Unrecognized pretransplant and donor‐derived cryptococcal disease in organ transplant recipients.

BACKGROUND: Cryptococcosis occurring ≤30 days after transplantation is an unusual event, and its characteristics are not known. METHODS: Patients included 175 solid-organ transplant (SOT) recipients with cryptococcosis in a multicenter cohort. Very early-onset and late-onset cryptococcosis were defined as disease occurring ≤30 days or >30 days after transplantation, respectively. RESULTS: Very early-onset disease developed in 9 (5%) of the 175 patients at a mean of 5.7 days after transplantation. Overall, 55.6% (5 of 9) of the patients with very early-onset disease versus 25.9% (43 of 166) of the patients with late-onset disease were liver transplant recipients (P = .05). Very early cases were more likely to present with disease at unusual locations, including transplanted allograft and surgical fossa/site infections (55.6% vs 7.2%; P < .001). Two very early cases with onset on day 1 after transplantation (in a liver transplant recipient with Cryptococcus isolated from the lung and a heart transplant recipient with fungemia) likely were the result of undetected pretransplant disease. An additional 5 cases involving the allograft or surgical sites were likely the result of donor‐acquired infection. CONCLUSIONS: A subset of SOT recipients with cryptococcosis present very early after transplantation with disease that appears to occur preferentially in liver transplant recipients and involves unusual sites, such as the transplanted organ or the surgical site. These patients may have unrecognized pretransplant or donor-derived cryptococcosis.

The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.

Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.

Integrated vector management for malaria control in Uganda: knowledge, perceptions and policy development.

BACKGROUND: Integrated vector management (IVM) is increasingly being recommended as an option for sustainable malaria control. However, many malaria-endemic countries lack a policy framework to guide and promote the approach. The objective of the study was to assess knowledge and perceptions in relation to current malaria vector control policy and IVM in Uganda, and to make recommendations for consideration during future development of a specific IVM policy. METHODS: The study used a structured questionnaire to interview 34 individuals working at technical or policy-making levels in health, environment, agriculture and fisheries sectors. Specific questions on IVM focused on the following key elements of the approach: integration of chemical and non-chemical interventions of vector control; evidence-based decision making; inter-sectoral collaboration; capacity building; legislation; advocacy and community mobilization. RESULTS: All participants were familiar with the term IVM and knew various conventional malaria vector control (MVC) methods. Only 75% thought that Uganda had a MVC policy. Eighty percent (80%) felt there was inter-sectoral collaboration towards IVM, but that it was poor due to financial constraints, difficulties in involving all possible sectors and political differences. The health, environment and agricultural sectors were cited as key areas requiring cooperation in order for IVM to succeed. Sixty-seven percent (67%) of participants responded that communities were actively being involved in MVC, while 48% felt that the use of research results for evidence-based decision making was inadequate or poor. A majority of the participants felt that malaria research in Uganda was rarely used to facilitate policy changes. Suggestions by participants for formulation of specific and effective IVM policy included: revising the MVC policy and IVM-related policies in other sectors into a single, unified IVM policy and, using legislation to enforce IVM in development projects. CONCLUSION: Integrated management of malaria vectors in Uganda remains an underdeveloped component of malaria control policy. Cooperation between the health and other sectors needs strengthening and funding for MVC increased in order to develop and effectively implement an appropriate IVM policy. Continuous engagement of communities by government as well as monitoring and evaluation of vector control programmes will be crucial for sustaining IVM in the country.

Setting an agenda for comparative effectiveness systematic reviews in CKD care.

Systematic reviews comparing the effectiveness of strategies to prevent, detect, and treat chronic kidney disease are needed to inform patient care. We engaged stakeholders in the chronic kidney disease community to prioritize topics for future comparative effectiveness research systematic reviews. We developed a preliminary list of suggested topics and stakeholders refined and ranked topics based on their importance. Among 46 topics identified, stakeholders nominated 18 as 'high' priority. Most pertained to strategies to slow disease progression, including: (a) treat proteinuria, (b) improve access to care, (c) treat hypertension, (d) use health information technology, and (e) implement dietary strategies. Most (15 of 18) topics had been previously studied with two or more randomized controlled trials, indicating feasibility of rigorous systematic reviews. Chronic kidney disease topics rated by stakeholders as 'high priority' are varied in scope and may lead to quality systematic reviews impacting practice and policy.

Characteristics of primary care office visits to nurse practitioners, physician assistants and physicians in United States Veterans Health Administration facilities, 2005 to 2010: a retrospective cross-sectional analysis.

UNLABELLED: BACKGROUND: Primary care, an essential determinant of health system equity, efficiency, and effectiveness, is threatened by inadequate supply and distribution of the provider workforce. The Veterans Health Administration (VHA) has been a frontrunner in the use of nurse practitioners (NPs) and physician assistants (PAs). Evaluation of the roles and impact of NPs and PAs in the VHA is critical to ensuring optimal care for veterans and may inform best practices for use of PAs and NPs in other settings around the world. The purpose of this study was to characterize the use of NPs and PAs in VHA primary care and to examine whether their patients and patient care activities were, on average, less medically complex than those of physicians. METHODS: This is a retrospective cross-sectional analysis of administrative data from VHA primary care encounters between 2005 and 2010. Patient and patient encounter characteristics were compared across provider types (PA, NP, and physician). RESULTS: NPs and PAs attend about 30% of all VHA primary care encounters. NPs, PAs, and physicians fill similar roles in VHA primary care, but patients of PAs and NPs are slightly less complex than those of physicians, and PAs attend a higher proportion of visits for the purpose of determining eligibility for benefits. CONCLUSIONS: This study demonstrates that a highly successful nationwide primary care system relies on NPs and PAs to provide over one quarter of primary care visits, and that these visits are similar to those of physicians with regard to patient and encounter characteristics. These findings can inform health workforce solutions to physician shortages in the USA and around the world. Future research should compare the quality and costs associated with various combinations of providers and allocations of patient care work, and should elucidate the approaches that maximize quality and efficiency.

Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up.

BACKGROUND: In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up. METHODS: This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained. RESULTS: 161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01). CONCLUSIONS: After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.

Nursing resources and patient outcomes in intensive care: a systematic review of the literature

Objectives: To evaluate the empirical evidence linking nursing resources to patient outcomes in intensive care settings as a framework for future research in this area. Background: Concerns about patient safely and the quality of care are driving research on the clinical and cost-effectiveness of health care interventions, including the deployment of human resources. This is particularly important in intensive care where a large proportion of the health care budget is consumed and where nursing staff is the main item of expenditure. Recommendations about staffing levels have been trade but may not be evidence based and may not always be achieved in practice. Methods: We searched systematically for studies of the impact of nursing resources (e.g. nurse-patient ratios, nurses' level of education, training and experience) on patient Outcomes, including mortality and adverse events, in adult intensive care. Abstracts of articles were reviewed and retrieved if they investigated the relationship between nursing resources and patient Outcomes. Characteristics of the studies were tabulated and the quality of the Studies assessed. Results: Of the 15 studies included in this review, two reported it statistical relationship between nursing resources and both mortality and adverse events, one reported ail association to mortality only, seven studies reported that they Could not reject the null hypothesis of no relationship to mortality and 10 studies (out of 10 that tested the hypothesis) reported a relationship to adverse events. The main explanatory mechanisms were the lack of time for nurses to perform preventative measures, or for patient surveillance. The nurses' role in pain control was noted by One author. Studies were mainly observational and retrospective and varied in scope from 1 to 52 units. Recommendations for future research include developing the mechanisms linking nursing resources to patient Outcomes, and designing large multi-centre prospective Studies that link patient's exposure to nursing care oil a shift-by-shift basis over time. (C) 2007 Elsevier Ltd. All rights reserved.

Association between polymorphism in regulatory region of gene encoding tumour necrosis factor alpha and risk of Alzheimer's disease and vascular dementia: a case-control study

BACKGROUND: Deposition of beta-amyloid in the brains of patients with Alzheimer's disease is thought to precede a chain of events that leads to an inflammatory response by the brain. We postulated that genetic variation in the regulatory region of the gene for the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha) leads to increased risk of Alzheimer's disease and vascular dementia. METHODS: A polymorphism in the regulatory region of the TNF-alpha gene was analysed in a case-control study. The polymorphism (C-850T) was typed in 242 patients with sporadic Alzheimer's disease, 81 patients with vascular dementia, 61 stroke patients without dementia, and 235 normal controls. These groups of individuals were also genotyped for the apolipoprotein E polymorphism, and the vascular dementia and stroke groups were typed at the HLA-DR locus. FINDINGS: The distribution of TNF-alpha genotypes in the vascular dementia group differed significantly from that in the stroke and normal control groups, giving an odds ratio of 2.51 (95% CI 1.49-4.21) for the development of vascular dementia for individuals with a CT or TT genotype. Logistic regression analysis indicated that the possession of the T allele significantly increased the risk of Alzheimer's disease associated with carriage of the apolipoprotein E epsilon4 allele (odds ratio 2.73 [1.68-4.44] for those with apolipoprotein E epsilon4 but no TNF-alpha T, vs 4.62 [2.38-8.96] for those with apolipoprotein E epsilon4 and TNF-alpha T; p=0.03). INTERPRETATION: Possession of the TNF-alpha T allele significantly increases the risk of vascular dementia, and increases the risk of Alzheimer's disease associated with apolipoprotein E. Although further research is needed, these findings suggest a potential role for anti-inflammatory therapy in vascular dementia and Alzheimer's disease, and perhaps especially in patients who have had a stroke.

Transmission loss allocation in a deregulated electrical energy market

This paper presents a new method for transmission loss allocation in a deregulated electrical power market. The proposed method is based on physical flow through transmission lines. The contributions of individual loads to the line flows are used as basis for allocating transmission losses to different loads. With minimum assumptions, that sound to be reasonable and cannot be rejected, a novel loss allocation formula is derived. The assumptions made are: a number of currents sharing a transmission line distribute themselves over the cross section in the same manner; that distribution causes the minimum possible power loss. Application of the proposed method is straightforward. It requires only a solved power flow and any simple algorithm for power flow tracing. Both active and reactive powers are considered in the loss allocation procedure. Results of application show the accuracy of the proposed method compared with the commonly used procedures.

'An aid to mental health': natural history, alienists and therapeutics in Victorian Scotland

In the nineteenth century natural history was widely regarded as a rational and ‘distracting’ pursuit that countered the ill-effects, physical and mental, of urban life. This familiar argument was not only made by members of naturalists’ societies but was also borrowed and adapted by alienists concerned with the moral treatment of the insane. This paper examines the work of five long-serving superintendents in Victorian Scotland and uncovers the connections made between an interest in natural history and the management of mental disease. In addition to recovering a significant influence on the conduct of several alienists the paper explores arguments made outside the asylum walls in favour of natural history as an aid to mental health. Investigating the promotion of natural history as a therapeutic recreation in Scotland and elsewhere reveals more fully the moral and cultural significance attached to natural history pursuits in the nineteenth century.

Bimanual co-ordination in Huntington's disease

The ability of Huntington's disease patients to co-ordinate their two hands with and without external cueing was investigated. Twelve Huntington's disease patients and sex- and age-matched controls performed a bimanual cranking task at two speeds (0.5 Hz, 1.5 Hz) and phase relationships (in-phase, anti-phase), with and without an external metronome cue. Data were sampled at 200 Hz, and raw displacement data for each hand, mean and standard deviation measures of the relative positions of the two hands and their velocities were then calculated. All participants could perform the in-phase movement, at both speeds; however, the Huntington's disease patients were more variable and less accurate than the control participants, particularly at the fast speed. While controls could perform the anti-phase movement, in which rotation of the cranks differed by 180 degrees at both speeds, Huntington's disease patients were unable to do so at either speed, reverting to the in-phase movement at the slow speed. An external metronome cue did not improve the performance of the Huntington's disease patients, which differentiated this group from patients suffering from Parkinson's disease. The Huntington's disease patients' inability to perform the anti-phase movement may be due to damage to the basal ganglia and its output regions.

Secular trends, disease maps and ecological analyses of the incidence of childhood onset type 1 diabetes in Northern Ireland, 1989-2003

Aims To investigate secular trends in the incidence of Type 1 diabetes in Northern Ireland over the period 1989-2003. To highlight geographical variations in the incidence of Type 1 diabetes by producing disease maps and to compare incidence rates by relevant area characteristics.

Density-dependent prophylaxis and condition-dependent immune function in Lepidopteran larvae: a multivariate approach

1. The risk of parasitism and infectious disease is expected to increase with population density as a consequence of positive density-dependent transmission rates. Therefore, species that encounter large fluctuations in population density are predicted to exhibit plasticity in their immune system, such that investment in costly immune defences is adjusted to match the probability of exposure to parasites and pathogens (i.e. density-dependent prophylaxis).

A phase I study of the Heat Shock Protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced, solid tumours.

PURPOSE: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). PATIENTS AND METHODS: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which = 1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. RESULTS: Twenty-five patients received 17-DMAG (range 2.5-106 mg/m(2)). At 106 mg/m(2) of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m(2). Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m(2) or less. In peripheral blood mononuclear cells significant (P

Promoting Health Behaviour Change in the Cardiac Patient

The importance of giving patients advice in relation to positive health behaviour change geared towards maximizing physical health must not be overlooked and is an important role of the cardiac nurse in contemporary health care. However, over-reliance on offering advice can often be counter-productive and less likely to achieve effective change. Patients are more likely to make positive health behaviour changes when they self-generate their own solutions to the health issues and problems that they face. In this article, the authors encourage cardiac nurses to embrace a less directive and more facilitative approach to patient health behaviour change in light of the mounting evidence that exists to the effectiveness of motivational interviewing techniques.