Deciphering the folding kinetics of transmembrane helical proteins

Nearly a quarter of genomic sequences and almost half of all receptors that are likely to be targets for drug design are integral membrane proteins. Understanding the detailed mechanisms of the folding of membrane proteins is a largely unsolved, key problem in structural biology. Here, we introduce a general model and use computer simulations to study the equilibrium properties and the folding kinetics of a $C_{\alpha}$-based two helix bundle fragment (comprised of 66 amino-acids) of Bacteriorhodopsin. Various intermediates are identified and their free energy are calculated toghether with the free energy barrier between them. In 40% of folding trajectories, the folding rate is considerably increased by the presence of non-obligatory intermediates acting as traps. In all cases, a substantial portion of the helices is rapidly formed. This initial stage is followed by a long period of consolidation of the helices accompanied by their correct packing within the membrane. Our results provide the framework for understanding the variety of folding pathways of helical transmembrane proteins

SARS and hospital priority setting: a qualitative case study and evaluation

BACKGROUND: Priority setting is one of the most difficult issues facing hospitals because of funding restrictions and changing patient need. A deadly communicable disease outbreak, such as the Severe Acute Respiratory Syndrome (SARS) in Toronto in 2003, amplifies the difficulties of hospital priority setting. The purpose of this study is to describe and evaluate priority setting in a hospital in response to SARS using the ethical framework 'accountability for reasonableness'. METHODS: This study was conducted at a large tertiary hospital in Toronto, Canada. There were two data sources: 1) over 200 key documents (e.g. emails, bulletins), and 2) 35 interviews with key informants. Analysis used a modified thematic technique in three phases: open coding, axial coding, and evaluation. RESULTS: Participants described the types of priority setting decisions, the decision making process and the reasoning used. Although the hospital leadership made an effort to meet the conditions of 'accountability for reasonableness', they acknowledged that the decision making was not ideal. We described good practices and opportunities for improvement. CONCLUSIONS: 'Accountability for reasonableness' is a framework that can be used to guide fair priority setting in health care organizations, such as hospitals. In the midst of a crisis such as SARS where guidance is incomplete, consequences uncertain, and information constantly changing, where hour-by-hour decisions involve life and death, fairness is more important rather than less

Setting priorities in health care organizations: criteria, processes, and parameters of success

BACKGROUND: Hospitals and regional health authorities must set priorities in the face of resource constraints. Decision-makers seek practical ways to set priorities fairly in strategic planning, but find limited guidance from the literature. Very little has been reported from the perspective of Board members and senior managers about what criteria, processes and parameters of success they would use to set priorities fairly. DISCUSSION: We facilitated workshops for board members and senior leadership at three health care organizations to assist them in developing a strategy for fair priority setting. Workshop participants identified 8 priority setting criteria, 10 key priority setting process elements, and 6 parameters of success that they would use to set priorities in their organizations. Decision-makers in other organizations can draw lessons from these findings to enhance the fairness of their priority setting decision-making. SUMMARY: Lessons learned in three workshops fill an important gap in the literature about what criteria, processes, and parameters of success Board members and senior managers would use to set priorities fairly

Congenital Heart Block Maternal Sera Autoantibodies Target an Extracellular Epitope on the α1G T-Type Calcium Channel in Human Fetal Hearts

Background:Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.Methodology/Principal Findings:We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.Conclusions/Significance:Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets. © 2013 Strandberg et al

Towards an understanding of the information and support needs of surgical adolescent idiopathic scoliosis patients: a qualitative analysis

<p>Abstract</p> <p>Background</p> <p>Informed decision making for adolescents and families considering surgery for scoliosis requires essential information, including expected outcomes with or without treatment and the associated risks and benefits of treatment. Ideally families should also receive support in response to their individual concerns. The aim of this study was to identify health-specific needs for online information and support for patients with adolescent idiopathic scoliosis who have had or anticipate having spinal surgery.</p> <p>Methods</p> <p>Focus group methodology was chosen as the primary method of data collection to encourage shared understandings, as well as permit expression of specific, individual views. Participants were considered eligible to participate if they had either experienced or were anticipating surgery for adolescent idiopathic scoliosis within 12 months, were between the ages of 10 and 18 years of age, and were English-speaking.</p> <p>Results</p> <p>Two focus groups consisting of 8 adolescents (1 male, 7 female) and subsequent individual interviews with 3 adolescents (1 male, 2 female) yielded a range of participant concerns, in order of prominence: (1) recovery at home; (2) recovery in hospital; (3) post-surgical appearance; (4) emotional impact of surgery and coping; (5) intrusion of surgery and recovery of daily activities; (6) impact of surgery on school, peer relationships and other social interactions; (7) decision-making about surgery; (8) being in the operating room and; (9) future worries.</p> <p>Conclusion</p> <p>In conclusion, adolescents welcomed the possibility of an accessible, youth-focused website with comprehensive and accurate information that would include the opportunity for health professional-moderated, online peer support.</p

Understanding, comprehensibility and acceptance of an evidence-based consumer information brochure on fall prevention in old age: a focus group study

<p>Abstract</p> <p>Background</p> <p>Evidence-based patient and consumer information (EBPI) is an indispensable component of the patients' decision making process in health care. Prevention of accidental falls in the elderly has gained a lot of public interest during preceding years. Several consumer information brochures on fall prevention have been published; however, none fulfilled the criteria of an EBPI. Little is known about the reception of EBPI by seniors. Therefore we aimed to evaluate a recently developed EBPI brochure on fall prevention with regard to seniors' acceptance and comprehensibility in focus groups and to explore whether the participants' judgements differed depending on the educational background of the study participants.</p> <p>Methods</p> <p>Seven focus groups were conducted with 40 seniors, aged 60 years or older living independently in a community. Participants were recruited by two gatekeepers. A discussion guide was used and seniors were asked to judge the EBPI brochure on fall prevention using a Likert scale 1-6. The focus group discussions were tape recorded, transcribed verbatim, and analysed using content analysis.</p> <p>Results</p> <p>The participants generally accepted the EBPI brochure on fall prevention. Several participants expressed a need for more practical advice. The comprehensibility of the brochure was influenced positively by brief chapter summaries. Participants dismissed the statistical illustrations such as confidence intervals or a Fagan nomogram and only half of them agreed with the meta-information presented in the first chapter. The detailed information about fall prevalence was criticised by some seniors. The use of a case story was well tolerated by the majority of participants.</p> <p>Conclusion</p> <p>Our findings indicate that the recently developed EBPI brochure on fall prevention in old age was generally well accepted by seniors, but some statistical descriptions were difficult for them to understand. The brochure has to be updated. However, not all issues raised by the participants will be taken into account since some of them are contrary to the principles of EBPI.</p

How do patients with inflammatory bowel disease want their biological therapy administered?

<p>Abstract</p> <p>Background</p> <p>Infliximab is usually administered by two monthly intravenous (iv) infusions, therefore requiring visits to hospital. Adalimumab is administered by self subcutaneous (sc) injections every other week. Both of these anti-TNF drugs appear to be equally efficacious in the treatment of Crohn's Disease and therefore the decision regarding which drug to choose will depend to some extent on patient choice, which may be based on the mode of administration.</p> <p>The aims of this study were to compare preferences in Inflammatory Bowel Disease (IBD) patients for two currently available anti-TNF agents and the reasons for their choices.</p> <p>Methods</p> <p>An anonymous questionnaire was distributed to IBD patients who had attended the Gastroenterology service (Ulster Hospital, Dundonald, Belfast, N. Ireland. UK) between January 2007 and December 2007. The patients were asked in a hypothetical situation if the following administering methods of anti-TNF drugs (intravenous or subcutaneous) were available, which drug route of administration would they choose.</p> <p>Results</p> <p>One hundred and twenty-five patients fulfilled the inclusion criteria and were issued questionnaires, of these 78 questionnaires were returned (62 percent response). The mean age of respondent was 44 years. Of the total number of respondents, 33 patients (42 percent) preferred infliximab and 19 patients (24 percent) preferred adalimumab (p = 0.07). Twenty-six patients (33 percent) did not indicate a preference for either biological therapy and were not included in the final analysis. The commonest reason cited for those who chose infliximab (iv) was: <it>"I do not like the idea of self-injecting," </it>(67 percent). For those patients who preferred adalimumab (sc) the commonest reason cited was: <it>"I prefer the convenience of injecting at home," </it>(79 percent). Of those patients who had previously been treated with an anti-TNF therapy (n = 10, all infliximab) six patients stated that they would prefer infliximab if given the choice in the future (p = 0.75).</p> <p>Conclusions</p> <p>There was a trend towards patient preference for infliximab (iv) treatment as opposed to adalimumab (sc) in patients with IBD. This difference may be due to the frequency of administration, mode of administration or differing 'times in the market-place', as infliximab had been approved for a longer period of time in Crohn's disease. Further studies are required in IBD patients to investigate whether patient choice will affect compliance, patient satisfaction and efficacy of treatment with anti-TNF therapies.</p

What do hospital decision-makers in Ontario, Canada, have to say about the fairness of priority setting in their institutions?

BACKGROUND: Priority setting, also known as rationing or resource allocation, occurs at all levels of every health care system. Daniels and Sabin have proposed a framework for priority setting in health care institutions called 'accountability for reasonableness', which links priority setting to theories of democratic deliberation. Fairness is a key goal of priority setting. According to 'accountability for reasonableness', health care institutions engaged in priority setting have a claim to fairness if they satisfy four conditions of relevance, publicity, appeals/revision, and enforcement. This is the first study which has surveyed the views of hospital decision makers throughout an entire health system about the fairness of priority setting in their institutions. The purpose of this study is to elicit hospital decision-makers' self-report of the fairness of priority setting in their hospitals using an explicit conceptual framework, 'accountability for reasonableness'. METHODS: 160 Ontario hospital Chief Executive Officers, or their designates, were asked to complete a survey questionnaire concerning priority setting in their publicly funded institutions. Eight-six Ontario hospitals completed this survey, for a response rate of 54%. Six close-ended rating scale questions (e.g. Overall, how fair is priority setting at your hospital?), and 3 open-ended questions (e.g. What do you see as the goal(s) of priority setting in your hospital?) were used. RESULTS: Overall, 60.7% of respondents indicated their hospitals' priority setting was fair. With respect to the 'accountability for reasonableness' conditions, respondents indicated their hospitals performed best for the relevance (75.0%) condition, followed by appeals/revision (56.6%), publicity (56.0%), and enforcement (39.5%). CONCLUSIONS: For the first time hospital Chief Executive Officers within an entire health system were surveyed about the fairness of priority setting practices in their institutions using the conceptual framework 'accountability for reasonableness'. Although many hospital CEOs felt that their priority setting was fair, ample room for improvement was noted, especially for the enforcement condition