Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance.

Although tumor-specific CD8 T-cell responses often develop in cancer patients, they rarely result in tumor eradication. We aimed at studying directly the functional efficacy of tumor-specific CD8 T cells at the site of immune attack. Tumor lesions in lymphoid and nonlymphoid tissues (metastatic lymph nodes and soft tissue/visceral metastases, respectively) were collected from stage III/IV melanoma patients and investigated for the presence and function of CD8 T cells specific for the tumor differentiation antigen Melan-A/MART-1. Comparative analysis was conducted with peripheral blood T cells. We provide evidence that in vivo-priming selects, within the available naive Melan-A/MART-1-specific CD8 T-cell repertoire, cells with high T-cell receptor avidity that can efficiently kill melanoma cells in vitro. In vivo, primed Melan-A/MART-1-specific CD8 T cells accumulate at high frequency in both lymphoid and nonlymphoid tumor lesions. Unexpectedly, however, whereas primed Melan-A/MART-1-specific CD8 T cells that circulate in the blood display robust inflammatory and cytotoxic functions, those that reside in tumor lesions (particularly in metastatic lymph nodes) are functionally tolerant. We show that both the lymph node and the tumor environments blunt T-cell effector functions and offer a rationale for the failure of tumor-specific responses to effectively counter tumor progression.

Health Equity Audit Made Simple: A briefing for Primary Care Trusts and Local Strategic Partnerships

A working/ consultation document outlining the key drivers and steps for undertaking health equity audit as required in the Performance and Planning Framework (PPF) 2003-2006

How to set and monitor goals for prevalence of child obesity: guidance for Primary Care Trusts (PCTs) and local authorities

This guidance follows on from the publication of the Government's obesity strategy Healthy Weight, Healthy Lives: A Cross-Government strategy for England. The guidance provides advice to PCTs and local authorities on how to set child obesity goals as part of the Vital Signs and the National Indicator Set. This will be followed shortly with full guidance on developing local plans.

Health inequalities intervention tool: cost effectiveness of interventions

This note sets out the cost effectiveness performance of the interventions currently presented in the Health inequalities intervention tool . These interventions have been chosen for their cost effectiveness performance as health interventions as well as for their impact on the life expectancy gap.

Closing the gap: Setting local targets to reduce health inequalities

This briefing paper provides a summary of the policies, theory and practice of setting targets to reduce health inequalities. It offers some guidance for those responsible for setting local targets and sets this in the context of local experience drawn from documentary evidence from health improvement programmes (HImPs), community strategies and health action zones (HAZs).

Local anaesthetic medication for the treatment of asthma

It is presumed that drugs able to prevent bronchial spasm and/or inflammation may have therapeutic potential to control asthma symptoms. The local anaesthetic lidocaine has recently received increased attention as an alternative form of treatment for asthmatic patients. This paper reviews the major findings on the topic and summarizes the putative mechanisms underlying the airway effects of local anaesthetic agents. We think that lidocaine extends the spectrum of options in asthma therapy, probably by counteracting both spasmogenic and inflammatory stimuli in the bronchial airways. The possibility of development of new anti-asthma compounds based on the synthesis of lidocaine derivatives is also on the horizon.

Assessing, measuring and monitoring local health inequalities

This briefing has been put together by Eastern Region PHO outlining how to measure and monitor health inequalities in a local area, such as a primary care trust (PCT) or a local authority. It has been designed to help support action to tackle health inequalities in new NHS organisations and for Local Area Agreements (LAAs). Click on the link to view the document.

GWT RAD Base : desenvolupament d'un framework JEE.Aplicació pràctica : Registre E/S de la policia local

Aquest treball consta de 2 parts, la primera consisteix en desenvolupar el framework JEE amb arquitectura MVC que he denominat GWT RAD Base (qualsevol altre nom haguésvalgut també), i la segona és una aplicació pràctica de registre de entrada i sortida de la policialocal implementada mitjançant aquest framework.

Revised Criteria and Procedures for the Establishment of New Primary Schools - Report of the Commission on School Accommodation

Part One explores the background factors relating to new school establishment, outlines the views received as a result of consultation with the public and the New Schools Advisory Committee (NSAC) and reviews international practice in relation to establishment of new schools. The population of the country experienced an unprecedented increase in the past ten years. Despite the current economic downturn, the effect of this recent population increase is that growth in demand for school places is set to increase over the short to medium term. The overriding objective is to ensure that a school place is available to every child. Part Two explores issues around planning for new schools in the future. It discusses patron selection, the mechanism for identifying the need for a new school and proposals for cost effectiveness, including campus arrangements. A school is of central importance to a local community and therefore the establishment of a new school must be carried out with reference to the overall plan of the local authority for any given area. Guidelines published under Section 28 of the Planning Act entitled “The Provision of Schools and the Planning System” (July 2008) establish a 7 framework for co-operation between the Department and planning authorities to ensure the timely and cost-effective provision of school facilities.

The effect of patient, provider and financing regulations on the intensity of ambulatory physical therapy episodes : a multilevel analysis based on routinely available data

Background: Many studies have found considerable variations in the resource intensity of physical therapy episodes. Although they have identified several patient-and provider-related factors, few studies have examined their relative explanatory power. We sought to quantify the contribution of patients and providers to these differences and examine how effective Swiss regulations are (nine-session ceiling per prescription and bonus for first treatments). Methods: Our sample consisted of 87,866 first physical therapy episodes performed by 3,365 physiotherapists based on referrals by 6,131 physicians. We modeled the number of visits per episode using a multilevel log linear regression with crossed random effects for physiotherapists and physicians and with fixed effects for cantons. The three-level explanatory variables were patient, physiotherapist and physician characteristics. Results: The median number of sessions was nine (interquartile range 6-13). Physical therapy use increased with age, women, higher health care costs, lower deductibles, surgery and specific conditions. Use rose with the share of nine-session episodes among physiotherapists or physicians, but fell with the share of new treatments. Geographical area had no influence. Most of the variance was explained at the patient level, but the available factors explained only 4% thereof. Physiotherapists and physicians explained only 6% and 5% respectively of the variance, although the available factors explained most of this variance. Regulations were the most powerful factors. Conclusion: Against the backdrop of abundant physical therapy supply, Swiss financial regulations did not restrict utilization. Given that patient-related factors explained most of the variance, this group should be subject to closer scrutiny. Moreover, further research is needed on the determinants of patient demand.

The Provision of Schools and the Planning System

This Code of Practice sets out best practice approaches that should be followed by planning authorities in ensuring that the planning system plays its full part in facilitating the timely and cost-effective roll-out of school facilities by the Department of Education and Science and in line with the principles of proper planning and sustainable development. Complementing and expanding on previous planning guidelines issued by the Department of the Environment, Heritage and Local Government (DEHLG) in 2007 on the preparation of development plans (2007), these guidelines also include details of how: the Department of Education and Science will support the work of planning authorities in their planning functions, and planning authorities can complement and build on such interaction through site identification and acquisition

Policy for annual leave/ leave of absence cover for the Local Supervising Authority Midwifery Officer (LSAMO)

This guideline relating to cover for the absence of the LSAMO for annual leave covers the period from 2012-2015.The policy sets out the arrangements to be put in place for cover for the LSAMO role and the contact details.

Increased resistance to first-line agents among bacterial pathogens isolated from urinary tract infections in Latin America: time for local guidelines?

Emerging resistance phenotypes and antimicrobial resistance rates among pathogens recovered from community-acquired urinary tract infections (CA-UTI) is an increasing problem in specific regions, limiting therapeutic options. As part of the SENTRY Antimicrobial Surveillance Program, a total of 611 isolates were collected in 2003 from patients with CA-UTI presenting at Latin American medical centers. Each strain was tested in a central laboratory using Clinical Laboratory Standard Institute (CLSI) broth microdilution methods with appropriate controls. Escherichia coli was the leading pathogen (66%), followed by Klebsiella spp. (7%), Proteus mirabilis (6.4%), Enterococcus spp. (5.6%), and Pseudomonas aeruginosa (4.6%). Surprisingly high resistance rates were recorded for E. coli against first-line orally administered agents for CA-UTI, such as ampicillin (53.6%), TMP/SMX (40.4%), ciprofloxacin (21.6%), and gatifloxacin (17.1%). Decreased susceptibility rates to TMP/SMX and ciprofloxacin were also documented for Klebsiella spp. (79.1 and 81.4%, respectively), and P. mirabilis (71.8 and 84.6%, respectively). For Enterococcus spp., susceptibility rates to ampicillin, chloramphenicol, ciprofloxacin, and vancomycin were 88.2, 85.3, 55.9, and 97.1%, respectively. High-level resistance to gentamicin was detected in 24% of Enterococcus spp. Bacteria isolated from patients with CA-UTI in Latin America showed limited susceptibility to orally administered antimicrobials, especially for TMP/SMX and fluoroquinolones. Our results highlight the need for developing specific CA-UTI guidelines in geographic regions where elevated resistance to new and old compounds may influence prescribing decisions.

The cost-effectiveness and public health benefit of nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels: a Markov model.

OBJECTIVES: To determine whether nalmefene combined with psychosocial support is cost-effective compared with psychosocial support alone for reducing alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels (DRLs) as defined by the WHO, and to evaluate the public health benefit of reducing harmful alcohol-attributable diseases, injuries and deaths. DESIGN: Decision modelling using Markov chains compared costs and effects over 5 years. SETTING: The analysis was from the perspective of the National Health Service (NHS) in England and Wales. PARTICIPANTS: The model considered the licensed population for nalmefene, specifically adults with both alcohol dependence and high/very high DRLs, who do not require immediate detoxification and who continue to have high/very high DRLs after initial assessment. DATA SOURCES: We modelled treatment effect using data from three clinical trials for nalmefene (ESENSE 1 (NCT00811720), ESENSE 2 (NCT00812461) and SENSE (NCT00811941)). Baseline characteristics of the model population, treatment resource utilisation and utilities were from these trials. We estimated the number of alcohol-attributable events occurring at different levels of alcohol consumption based on published epidemiological risk-relation studies. Health-related costs were from UK sources. MAIN OUTCOME MEASURES: We measured incremental cost per quality-adjusted life year (QALY) gained and number of alcohol-attributable harmful events avoided. RESULTS: Nalmefene in combination with psychosocial support had an incremental cost-effectiveness ratio (ICER) of £5204 per QALY gained, and was therefore cost-effective at the £20,000 per QALY gained decision threshold. Sensitivity analyses showed that the conclusion was robust. Nalmefene plus psychosocial support led to the avoidance of 7179 alcohol-attributable diseases/injuries and 309 deaths per 100,000 patients compared to psychosocial support alone over the course of 5 years. CONCLUSIONS: Nalmefene can be seen as a cost-effective treatment for alcohol dependence, with substantial public health benefits. TRIAL REGISTRATION NUMBERS: This cost-effectiveness analysis was developed based on data from three randomised clinical trials: ESENSE 1 (NCT00811720), ESENSE 2 (NCT00812461) and SENSE (NCT00811941).