Implementation status of safety measures to prevent errors with non-oncologic methotrexate: surveys in community and hospital pharmacies.

BACKGROUND Accidental overdose of low-dose methotrexate can lead to serious patient harm. Different safety measures are recommended to prevent errors, yet, as errors continue to happen, their implementation is questionable. AIM To evaluate the implementation status of safety measures for methotrexate in community and hospital pharmacies. METHOD An electronic questionnaire was sent to head pharmacists of 163 community and 94 hospital pharmacies in Switzerland. The implementation of recommended safety measures (general measures, safety working procedures, IT-based measures) was assessed and descriptive analysis performed. An analysis of sales data underlined the relevance of our results, i.e., the population under risk for overdose. RESULTS A response was obtained from 53% (n = 87) of community and 50% (n = 47) of hospital pharmacists. Pharmacies had implemented a median of 6 (IQR 3, community) and 5 (IQR 5, hospital) safety measures overall. Most of these were defined safety procedures, instructing staff on how to handle methotrexate prescriptions. Across all safety measures, compliance with single procedures was perceived as "very likely" by 54% of community pharmacies. IT-based measures (e.g., alerts) were absent in 38% (n = 31) of community and 57% (n = 27) of hospital pharmacies. On average, every community pharmacy dispensed 22 packages annually. CONCLUSION Safety in relation to methotrexate in pharmacies relies mostly on staff instructions, which are considered weak measures. In light of the serious risk imposed on patients, pharmacies should set a focus on stronger IT-based measures that rely less on human performance

A GTPase-induced switch in phospholipid affinity of collybistin contributes to synaptic gephyrin clustering

Synaptic transmission between neurons relies on the exact spatial organization of postsynaptic transmitter receptors, which are recruited and positioned by dedicated scaffolding and regulatory proteins. At GABAergic synapses, the regulatory protein collybistin (Cb, also known as ARHGEF9) interacts with small GTPases, cell adhesion proteins and phosphoinositides to recruit the scaffolding protein gephyrin and GABAA receptors to nascent synapses. We dissected the interaction of Cb with the small Rho-like GTPase TC10 (also known as RhoQ) and phospholipids. Our data define a protein– lipid interaction network that controls the clustering of gephyrin at synapses. Within this network, TC10 and monophosphorylated phosphoinositides, particulary phosphatidylinositol 3-phosphate (PI3P), provide a coincidence detection platform that allows the accumulation and activation of Cb in endomembranes. Upon activation, TC10 induces a phospholipid affinity switch in Cb, which allows Cb to specifically interact with phosphoinositide species present at the plasma membrane. We propose that this GTPase- based regulatory switch mechanism represents an important step in the process of tethering of Cb-dependent scaffolds and receptors at nascent postsynapses

Post-translational modifications soften vimentin intermediate filaments

The mechanical properties of biological cells are determined by the cytoskeleton, a composite biopolymer network consisting of microtubules, actin filaments and intermediate filaments (IFs). By differential expression of cytoskeletal proteins, modulation of the network architecture and interactions between the filaments, cell mechanics may be adapted to varying requirements on the cell. Here, we focus on the intermediate filament protein vimentin and introduce post-translational modifications as an additional, much faster mechanism for mechanical modulation. We study the impact of phosphorylation on filament mechanics by recording force-strain curves using optical traps. Partial phosphorylation softens the filaments. We show that binding of the protein 14-3-3 to phosphorylated vimentin IFs further enhances this effect and speculate that in the cell 14-3-3 may serve to preserve the softening and thereby the altered cell mechanics. We explain our observation by the additional charges introduced during phosphorylation

An integrated model of care to counter high incidence of HIV and sexually transmitted diseases in men who have sex with men – initial analysis of service utilizers in Zurich

BACKGROUND: As other countries, Switzerland experiences a high or even rising incidence of HIV and sexually transmitted infections (STI) among men who have sex with men (MSM). An outpatient clinic for gay men ("Checkpoint") was opened in 2006 in Zurich (Switzerland) in order to provide sexual health services. The clinic provides counselling, testing, medical treatment and follow-up at one location under an "open-door-policy" and with a high level of personal continuity. We describe first experiences with the new service and report the characteristics of the population that utilized it. METHODS: During the 6-month evaluation period, individuals who requested counselling, testing or treatment were asked to participate in a survey at their first visit prior to the consultation. The instrument includes questions regarding personal data, reasons for presenting, sexual behaviour, and risk situations. Number and results of HIV/STI tests and treatments for STI were also recorded. RESULTS: During the evaluation period, 632 consultations were conducted and 247 patients were seen by the physician. 406 HIV tests were performed (3.4% positive). 402 men completed the entry survey (64% of all consultations). The majority of respondents had 4 and more partners during the last 12 months and engaged in either receptive, insertive or both forms of anal intercourse. More than half of the responders used drugs or alcohol to get to know other men or in conjunction with sexual activity (42% infrequently, 10% frequently and 0.5% used drugs always). The main reasons for requesting testing were a prior risk situation (46.3%), followed by routine screening without a prior risk situation (24.1%) and clarification of HIV/STI status due to a new relationship (29.6%). A fifth of men that consulted the service had no history of prior tests for HIV or other STIs. CONCLUSION: Since its first months of activity, the service achieved high levels of recognition, acceptance and demand in the MSM community. Contrary to common concepts of "testing clinics", the Checkpoint service provides post-exposure prophylaxis, HIV and STI treatment, psychological support and counselling and general medical care. It thus follows a holistic approach to health in the MSM community with the particular aim to serve as a "door opener" between the established system of care and those men that have no access to, or for any reason hesitate to utilize traditional health care

Structures of Get3, Get4, and Get5 Provide New Models for TA Membrane Protein Targeting

The GET pathway, using several proteins (Gets 1–5 and probably Sgt2), posttranslationally conducts tail-anchored (TA) proteins to the endoplasmic reticulum (ER). At the ER, TA proteins are inserted into the lipid bilayer and then sorted and directed to their respective destinations in the secretory pathway. Until last year, there was no structural information on any of the GET components but now there are ten crystal structures of Get3 in a variety of nucleotide-bound states and conformations. The structures of Get4 and a portion of Get5 also emerged in 2010. This minireview provides a detailed comparison of the GET structures and discusses their mechanistic relevance to TA protein insertion. It also addresses the outstanding gaps in detailed molecular information on this system, including the structures of Get5, Sgt2, and the transmembrane complex comprising Get1 and Get2

The SND proteins constitute an alternative targeting route to the endoplasmic reticulum.

In eukaryotes, up to one-third of cellular proteins are targeted to the endoplasmic reticulum, where they undergo folding, processing, sorting and trafficking to subsequent endomembrane compartments(1). Targeting to the endoplasmic reticulum has been shown to occur co-translationally by the signal recognition particle (SRP) pathway(2) or post-translationally by the mammalian transmembrane recognition complex of 40 kDa (TRC40)(3,4) and homologous yeast guided entry of tail-anchored proteins (GET)(5,6) pathways. Despite the range of proteins that can be catered for by these two pathways, many proteins are still known to be independent of both SRP and GET, so there seems to be a critical need for an additional dedicated pathway for endoplasmic reticulum relay(7,8). We set out to uncover additional targeting proteins using unbiased high-content screening approaches. To this end, we performed a systematic visual screen using the yeast Saccharomyces cerevisiae(9,10), and uncovered three uncharacterized proteins whose loss affected targeting. We suggest that these proteins work together and demonstrate that they function in parallel with SRP and GET to target a broad range of substrates to the endoplasmic reticulum. The three proteins, which we name Snd1, Snd2 and Snd3 (for SRP-independent targeting), can synthetically compensate for the loss of both the SRP and GET pathways, and act as a backup targeting system. This explains why it has previously been difficult to demonstrate complete loss of targeting for some substrates. Our discovery thus puts in place an essential piece of the endoplasmic reticulum targeting puzzle, highlighting how the targeting apparatus of the eukaryotic cell is robust, interlinked and flexible

Case management in oncology rehabilitation (CAMON): The effect of case management on the quality of life in patients with cancer after one year of ambulant rehabilitation. A study protocol for a randomized controlled clinical trial in oncology rehabilitation

Background Cancer diseases and their therapies have negative effects on the quality of life. The aim of this study is to assess the effectiveness of case management in a sample of oncological outpatients with the intent of rehabilitation after cancer treatment. Case management wants to support the complex information needs of the patients in addition to the segmented structure of the health care system. Emphasis is put on support for self-management in order to enhance health - conscious behaviour, learning to deal with the burden of the illness and providing the opportunity for regular contacts with care providers. We present a study protocol to investigate the efficacy of a case management in patients following oncology rehabilitation after cancer treatment. Methods The trial is a multicentre, two-arm randomised controlled study. Patients are randomised parallel in either 'usual care' plus case management or 'usual care' alone. Patients with all types of cancer can be included in the study, if they have completed the therapy with chemo- and/or radiotherapy/surgery with curative intention and are expected to have a survival time >1 year. To determine the health-related quality of life the general questionnaire FACT G is used. The direct correlation between self-management and perceived self-efficacy is measured with the Jerusalem & Schwarzer questionnaire. Patients satisfaction with the care received is measured using the Patient Assessment of Chronic Illness Care 5 As (PACIC-5A). Data are collected at the beginning of the trial and after 3, 6 and 12 months. The power analysis revealed a sample size of 102 patients. The recruitment of the centres began in 2009. The inclusion of patients began in May 2010. Discussion Case management has proved to be effective regarding quality of life of patients with chronic diseases. When it comes to oncology, case management is mainly used in cancer treatment, but it is not yet common in the rehabilitation of cancer patients. Case management in oncology rehabilitation is not well-established in Switzerland. A major challenge of the study will therefore probably be the recruitment of the patients due to the physicians' and patients' scarcely existing awareness of this issue

HEE-GER: a systematic review of German economic evaluations of health care published 1990–2004

BACKGROUND: Studies published in non-English languages are systematically missing in systematic reviews of growth and quality of economic evaluations of health care. The aims of this study were: to characterize German evaluations, published in English or German-language, in terms of various key parameters; to investigate methods to derive quality-of-life weights in cost-utility studies; and to examine changes in study characteristics over the years. METHODS: We conducted a country-specific systematic review of the German and English-language literature of German economic evaluations (assessment of or application to the German health care system) published 1990–2004. Generic and specialized health economic databases were searched. Two independent reviewers verified fulfillment of inclusion criteria and extracted study characteristics. RESULTS: The fulltexts of 730 articles were reviewed of which 283 fulfilled all entry criteria. 32% of included studies were published in German-language. 51% of studies evaluated pharmaceuticals and 63% were cost-effectiveness analyses. Economic appraisals concentrate on few disease categories and important health areas are strongly underrepresented. Declaration of sponsorship was associated with article language (49% English articles vs. 29% German articles, p < 0.001). The methodology used to obtain quality-of-life weights in published cost-utility studies was very diverse, poorly reported and most studies did not use German patients' or community health state valuations. CONCLUSION: Many of the German-language evaluations included in our study are likely to be missing in international reviews and may be systematically different from English-language reviews from Germany. Lack of transparency and adherence to recommended reporting practices constitute a serious problem in German economic evaluations

The equivalence of numbers: The social value of avoiding health decline: An experimental web-based study

BACKGROUND: Health economic analysis aimed at informing policy makers and supporting resource allocation decisions has to evaluate not only improvements in health but also avoided decline. Little is known however, whether the "direction" in which changes in health are experienced is important for the public in prioritizing among patients. This experimental study investigates the social value people place on avoiding (further) health decline when directly compared to curative treatments in resource allocation decisions. METHODS: 127 individuals completed an interactive survey that was published in the World Wide Web. They were confronted with a standard gamble (SG) and three person trade-off tasks, either comparing improvements in health (PTO-Up), avoided decline (PTO-Down), or both, contrasting health changes of equal magnitude differing in the direction in which they are experienced (PTO-WAD). Finally, a direct priority ranking of various interventions was obtained. RESULTS: Participants strongly prioritized improving patients' health rather than avoiding decline. The mean substitution rate between health improvements and avoided decline (WAD) ranged between 0.47 and 0.64 dependent on the intervention. Weighting PTO values according to the direction in which changes in health are experienced improved their accuracy in predicting a direct prioritization ranking. Health state utilities obtained by the standard gamble method seem not to reflect social values in resource allocation contexts. CONCLUSION: Results suggest that the utility of being cured of a given health state might not be a good approximation for the societal value of avoiding this health state, especially in cases of competition between preventive and curative interventions

Balancing equity and efficiency in the Dutch basic benefits package using the principle of proportional shortfall

Economic evaluations are increasingly used to inform decisions regarding the allocation of scarce health care resources. To systematically incorporate societal preferences into these evaluations, quality-adjusted life year gains could be weighted according to some equity principle, the most suitable of which is a matter of frequent debate. While many countries still struggle with equity concerns for priority setting in health care, the Netherlands has reached a broad consensus to use the concept of proportional shortfall. Our study evaluates the concept and its support in the Dutch health care context. We discuss arguments in the Netherlands for using proportional shortfall and difficulties in transitioning from principle to practice. In doing so, we address universal issues leading to a systematic consideration of equity concerns for priority setting in health care. The article thus has relevance to all countries struggling with the formalization of equity concerns for priority setting