Impact of peer-trainer leadership style on uptake of a peer led educational outreach intervention to improve tuberculosis care and outcomes in Malawi: a qualitative study.

BACKGROUND: Little is known about how to build leadership capacity to support implementation of evidence-based practices within health systems. We observed substantial variability across sites in uptake and sustainability of a peer-led educational outreach intervention for lay health workers (LHWs) providing tuberculosis care in Malawi. Feedback from peer-trainers (PTs) suggested that leadership may have contributed to the variation. We sought to assess the impact of PT leadership style on implementation, and to identify leadership traits of more successful PTs, to inform future implementation planning and to identify targets for leadership capacity building. METHODS: Qualitative study employing interviews with PTs and LHWs at high and low implementation sites, and review of study team and quarterly PT meeting notes. High implementation sites achieved high uptake, sustainability and fidelity of implementation including: close adherence to training content and process, high levels of coverage (training most or all eligible LHWs at their site), and outcomes were achieved with high levels of self reported competence with the intervention among both PTs and LHWs. Low implementation sites achieved limited coverage (<= 50% of LHWs trained), and intervention fidelity. RESULTS: Eight PTs and 10 LHWs from eight high and 10 low implementation sites participated in interviews. Leadership traits of more successful PTs included: flexibility in their approach to training, role modeling and provision of supportive supervision to support learning; addressing challenges proactively and as they occurred; collaborative planning; knowledgeable; and availability to support implementation. Traits unique to less successful PTs included: a poor attitude toward their role as PT and a passive-avoidant approach to challenges. CONCLUSION: This study identified leadership traits more common among unit level leaders at sites with higher uptake, sustainability, and fidelity of implementation. These findings provide a starting point for development and evaluation of a leadership capacity building intervention for unit level leaders to support implementation.

Are patient education materials about cancer screening more effective when co-created with patients? A qualitative interview study and randomized controlled trial.

Background: Patient education materials (pems) are frequently used to help patients make cancer screening decisions. However, because pems are typically developed by experts, they might inadequately address patient barriers to screening. We co-created, with patients, a prostate cancer (pca) screening pem, and we compared how the co-created pem and a pem developed by experts affected decisional conflict and screening intention in patients. Methods: We identified and used patient barriers to pca screening to co-create a pca screening pem with patients, clinicians, and researchers. We then conducted a parallel-group randomized controlled trial with men 40 years of age and older in Ontario to compare decisional conflict and intention about pca screening after those men had viewed the co-created pem (intervention) or an expert-created pem (control). Participants were randomized using dynamic block randomization, and the study team was blinded to the allocation. Results: Of 287 participants randomized to exposure to the co-created pem, 230 were analyzed, and of 287 randomized to exposure to the expert-created pem, 223 were analyzed. After pem exposure, intervention and control participants did not differ significantly in Decisional Conflict Scale scores [mean difference: 0.37 ± 1.23; 95% confidence interval (ci): -2.05 to 2.79]; in sure (Sure of myself, Understand information, Risk-benefit ratio, or Encouragement) scores (odds ratio: 0.75; 95% ci: 0.52 to 1.08); or in screening intention (mean difference: 0.09 ± 0.08; 95% ci: -0.06 to 0.24]). Conclusions: The effectiveness of the co-created pem did not differ from that of the pem developed by experts. Thus, pem developers should choose the method that best fits their goals and resources.

Complex interventions can increase osteoporosis investigations and treatment: a systematic review and meta-analysis.

Osteoporosis is affecting over 200 million people worldwide. Despite available guidelines, care for these patients remains sub-optimal. We developed an osteoporosis tool to address the multiple dimensions of chronic disease management. Findings from its evaluation showed a significant increase from baseline in osteoporosis investigations and treatment, so we are revising this tool to include multiple chronic conditions including an update of evidence about osteoporosis. Our objectives were to conduct a systematic review of osteoporosis interventions in adults at risk for osteoporosis. We searched bibliometric databases for randomized controlled trials (RCTs) in any language evaluating osteoporosis disease management interventions in adults at risk for osteoporosis. Reviewer pairs independently screened citations and full-text articles, extracted data, and assessed risk of bias. Analysis included random effects meta-analysis. Primary outcomes were osteoporosis investigations and treatment, and fragility fractures. Fifty-five RCTs and one companion report were included in the analysis representing 165,703 patients. Our findings from 55 RCTs and 18 sub-group meta-analyses showed that complex implementation interventions with multiple components consisting of at least education + feedback + follow-up significantly increased the initiation of osteoporosis medications, and interventions with at least education + follow-up significantly increased the initiation of osteoporosis investigations. No significant impact was found for any type of intervention to reduce fracture. Complex interventions that include at least education + follow-up or feedback have the most potential for increasing osteoporosis investigations and treatment. Patient education appears to be an important component in osteoporosis disease management.

Utility of social media and crowd-sourced data for pharmacovigilance: a scoping review protocol

: Adverse events associated with medications are under-reported in postmarketing surveillance systems. A systematic review of published data from 37 studies worldwide (including Canada) found the median under-reporting rate of adverse events to be 94% in spontaneous reporting systems. This scoping review aims to assess the utility of social media and crowd-sourced data to detect and monitor adverse events related to health products including pharmaceuticals, medical devices, biologics and natural health products.

Impact of psychological characteristics in self-management in individuals with traumatic spinal cord injury.

STUDY DESIGN: Cross-sectional survey. OBJECTIVE: To examine the association between psychological characteristics in self-management and probable depression status in individuals with a traumatic spinal cord injury (SCI). SETTING: Community-dwelling individuals with traumatic SCI living across Canada. METHODS: Individuals with SCI were recruited by email via the Rick Hansen Institute as well as an outpatient hospital spinal clinic. Data were collected by self-report using an online survey. Standardized questionnaires were embedded within a larger survey and included the Hospital Anxiety and Depression Scale (HADS), the short version of the Patient Activation Measure (PAM), the Moorong Self-Efficacy Scale (MSES) and the Pearlin-Schooler Mastery Scale (PMS). RESULTS: Individuals with probable depression (n=25) had lower self-efficacy (67.9 vs 94.2, P<0.0001), mastery (18.9 vs 22.9, P<0.0001) and patient activation (60.4 vs 71.6, P<0.0001) as well as higher anxiety (9.0 vs 5.5, P<0.0001), compared with their non-depressed counterparts (n=75). A logistic regression determined that lower self-efficacy and mastery scores as well as less time since injury were associated with depression status (P=0.002; P=0.02 and P=0.02, respectively). Individuals with higher anxiety scores were almost 1.5 times more likely to be depressed, while older age was positively associated with depression status (P=0.016 and P=0.024, respectively). CONCLUSION: Interventions for depression in SCI, including a self-management program, should target factors such as self-efficacy and mastery, which could improve secondary medical complications and overall quality of life.

Clinical assessment of reactive postural control among physiotherapists in Ontario, Canada.

Reactive postural control, the ability to recover from an external perturbation to stability, ultimately determines whether an individual will fall following a loss of balance and should be routinely incorporated in balance assessment. The purpose of this study was to identify (1) methods used to assess reactive postural control in clinical practice and (2) factors associated with regular assessment of reactive postural control. A cross-sectional survey was conducted. Three hundred and fifty-seven physiotherapists in Ontario, Canada who treated adults with balance impairments answered questions about the components of balance they assess and how they assess reactive control in their practice. Of the 273 respondents who assessed reactive postural control at least some of the time, 15.4% used a standardized measure, 79.1% used a non-standardized approach, and 5.5% used both. Forty-five methods of assessing reactive control were reported. The most common methods used were non-standardized perturbations (43.5%; 104/239 respondents) and movement observation (18.8%; 45/239). The remaining 43 methods were each used by less than 8% of respondents. Practice area had the strongest association with regular assessment of reactive postural control (>60% of the time), and respondents working with neurological disorders were more likely to regularly evaluate reactive control than those working with people with orthopedic conditions. Despite the availability of valid standardized measures to evaluate reactive postural control, respondents relied primarily on non-standardized approaches and observational assessment. Future work should examine the factors influencing choice of reactive control assessment tools and awareness of standardized measures for reactive postural control.

Asthma action plans are highly variable and do not conform to best visual design practices.

BACKGROUND: Asthma action plans improve asthma outcomes and are recommended in guidelines. However, delivery by physicians and usage by patients remain low. This may be because of variability in existing plans and a failure to consider visual design and usability factors in plan development. OBJECTIVE: To characterize the variability in both the content and the format of existing plans, and the extent to which their format conforms to evidence-based visual design recommendations. METHODS: We collected plans from the internet, Canadian experts and associations, guidelines, and published trials. We inductively developed analytic criteria for format and content analyses. RESULTS: We collected 69 unique English or French-language adult outpatient plans from around the world. We found large variability in format, and plans fulfilled a mean of only 3.5 out of 8 evidence-based visual design recommendations. Content was also variable, including different descriptions of the baseline clinical state and descriptions and instructions at each "action point" (point recommending a change in treatment). CONCLUSION: Existing plans vary widely in content and format. Accordingly, studies evaluating the effectiveness of action plans may not be directly comparable. Also, visual design may affect usability, uptake, and effectiveness. Our results suggest that this has not been adequately addressed in most plans, and design evidence and experts should be included in future development.

Personal health records: a scoping review.

Electronic personal health record systems (PHRs) support patient centered healthcare by making medical records and other relevant information accessible to patients, thus assisting patients in health self-management. We reviewed the literature on PHRs including design, functionality, implementation, applications, outcomes, and benefits. We found that, because primary care physicians play a key role in patient health, PHRs are likely to be linked to physician electronic medical record systems, so PHR adoption is dependent on growth in electronic medical record adoption. Many PHR systems are physician-oriented, and do not include patient-oriented functionalities. These must be provided to support self-management and disease prevention if improvements in health outcomes are to be expected. Differences in patient motivation to use PHRs exist, but an overall low adoption rate is to be expected, except for the disabled, chronically ill, or caregivers for the elderly. Finally, trials of PHR effectiveness and sustainability for patient self-management are needed.

Moving balance and mobility evidence in to action: a primer in knowledge translation.

Knowledge generated by research into the control of posture and gait has many implications for individuals with balance and mobility impairments. Communicating such knowledge through conference presentations and peer-reviewed manuscripts is appropriate for some audiences, but does not effectively reach all potential knowledge users (for example: clinicians, policy-makers, and the public). Expanding interest in promoting evidence-based decision-making and practice to ensure that research results reach the target end-user has lead to the emergence of the field of knowledge translation (KT). The focus of KT is to improve the dissemination and uptake of knowledge in decision-making, and is grounded in a number of theoretical frameworks and its own rapidly expanding literature base. As many general principles of KT can be applied to the optimization of balance and mobility, the purpose of this review is to serve as a primer for gait and posture researchers. Two major models of KT are summarized: the National Institutes of Health (NIH) Roadmap and Knowledge-to-Action Framework. The principles outlined in these frameworks are applied to guidelines to assist researchers with developing their own evidence-based KT strategies. Examples of balance and mobility-specific KT activities are provided when appropriate, but there is a need for more studies that attempt to use evidence-based KT strategies to change practice in this particular field.

Community-based intervention to optimise falls risk management: a randomised controlled trial.

BACKGROUND: falls are the leading causes of accidental death and fragility fractures in older adults. Interventions that assess and reduce falls risk are underutilised. OBJECTIVE: to evaluate the impact of a multifaceted community-based programme aimed at optimising evidence-based management of patients at risk for fall-related fractures. DESIGN: this was a randomised trial performed from 2003 to 2006. SETTING: community-based intervention in Ontario, Canada. PARTICIPANTS: eligible patients were community-dwelling, aged > or =55 years and identified to be at risk for fall-related fractures. A total of 201 patients were allocated to the intervention group or to usual care. INTERVENTION: components of the intervention included assessment of falls risk, functional status and home environment, and patient education. MEASUREMENTS: primary outcome was the implementation of appropriate falls risk assessment at 6 months. Secondary outcomes included falls and fractures at 6 and 12 months. RESULTS: the mean age of participants was 72 years, and 41% had fallen with injury in the previous year. Compared to usual care, the intervention increased the number of referrals made to physiotherapy [21% (21/101) vs 6.0% (6/100); relative risk (RR) 3.47, 95% confidence interval (CI) 1.46-8.22] and occupational therapy [15% (15/101) vs 0%; RR 30.7, 95% CI 1.86 to >500]. At 12 months, the number of falls in the intervention group was greater than in the usual care group [23% (23/101) vs 11% (11/100); RR 2.07, 95% CI 1.07-4.02]. CONCLUSIONS: compared to usual care, a multi-faceted intervention increased referrals to physiotherapy and occupational therapy but did not reduce risk of falls. Similar falls reduction interventions cannot be recommended based on the results of this study.

Community-based randomised controlled trial evaluating falls and osteoporosis risk management strategies.

BACKGROUND: Osteoporosis-related fractures are a significant public health concern. Interventions that increase detection and treatment of osteoporosis, as well as prevention of fractures and falls, are substantially underutilized. This paper outlines the protocol for a pragmatic randomised trial of a multifaceted community-based care program aimed at optimizing the evidence-based management of falls and fractures in patients at risk. DESIGN: 6-month randomised controlled study. METHODS: This population-based study was completed in the Algoma District of Ontario, Canada a geographically vast area with Sault Ste Marie (population 78,000) as its main city. Eligible patients were allocated to an immediate intervention protocol (IP) group, or a delayed intervention protocol (DP) group. The DP group received usual care for 6 months and then was crossed over to receive the interventions. Components of the intervention were directed at the physicians and their patients and included patient-specific recommendations for osteoporosis therapy as outlined by the clinical practice guidelines developed by Osteoporosis Canada, and falls risk assessment and treatment. Two primary outcomes were measured including implementation of appropriate osteoporosis and falls risk management. Secondary outcomes included quality of life and the number of falls, fractures, and hospital admissions over a twelve-month period. The patient is the unit of allocation and analysis. Analyses will be performed on an intention to treat basis. DISCUSSION: This paper outlines the protocol for a pragmatic randomised trial of a multi-faceted, community-based intervention to optimize the implementation of evidence based management for patients at risk for falls and osteoporosis. TRIAL REGISTRATION: This trial has been registered with clinicaltrials.gov (ID: NCT00465387).

Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine.

BACKGROUND: A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome. METHODS: The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA. RESULTS: VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old. CONCLUSIONS: The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.

Interventions to improve antibiotic prescribing practices in ambulatory care.

BACKGROUND: The development of resistance to antibiotics by many important human pathogens has been linked to exposure to antibiotics over time. The misuse of antibiotics for viral infections (for which they are of no value) and the excessive use of broad spectrum antibiotics in place of narrower spectrum antibiotics have been well-documented throughout the world. Many studies have helped to elucidate the reasons physicians use antibiotics inappropriately. OBJECTIVES: To systematically review the literature to estimate the effectiveness of professional interventions, alone or in combination, in improving the selection, dose and treatment duration of antibiotics prescribed by healthcare providers in the outpatient setting; and to evaluate the impact of these interventions on reducing the incidence of antimicrobial resistant pathogens. SEARCH STRATEGY: We searched the Cochrane Effective Practice and Organisation of Care Group (EPOC) specialized register for studies relating to antibiotic prescribing and ambulatory care. Additional studies were obtained from the bibliographies of retrieved articles, the Scientific Citation Index and personal files. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials (RCT and QRCT), controlled before and after studies (CBA) and interrupted time series (ITS) studies of healthcare consumers or healthcare professionals who provide primary care in the outpatient setting. Interventions included any professional intervention, as defined by EPOC, or a patient-based intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed study quality. MAIN RESULTS: Thirty-nine studies examined the effect of printed educational materials for physicians, audit and feedback, educational meetings, educational outreach visits, financial and healthcare system changes, physician reminders, patient-based interventions and multi-faceted interventions. These interventions addressed the overuse of antibiotics for viral infections, the choice of antibiotic for bacterial infections such as streptococcal pharyngitis and urinary tract infection, and the duration of use of antibiotics for conditions such as acute otitis media. Use of printed educational materials or audit and feedback alone resulted in no or only small changes in prescribing. The exception was a study documenting a sustained reduction in macrolide use in Finland following the publication of a warning against their use for group A streptococcal infections. Interactive educational meetings appeared to be more effective than didactic lectures. Educational outreach visits and physician reminders produced mixed results. Patient-based interventions, particularly the use of delayed prescriptions for infections for which antibiotics were not immediately indicated effectively reduced antibiotic use by patients and did not result in excess morbidity. Multi-faceted interventions combining physician, patient and public education in a variety of venues and formats were the most successful in reducing antibiotic prescribing for inappropriate indications. Only one of four studies demonstrated a sustained reduction in the incidence of antibiotic-resistant bacteria associated with the intervention. AUTHORS' CONCLUSIONS: The effectiveness of an intervention on antibiotic prescribing depends to a large degree on the particular prescribing behaviour and the barriers to change in the particular community. No single intervention can be recommended for all behaviours in any setting. Multi-faceted interventions where educational interventions occur on many levels may be successfully applied to communities after addressing local barriers to change. These were the only interventions with effect sizes of sufficient magnitude to potentially reduce the incidence of antibiotic-resistant bacteria. Future research should focus on which elements of these interventions are the most effective. In addition, patient-based interventions and physician reminders show promise and innovative methods such as these deserve further study.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Neutrophil and platelet antibodies in autoimmune lymphoproliferative syndrome.

BACKGROUND AND OBJECTIVES: Autoimmune lymphoproliferative syndrome (ALPS), is an inherited disorder characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly, accumulation of T-cell receptor (TCR)-alphabeta+ CD4- CD8- T cells (double-negative T cells) and autoimmunity. We investigated the incidence and nature of neutrophil and platelet antibodies in patients with ALPS. MATERIALS AND METHODS: Sera from 26 patients with ALPS were tested for neutrophil antibodies by granulocyte immunofluorescence, granulocyte agglutination and monoclonal antibody immobilization assays of granulocyte antigens, and for platelet antibodies using a solid-phase antibody-detection system. RESULTS: Neutrophil antibodies were detected in 46% of patients with ALPS. Antibody specificity could be defined in eight of the 12 patients with neutrophil antibodies. Among these eight patients, four had antibodies directed against more than one antigen. Overall, 14 antibodies directed to specific antigens were identified: three were directed to the HNA-1a antigen of FcgammaRIIIb; two to the HNA-1b antigen of Fcgamma-RIIIb; two to epitopes common to all FcgammaRIIIb molecules; four to the HNA-2a antigen of the NB1 glycoprotein; and three to neutrophil beta2 integrins. Platelet antibodies were detected in 35% of patients with ALPS. No antibody specificities were identified among the platelet antibodies. There was no association between the detection of neutrophil antibodies and a history of clinical neutropenia, or between the detection of platelet antibodies and a history of clinical thromobocytopenia. CONCLUSIONS: Neutrophil and platelet antibodies are important markers of ALPS, but do not always cause clinical cytopenias. The specificities of neutrophil antibody were similar to those found in children with autoimmune neutropenia but without ALPS.

Using an interleukin-6 challenge to evaluate neuropsychological performance in chronic fatigue syndrome.

BACKGROUND: Individuals with acute infections experience a range of symptoms including fatigue, malaise, muscle aches, and difficulties with concentration and memory that are usually self-limited. This cluster of symptoms is otherwise, similar to those that characterize chronic fatigue syndrome (CFS). The goal of the present study was to evaluate the cognitive and psychological functioning of CFS patients and normal controls (NCs) when they both were experiencing acute influenza-like symptoms. To induce influenza-like symptoms, we administered interleukin-6 (IL-6), a cytokine that temporarily activates the acute phase immunological and endocrine responses. METHODS: Nineteen patients who met the 1994 International CFS Study Group Criteria and ten normal controls (NCs) completed routine clinical evaluations, neuropsychological tests of short-term memory, selective attention, and executive control, and self-ratings of somatic symptoms and psychological mood before, shortly following, and 1 day after IL-6 administration. RESULTS: CFS patients consistently reported more somatic symptoms, even when both groups perceived that they were ill. Both groups somatic symptoms increased during the IL-6 challenge, but the CFS patients symptoms increased more rapidly than controls. In general, the CFS patients performed similarly to NCs on the cognitive measures before, during, and after the IL-6. In contrast to predictions, IL-6 provocation did not impair the cognitive performance of either CFS patients or NCs. CONCLUSIONS: The IL-6 provocation exacerbated the patients self-reported symptoms but did not reveal notable cognitive impairments between patients and controls during cytokine-induced acute influenza-like symptoms.

Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) type Ia is caused by inherited defects in apoptosis and is characterized by nonmalignant lymphoaccumulation, autoimmunity, and increased alpha/beta(+) double-negative T cells (alpha/beta(+)-DNT cells). This study reports immunophenotypic findings in 166 members of 31 families with ALPS type Ia, associated with genetic mutations in the TNFRSF6 gene encoding Fas. The ALPS type Ia probands (n = 31) and relatives having both a Fas mutation and clinically proven ALPS (n = 28) showed significant expansion of CD8(+) T cells, alpha/beta(+)-DNT cells, gamma/delta(+)-DNT cells, CD3(+)/ HLA-DR(+) T cells, CD8(+)/CD57(+) T cells, and CD5(+) B cells. Relatives with Fas mutations, but without all the required criteria for ALPS (n = 42), had expansions of CD8(+) T cells, alpha/beta(+)-DNT cells, and gamma/delta(+)-DNT cells. Interestingly, relatives without a Fas mutation and with no features of ALPS (n = 65) demonstrated a small but significant expansion of CD8(+) T cells, both DNT cell subsets, and CD5(+) B cells. As compared to unrelated healthy controls, lymphocyte subset alterations were greatest in the probands, followed by the relatives with mutations and ALPS. Probands and relatives with mutations and ALPS also showed a lower number of CD4(+)/CD25(+) T cells that, in combination with an independent increase in HLA-DR(+) T cells, provided a profile predictive of the presence of clinical ALPS. Because quantitative defects in apoptosis were similar in mutation-positive relatives regardless of the presence of clinical ALPS, factors, other than modifiers of the Fas apoptosis pathway, leading to these distinctive immunophenotypic profiles most likely contribute to disease penetrance in ALPS.

What is chronic fatigue syndrome? Heterogeneity within an international multicentre study.

OBJECTIVE: We sought to compare the characteristics of patients presenting with chronic fatigue (CF) and related syndromes in eight international centres and to subclassify these subjects based on symptom profiles. The validity of the subclasses was then tested against clinical data. METHOD: Subjects with a clinical diagnosis of CF completed a 119-item self-report questionnaire to provide clinical symptom data and other information such as illness course and functional impairment. Subclasses were generated using a principal components-like analysis followed by latent profile analysis (LPA). RESULTS: 744 subjects returned complete data sets (mean age 40.8 years, mean length of illness 7.9 years, female to male ratio 3:1). Overall, the subjects had a high rate of reporting typical CF symptoms (fatigue, neuropsychological dysfunction, sleep disturbance). Using LPA, two subclasses were generated. Class one (68% sample) was characterized by: younger age, lower female to male ratio; shorter episode duration; less premorbid, current and familial psychiatric morbidity; and, less functional disability. Class two subjects (32%) had features more consistent with a somatoform illness. There was substantial variation in subclass prevalences between the study centres (Class two range 6-48%). CONCLUSIONS: Criteria-based approaches to the diagnosis of CF and related syndromes do not select a homogeneous patient group. While substratification of patients is essential for further aetiological and treatment research, the basis for allocating such subcategories remains controversial.

The 2.2-kilobase latency-associated transcript of herpes simplex virus type 2 does not modulate viral replication, reactivation, or establishment of latency in transgenic mice.

To better understand the mechanisms responsible for the observed effects of deletions in the promoter region of the latency-associated transcript (LAT) gene in impairing herpes simplex virus (HSV) reactivation, we generated mice transgenic for a 5.5-kb HSV type 2 (HSV-2) genomic fragment spanning the major LAT, along with the LAT promoter and flanking regions, in the C57BL/6 background. The mice expressed abundant 2.2-kb major LATs in trigeminal ganglia (TG) and other tissues. The effects of the transgene on HSV-2 infection, latency, and reactivation were assessed. When infected with wild-type (WT) HSV-2 or its LAT promoter deletion (LAT(-)) mutant, primary lung fibroblast lines established from normal C57BL/6 and transgenic mice supported virus growth equally well. The replication of these viruses in the mouse eye and their spread to TG and brains were similar. The quantities of latent viral DNA in TG of transgenic and normal mice, as determined by real-time PCR, were comparable. UV light-induced reactivation of the LAT(-) mutant from transgenic mice (0 to 7%) was no more frequent than that from normal mice (0 to 14%), while WT virus was reactivated from 13 to 54% of normal mice and 22 to 54% of transgenic mice. The cumulative data indicate that, when expressed transgenically, the HSV-2 major LAT cannot influence HSV-2 infection or latency and cannot complement the defect in reactivation of the LAT(-) mutant. These results imply that the phenotype of reduced reactivation associated with the LAT(-) mutant is related to a function encoded in the LAT promoter but not to the major LAT itself.

TcR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis.

Autoimmune lymphoproliferative syndrome (ALPS), caused by inherited defects in apoptosis secondary to mutations in genes encoding Fas/CD95/APO-1 and Fas ligand (Fasl)/CD95L, is characterized by nonmalignant lymphadenopathy and splenomegaly, increased T cell receptor alpha/beta(+) CD4(-)CD8(-) T cells (alpha/beta(+) double-negative T cells [alpha/beta(+)-DNT cells]), autoimmunity, hypergammaglobulinemia, and cytokine abnormalities. The alpha/beta(+)-DNT cells are immunophenotypically and functionally similar to alpha/beta(+)-DNT cells that accumulate in lpr and gld mice, which bear genetic mutations in Fas and FasL. In these mice, alpha/beta(+)-DNT cells express the B-cell-specific CD45R isoform B220. We show that alpha/beta(+)-DNT cells of ALPS patients, with either Fas or FasL mutations, also express B220. In addition, also similar to LPR/gLD mice, they have an unusual population of B220-positive CD4(+) T cells. B220 expression, together with our finding of characteristic lectin binding profiles, demonstrates that cell surface O-linked glycoproteins have undergone specific modifications, which may have consequences for lymphocyte trafficking, cell-cell interactions, and access to alternative apoptosis pathways.