T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva (TM)): Mechanisms of action

Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous manifestations. New evidence on the central role of the immune system in the pathogenesis of psoriasis increasingly provides insight into pathogenic steps that can be modulated to provide disease control. Numerous biological therapies are in various stages of clinical development, with expectation of providing enhanced safety and efficacy over currently available psoriasis therapies. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted T-cell modulator that inhibits multiple steps in the immune cascade that result in the production and maintenance of psoriatic plaques, including initial T-cell activation and T-cell trafficking into sites of inflammation, including psoriatic skin, with subsequent reactivation in these sites. This article reviews the pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II and III efalizumab trials in patients with moderate to severe chronic plaque psoriasis. Copyright (C) 2004 S. Karger AG, Basel

Economic evaluation of short treatment for multidrugresistant tuberculosis, Ethiopia and South Africa : the STREAM trial

OBJECTIVE STREAM was a phase-III non-inferiority randomised controlled trial (RCT) to evaluate a shortened regimen for multi-drug resistant tuberculosis (MDR-TB), and included the first-ever within-trial economic evaluation of such regimens, reported here. METHODS We compared the costs of ‘Long’ (20-22 months) and ‘Short’ (9-11 months) regimens in Ethiopia and South Africa. Cost data were collected from trial participants, and health system costs estimated using ‘bottom-up’ and ‘top-down’ costing approaches. A cost-effectiveness analysis was conducted with the trial primary outcome as the measure of effectiveness, including a probabilistic sensitivity analysis (PSA) to illustrate decision uncertainty. FINDINGS The Short-regimen reduced healthcare costs per case by 21% in South Africa (US$8,341 Long vs US$6,619 Short) and 25% in Ethiopia (US$6,097 Long vs US$4,552 Short). The largest component of this saving was medication in South Africa (67%) and social support in Ethiopia (35%). In Ethiopia, participants on the Short-regimen reported reductions in dietary supplementation expenditure (US$225 per case (95$13 (95%CI 11-14), South Africa US$64 (95$19,000 (Ethiopia) or <US$14,500 (South Africa). CONCLUSION The Short-regimen provided substantial health system cost savings and reduced financial burden on participants. Shorter regimens are likely to be cost-effective in most settings, and an effective strategy to support the WHO goal of eliminating catastrophic costs in T

Using patient experience data to develop a patient experience toolkit to improve hospital care: a mixed-methods study

Background Patients are increasingly being asked to provide feedback about their experience of health-care services. Within the NHS, a significant level of resource is now allocated to the collection of this feedback. However, it is not well understood whether or not, or how, health-care staff are able to use these data to make improvements to future care delivery. Objective To understand and enhance how hospital staff learn from and act on patient experience (PE) feedback in order to co-design, test, refine and evaluate a Patient Experience Toolkit (PET). Design A predominantly qualitative study with four interlinking work packages. Setting Three NHS trusts in the north of England, focusing on six ward-based clinical teams (two at each trust). Methods A scoping review and qualitative exploratory study were conducted between November 2015 and August 2016. The findings of this work fed into a participatory co-design process with ward staff and patient representatives, which led to the production of the PET. This was primarily based on activities undertaken in three workshops (over the winter of 2016/17). Then, the facilitated use of the PET took place across the six wards over a 12-month period (February 2017 to February 2018). This involved testing and refinement through an action research (AR) methodology. A large, mixed-methods, independent process evaluation was conducted over the same 12-month period. Findings The testing and refinement of the PET during the AR phase, with the mixed-methods evaluation running alongside it, produced noteworthy findings. The idea that current PE data can be effectively triangulated for the purpose of improvement is largely a fallacy. Rather, additional but more relational feedback had to be collected by patient representatives, an unanticipated element of the study, to provide health-care staff with data that they could work with more easily. Multidisciplinary involvement in PE initiatives is difficult to establish unless teams already work in this way. Regardless, there is merit in involving different levels of the nursing hierarchy. Consideration of patient feedback by health-care staff can be an emotive process that may be difficult initially and that needs dedicated time and sensitive management. The six ward teams engaged variably with the AR process over a 12-month period. Some teams implemented far-reaching plans, whereas other teams focused on time-minimising ‘quick wins’. The evaluation found that facilitation of the toolkit was central to its implementation. The most important factors here were the development of relationships between people and the facilitator’s ability to navigate organisational complexity. Limitations The settings in which the PET was tested were extremely diverse, so the influence of variable context limits hard conclusions about its success. Conclusions The current manner in which PE feedback is collected and used is generally not fit for the purpose of enabling health-care staff to make meaningful local improvements. The PET was co-designed with health-care staff and patient representatives but it requires skilled facilitation to achieve successful outcomes. Funding The National Institute for Health Research Health Services and Delivery Research programme

Cell Cycle Regulation and Cytoskeletal Remodelling Are Critical Processes in the Nutritional Programming of Embryonic Development

Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common “gatekeepers” which may drive nutritional programming

Lack of self-averaging in neutral evolution of proteins

We simulate neutral evolution of proteins imposing conservation of the thermodynamic stability of the native state in the framework of an effective model of folding thermodynamics. This procedure generates evolutionary trajectories in sequence space which share two universal features for all of the examined proteins. First, the number of neutral mutations fluctuates broadly from one sequence to another, leading to a non-Poissonian substitution process. Second, the number of neutral mutations displays strong correlations along the trajectory, thus causing the breakdown of self-averaging of the resulting evolutionary substitution process.Comment: 4 pages, 2 figure

Potencjalne zmniejszenie kosztów leczenia cukrzycy związane z poprawą kontroli glikemii

WSTĘP. W literaturze są dostępne jedynie ograniczone dane dotyczące wpływu kontroli glikemii na koszty leczenia chorych na cukrzycę. Celem tej pracy było zbadanie potencjalnego wpływu ściślejszej kontroli glikemii na niektóre wczesne powikłania cukrzycy i koszty ich leczenia. MATERIAŁ I METODY. Przeprowadzono retrospektywne badanie obejmujące dużą grupę chorych na cukrzycę, zarejestrowanych w komputerowej bazie danych kliniki Fallon od 1 stycznia 1994 roku do 30 czerwca 1998 roku. Chorych podzielono na trzy grupy w zależności od stężenia HBA1C: cukrzycy wyrównanej ( 10%). Oceniano częstość hospitalizacji z powodu takich zaburzeń towarzyszących cukrzycy, jak: niektóre zakażenia, epizody hiper- i hipoglikemii, zaburzenia elektrolitowe, a także koszty leczenia. Aby wyeliminować wpływ przypadkowych parametrów w poszczególnych grupach, zastosowano wieloczynnikową analizę statystyczną, obejmującą okres 3 lat. WYNIKI. Z 2394 chorych na cukrzycę około 10% (251 osób) hospitalizowano przynajmniej raz z powodu wczesnych powikłań choroby &#8212; łącznie odnotowano 447 przyjęć. Ustalono, że w okresie objętym analizą liczba hospitalizacji w grupie chorych na cukrzycę wyrównaną wynosiła 13 na 100 chorych, w grupie cukrzycy względnie wyrównanej &#8212; 16 na 100, a w grupie chorych na cukrzycę niewyrównaną &#8212; 31 hospitalizacji na 100 chorych (p < 0,05). Skorygowane średnie koszty wynosiły odpowiednio około 970, 1380 i 3040 USD. U osób z późnymi powikłaniami choroby, którzy stanowili 30% badanej populacji, częstość przyjęć i koszty związane z hospitalizacjami były wyższe. Częstość ta w poszczególnych grupach wynosiła 30, 38 i 74 na 100 pacjentów, natomiast średnie koszty leczenia &#8212; odpowiednio 2610, 3810 i 8320 USD w poddanym analizie okresie 3 lat. WNIOSKI. W typowej praktyce lekarskiej poprawa kontroli glikemii wiąże się ze zmniejszeniem częstości hospitalizacji z powodu wczesnych powikłań cukrzycy, a w związku z tym z redukcją kosztów leczenia w okresie 3-letnim. Te potencjalne korzyści mogą wpływać na decyzje o wdrożeniu nowych metod leczenia cukrzycy

Pathological regression of primary tumour and metastatic lymph nodes following chemotherapy in resectable OG cancer: pooled analysis of two trials

Background: No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival. / Methods: Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis. / Results: Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable. / Conclusions: Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further