located in counties with intermediate to high AIDS case rates) completed a survey about HIV and AIDS services, training needs, and barriers to care. Most of the sites served one to ten persons with HIV infection annually and had staff members who were trained in providing at least one HIV-related service. Nonetheless, 84 percent of the respondents reported unmet needs for training. The likelihood of providing certain services was significantly increased in sites that were in urban locations, primarily served clients with comorbid alcohol or other drug use disorders, lacked funds for providing condoms, had staff members who were trained in HIV and AIDS services, identified particular HIV training needs, believed clients needed condoms, and viewed HIV-related services as very important.

HIV and people with serious mental illness: the public sector's role in reducing HIV risk and improving care.

OBJECTIVE: The paper discusses issues related to the detection, prevention of transmission, and treatment of human immunodeficiency virus (HIV) infection among persons with serious mental illness and suggests ways public mental health systems can address these issues. METHODS: MEDLINE was searched from 1980 through 1998, and all pertinent references were reviewed. RESULTS: Persons with severe mental illness are at greatly increased risk of HIV infection due to increased likelihood of high-risk sexual behaviors and injection drug use. The formidable barriers to detection and effective treatment of HIV that exist in this population can be attributed to the unique characteristics of this population, lack of knowledge and expertise among mental and physical health care providers, and fragmented mental and physical health care systems. CONCLUSIONS: In the last five years, treatments for HIV that are far more efficacious than earlier treatments have become available, making it more important for HIV infection be detected and treated among persons with serious mental illness. Public mental health systems need to implement active prevention policies and practices, educate both mental health and physical health care providers about key treatment issues, and develop effective linkages between mental and physical health care providers and systems.

Dendritic cells improve the generation of Epstein-Barr virus-specific cytotoxic T lymphocytes for the treatment of posttransplantation lymphoma.

BACKGROUND: The use of immunosuppressive therapies after solid organ transplantation has been shown to increase a patient's risk for Epstein-Barr virus (EBV)-associated lymphoma. A potential therapy for this disorder is the adoptive transfer of EBV-specific cytotoxic T lymphocytes (CTLs). We proposed that dendritic cells (DCs) could be loaded with EBV antigens and be used to improve the in vitro generation of EBV-specific CTLs. METHODS: Autologous EBV-transformed B-lymphoblastoid cell lines (BLCLs) were generated from normal donors, and CTLs were initiated by culturing peripheral blood mononuclear cells with DCs alone, disrupted BLCLs alone, intact, irradiated BLCLs alone, and DCs loaded with disrupted BLCLs. Lytic activities were determined with a 4-hour chromium-release assay against autologous BLCLs, and statistical calculations were performed by a Student t test assuming equal variance. RESULTS: The lytic activity of CTLs generated with DCs loaded with disrupted BLCLs reached 78% and was statistically significant (P < .01) at all effector/target ratios compared with CTLs generated with DCs alone, disrupted BLCLs alone, or intact BLCLs alone. Total numbers of CTLs were also greater than those of control groups for DCs loaded with disrupted BLCLs. CONCLUSIONS: DCs improved the in vitro generation of EBV-specific CTLs as evidenced by this group's significantly increased lytic activity over that of the control group. The improved lytic activity of DC-generated EBV-CTLs suggests that adoptive transfer of these cells could lead to a more effective immunotherapeutic response against posttransplantation EBV-associated lymphoma.

The outpatient experience: results of a patient feedback survey.

Patient surveys can be used to enable hospital management to evaluate the services they provide. This study shows high levels of patient satisfaction with the quality of their consultations and the attitude shown to them by medical staff. Patient feedback shows that despite the introduction of the Patients' Charter, waiting times from referral to appointment and delays in clinics are still identified as the main areas for improvement. Findings show that patients are, however, remarkably tolerant and understanding of the pressures and demands placed upon outpatient staff.

Characteristics of the CD8+ lymphocytosis during primary simian immunodeficiency virus infections.

OBJECTIVE: To investigate the source of the expanded blood CD8+ subsets during an acute primary simian immunodeficiency virus (SIV) infection of macaques and the potential role of these cells in disease progression. DESIGN AND METHODS: The primary CD8+ lymphocytosis, which occurs at 1-2 weeks following infection with SIVsmm/PBj-14, was examined in rhesus and cynomolgus macaques. Extensive subset analysis of the expanded blood CD8+ cell pool in a rhesus macaque was compared phenotypically with those in thymus, lymph nodes, spleen, ileum and lung washouts obtained at necropsy during blood lymphocytosis. The influence of the primary CD8+ cells expansion on disease progression was assessed at days 175-679 post-infection in long-term PBj-14 survivors staged according to immunological, virological and histopathological changes in their lymphoid organs. RESULT: The very rapid and transient blood lymphocytosis following infection consisted of two distinct CD45RA(low), CD8+ and CD28-, lymphocyte function-associated antigen (LFA)-1(high), CD45RA(high), CD8+ populations. These populations were present in low levels in thymus, lymph and spleen but were highly represented in mucosal tissues, such as long washout, in which CD28- LFA-1(high) CD45RA(high) CD8+ cells comprised 86% of CD8+ cells, and gut, which was predominantly CD45RA(low) CD28- CD8+ cells. A comparison of progressor and non-progressor PBj-14-infected rhesus and cynomolgus macaques also indicated that the existence or magnitude of a blood CD8+ lymphocytosis during the acute phase of infection did not by itself appear to influence or be predictive of disease progression. CONCLUSION: The marked blood CD8+ lymphocytosis observed during acute SIV infection did not result from expansion of virus-specific precursors in peripheral lymph node and did not appear to influence the rate of disease progression. The findings provide a novel explanation for the primary CD8+ cell lymphocytosis and invoke a mechanism whereby virus-induced cytokine/chemokine production in mucosal sites initiate the transient migration of a pre-existing CD8+ population into the blood from compartments such as lung and gut. Such results suggest that the magnitude of lymphocytosis may depend on the level of viral replication in mucosal tissues and the presence of other infections, for example, cytomegalovirus.

Virus-induced cytokines regulate circulating lymphocyte levels during primary SIV infections.

Decline in blood CD4+ lymphocytes during primary symptomatic infections with HIV is usually attributed to viral killing, and has not been considered in terms of altered lymphocyte migration and sequestration. We therefore sought to examine whether CD4+ cell loss from blood of macaques undergoing an acute primary SIV infection might be due to increased synthesis of cytokines, known to profoundly affect lymphocyte trafficking, rather than to direct lymphocyte destruction by virus. The findings indicate that rapid lymphocyte depletion following acute infection is not selective for CD4+ cells, correlates precisely with increased plasma IFN-gamma and tumor necrosis factor-alpha levels, and is reversible. CD4/CD8 ratios in lymph nodes with high viral burdens remain relatively unchanged despite lymphocyte loss from blood. Levels of cytokine mRNA measured in lymphoid organs reflect neither cytokine plasma levels nor their potential to induce sequestration. These results support a model of cytokine-induced lymphocyte extravasation to account for the acute HIV/SIV-induced CD4+ cell lymphopenia and raise questions regarding the extent to which altered lymphocyte migration plays a role in the gradual CD4+ cell depletion throughout infection.