Barriers and facilitators to primary care research: views of GP trainees and trainers.

BACKGROUND: Primary care plays an important role in the conception and delivery of transformational research but GP engagement is lacking, prompting calls for the promotion of academic opportunities in primary care. AIM: To identify potential barriers and facilitators among GP trainees and trainers in primary care research to inform support given by Local Clinical Research Networks (LCRNs). DESIGN & SETTING: A cross-sectional online survey was developed and distributed by the CRN to GP trainees and trainers in the North East and North West. METHOD: The survey covered areas including demographics, career intentions, current and potential engagement with research, as well as their general understanding of research in primary care, which included barriers and facilitators to primary care research. RESULTS: Trainees had low intentionality to pursue research and half of trainees did not engage with any research activity. Despite one in five trainees reporting intentions to include research in their career, only 1% would undertake a solely academic career. Medical school region was the only strongly associated factor with academic career intention. Just under 30% of trainers reported engagement in research, but far fewer (8.6%) were interested in contributing to research, and only 10% felt prepared to mentor in research. CONCLUSION: Among trainees, there is limited engagement in and intentionality to pursue research, and this was crucially reflected by responses from trainers. This study identified the need for LCRNs to assist with training in research mentoring and skills, funding opportunities, and to develop resources to promote research in primary care.

Near-atomic resolution using electron cryomicroscopy and single-particle reconstruction.

Electron cryomicroscopy (cryo-EM) yields images of macromolecular assemblies and their components, from which 3D structures can be determined, by using an image processing method commonly known as "single-particle reconstruction." During the past two decades, this technique has become an important tool for 3D structure determination, but it generally has not been possible to determine atomic models. In principle, individual molecular images contain high-resolution information contaminated by a much higher level of noise. In practice, it has been unclear whether current averaging methods are adequate to extract this information from the background. We present here a reconstruction, obtained by using recently developed image processing methods, of the rotavirus inner capsid particle ("double-layer particle" or DLP) at a resolution suitable for interpretation by an atomic model. The result establishes single-particle reconstruction as a high-resolution technique. We show by direct comparison that the cryo-EM reconstruction of viral protein 6 (VP6) of the rotavirus DLP is similar in clarity to a 3.8-A resolution map obtained from x-ray crystallography. At this resolution, most of the amino acid side chains produce recognizable density. The icosahedral symmetry of the particle was an important factor in achieving this resolution in the cryo-EM analysis, but as the size of recordable datasets increases, single-particle reconstruction also is likely to yield structures at comparable resolution from samples of much lower symmetry. This potential has broad implications for structural cell biology.

Vaccines for preventing anthrax.

BACKGROUND: Anthrax is a bacterial zoonosis that occasionally causes human disease and is potentially fatal. Anthrax vaccines include a live-attenuated vaccine, an alum-precipitated cell-free filtrate vaccine, and a recombinant protein vaccine. OBJECTIVES: To evaluate the effectiveness, immunogenicity, and safety of vaccines for preventing anthrax. SEARCH STRATEGY: We searched the following databases (November 2008): Cochrane Infectious Diseases Group Specialized Register; CENTRAL (The Cochrane Library 2008, Issue 4); MEDLINE; EMBASE; LILACS; and mRCT. We also searched reference lists. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of individuals and cluster-RCTs comparing anthrax vaccine with placebo, other (non-anthrax) vaccines, or no intervention; or comparing administration routes or treatment regimens of anthrax vaccine. DATA COLLECTION AND ANALYSIS: Two authors independently considered trial eligibility, assessed risk of bias, and extracted data. We presented cases of anthrax and seroconversion rates using risk ratios (RR) and 95% confidence intervals (CI). We summarized immunoglobulin G (IgG) concentrations using geometric means. We carried out a sensitivity analysis to investigate the effect of clustering on the results from one cluster-RCT. No meta-analysis was undertaken. MAIN RESULTS: One cluster-RCT (with 157,259 participants) and four RCTs of individuals (1917 participants) met the inclusion criteria. The cluster-RCT from the former USSR showed that, compared with no vaccine, a live-attenuated vaccine (called STI) protected against clinical anthrax whether given by a needleless device (RR 0.16; 102,737 participants, 154 clusters) or the scarification method (RR 0.25; 104,496 participants, 151 clusters). Confidence intervals were statistically significant in unadjusted calculations, but when a small amount of association within clusters was assumed, the differences were not statistically significant. The four RCTs (of individuals) of inactivated vaccines (anthrax vaccine absorbed and recombinant protective antigen) showed a dose response relationship for the anti-protective antigen IgG antibody titre. Intramuscular administration was associated with fewer injection site reactions than subcutaneous injection, and injection site reaction rates were lower when the dosage interval was longer. AUTHORS' CONCLUSIONS: One cluster-RCT provides limited evidence that a live-attenuated vaccine is effective in preventing cutaneous anthrax. Vaccines based on anthrax antigens are immunogenic in most vaccinees with few adverse events or reactions. Ongoing randomized controlled trials are investigating the immunogenicity and safety of anthrax vaccines.

Fever of unknown origin.

There are many potential causes of FUO. Most cases are due to unusual presentations of common diseases rather than rare or exotic diseases. The key to establishing the diagnosis is a careful history and careful repeated examinations followed by targeted investigations.

Outpatient parenteral antimicrobial therapy.

Outpatient parenteral antibiotic therapy enables patients to receive intravenous antibiotics without having to be an inpatient. Outpatient parenteral antibiotic therapy can be delivered in an outpatient setting or in the patient's own home by a visiting nurse or the patient can be trained to self-administer antibiotic treatment. The advantages and limitations of each of these methods are discussed in this article. Common clinical situations in which outpatient parenteral antibiotic therapy is used are described. The article also considers the advantages of outpatient parenteral antibiotic therapy, how to ensure that care is safe and effective and how to obtain funding to set up a service.

Transparent development of the WHO rapid advice guidelines.

Emerging health problems require rapid advice. We describe the development and pilot testing of a systematic, transparent approach used by the World Health Organization (WHO) to develop rapid advice guidelines in response to requests from member states confronted with uncertainty about the pharmacological management of avian influenza A (H5N1) virus infection. We first searched for systematic reviews of randomized trials of treatment and prevention of seasonal influenza and for non-trial evidence on H5N1 infection, including case reports and animal and in vitro studies. A panel of clinical experts, clinicians with experience in treating patients with H5N1, influenza researchers, and methodologists was convened for a two-day meeting. Panel members reviewed the evidence prior to the meeting and agreed on the process. It took one month to put together a team to prepare the evidence profiles (i.e., summaries of the evidence on important clinical and policy questions), and it took the team only five weeks to prepare and revise the evidence profiles and to prepare draft guidelines prior to the panel meeting. A draft manuscript for publication was prepared within 10 days following the panel meeting. Strengths of the process include its transparency and the short amount of time used to prepare these WHO guidelines. The process could be improved by shortening the time required to commission evidence profiles. Further development is needed to facilitate stakeholder involvement, and evaluate and ensure the guideline's usefulness.

WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus.

Recent spread of avian influenza A (H5N1) virus to poultry and wild birds has increased the threat of human infections with H5N1 virus worldwide. Despite international agreement to stockpile antivirals, evidence-based guidelines for their use do not exist. WHO assembled an international multidisciplinary panel to develop rapid advice for the pharmacological management of human H5N1 virus infection in the current pandemic alert period. A transparent methodological guideline process on the basis of the Grading Recommendations, Assessment, Development and Evaluation (GRADE) approach was used to develop evidence-based guidelines. Our development of specific recommendations for treatment and chemoprophylaxis of sporadic H5N1 infection resulted from the benefits, harms, burden, and cost of interventions in several patient and exposure groups. Overall, the quality of the underlying evidence for all recommendations was rated as very low because it was based on small case series of H5N1 patients, on extrapolation from preclinical studies, and high quality studies of seasonal influenza. A strong recommendation to treat H5N1 patients with oseltamivir was made in part because of the severity of the disease. Similarly, strong recommendations were made to use neuraminidase inhibitors as chemoprophylaxis in high-risk exposure populations. Emergence of other novel influenza A viral subtypes with pandemic potential, or changes in the pathogenicity of H5N1 virus strains, will require an update of these guidelines and WHO will be monitoring this closely.

SARS: systematic review of treatment effects.

BACKGROUND: The SARS outbreak of 2002-2003 presented clinicians with a new, life-threatening disease for which they had no experience in treating and no research on the effectiveness of treatment options. The World Health Organization (WHO) expert panel on SARS treatment requested a systematic review and comprehensive summary of treatments used for SARS-infected patients in order to guide future treatment and identify priorities for research. METHODS AND FINDINGS: In response to the WHO request we conducted a systematic review of the published literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and in SARS patients. We also searched for clinical trial evidence of treatment for acute respiratory distress syndrome. Sources of data were the literature databases MEDLINE, EMBASE, BIOSIS, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 2005. Data from publications were extracted and evidence within studies was classified using predefined criteria. In total, 54 SARS treatment studies, 15 in vitro studies, and three acute respiratory distress syndrome studies met our inclusion criteria. Within in vitro studies, ribavirin, lopinavir, and type I IFN showed inhibition of SARS-CoV in tissue culture. In SARS-infected patient reports on ribavirin, 26 studies were classified as inconclusive, and four showed possible harm. Seven studies of convalescent plasma or IVIG, three of IFN type I, and two of LPV/r were inconclusive. In 29 studies of steroid use, 25 were inconclusive and four were classified as causing possible harm. CONCLUSIONS: Despite an extensive literature reporting on SARS treatments, it was not possible to determine whether treatments benefited patients during the SARS outbreak. Some may have been harmful. Clinical trials should be designed to validate a standard protocol for dosage and timing, and to accrue data in real time during future outbreaks to monitor specific adverse effects and help inform treatment.

Genome-wide approaches to identifying genetic factors in host susceptibility to tuberculosis.

Host genetic factors are important in determining susceptibility to Mycobacterium tuberculosis. Genome-wide linkage studies have been performed in humans and in murine models of tuberculosis susceptibility. These studies have identified several important candidate loci for susceptibility to tuberculosis. This is an important step in resolving the complex etiology of the disease.

Cost and cost-effectiveness of antiretroviral therapy for HIV infection in Singapore.

The objective of this study was to determine the cost and cost-effectiveness of antiretroviral therapy (ART) in Singapore. The use and cost of HIV services was calculated for patients managed at the national HIV referral centre in Singapore between 1996 and 2001 from a hospital perspective. Three groups of patients were compared by Centers for Disease Control and Prevention (CDC) stage of HIV infection: those who had never received ART; those who had received only dual therapy; and those who had only received highly active antiretroviral therapy (HAART). Hospital charges were used to estimate the average hospital inpatient and outpatient care costs. Life years gained (LYG) were calculated for different stages of HIV infection and the incremental costs per LYG were calculated comparing those on dual ART and HAART with those who did not receive ART. Patients on ART progressed less rapidly across all CDC stages. For CDC stage A, the incremental cost per LYG was 17,007 dollars (Singaporean dollar) (interquartile range [IQR] 7963-25,113 dollars ) and 22,511 dollars (IQR 11,299-33,724 dollars) for those on dual therapy and HAART, respectively. The incremental cost per LYG in stage B was 10,868 dollars (IQR 4506-17,239 dollars) and 21,094 dollars (IQR 7774-34,431 dollars) for patients on dual therapy and HAART, respectively, while the incremental cost per LYG for stage C patients was 9,848 dollars (IQR 5256-14,419 dollars ) and 16,513 dollars (IQR 8677-24,337 dollars) for dual therapy and HAART, respectively. Dual ART therapy and HAART were cost-effective interventions in Singapore. Cost-effectiveness is likely to improve if drug prices continue to decrease.

Genetic susceptibility to tuberculosis.

Host genetic factors are important in determining susceptibility and resistance to Mycobacterium tuberculosis. The etiology of tuberculosis is complex, and several host genes have been shown to contribute to the development of clinical disease. The success of the strategies used to investigate host genetic susceptibility to mycobacterial infections can serve as a model for the investigation of host susceptibility to other infectious diseases.

Political legitimacy and European monetary union: contracts, constitutionalism and the normative logic of two-level games.

The crisis of the euro area has severely tested the political authority of the European Union (EU). The crisis raises questions of normative legitimacy both because the EU is a normative order and because the construction of economic and monetary union (EMU) rested upon a theory that stressed the normative value of the depoliticization of money. However, this theory neglected the normative logic of the two-level game implicit in EMU. It also neglected the need for an impartial and publically acceptable constitutional order to acknowledge reasonable disagreements. By contrast, we contend that any reconstruction of the EU's economic constitution has to pay attention to reconciling a European monetary order with the legitimacy of member state governance. The EU requires a two-level contract to meet this standard. Member states must treat each other as equals and be representative of and accountable to their citizens on an equitable basis. These criteria entail that the EU's political legitimacy requires a form of demoicracy that we call 'republican intergovernmentalism'. Only rules that could be acceptable as the product of a political constitution among the peoples of Europe can ultimately meet the required standards of political legitimacy. Such a political constitution could be brought about through empowering national parliaments in EU decision-making.

Staphylococcus lugdunensis infection sites: predominance of abscesses in the pelvic girdle region.

We used a screening protocol to identify Staphylococcus lugdunensis in clinical specimens with pure or predominant growth of coagulase-negative staphylococci. S. lugdunensis was isolated from 17 patients in a 12-month period and was judged to be the cause of infection in 14 cases. In 13 cases, the patient had a soft-tissue abscess, and in 9 of these, the abscess was located in the pelvic girdle region, which suggests that this may be the natural habitat of S. lugdunensis.

AIDS-defining illnesses among patients with HIV in Singapore, 1985 to 2001: results from the Singapore HIV Observational Cohort Study (SHOCS).

BACKGROUND: The objective was to describe the causes of initial and overall AIDS-defining disease episodes among HIV patients in Singapore. METHODS: A retrospective observational cohort study was performed of all adult patients seen at the national HIV referral center between 1985 and 2001. Data were extracted from the patients' records by ten trained healthcare workers. AIDS-defining conditions were established using predefined criteria. RESULTS: Among 1504 patients, 834 had experienced one or more AIDS-defining diseases. The most frequent causes of the initial AIDS-defining episode were Pneumocystis carinii pneumonia (35.7%), Mycobacterium tuberculosis (22.7%) and herpes simplex (7.4%). In total 1742 AIDS-defining episodes occurred. The most frequent causes were Pneumocystis carinii pneumonia (25.1%), Mycobacterium tuberculosis (16.2%) and cytomegalovirus retinitis (9.5%). CONCLUSIONS: The most frequent causes of AIDS-defining illnesses in Singapore are similar to those reported in the West, prior to the introduction of anti-retroviral therapy. Opportunistic infections remain the most frequent AIDS-defining illnesses.

Novel respiratory viruses: what should the clinician be alert for?

Since 1990, several novel respiratory viruses affecting humans have been described. In this review, we focus on three pathogens that have caused significant human mortality and raise important public health concerns: severe acute respiratory syndrome (SARS)-coronavirus, Middle East respiratory syndrome (MERS)-coronavirus and avian influenza A viruses (H5N1 and H7N9). Novel respiratory viruses have the potential to instil fear in the public and physicians alike if they are associated with a high case fatality rate. Those viruses with a significant potential for onward human-to-human transmission (including in healthcare settings) might present significant challenges for national public health services and local hospital infection control.

Outpatient parenteral antibiotic therapy in primary hip and knee arthroplasty infection managed with debridement and retention of prosthesis: a retrospective cohort study.

BACKGROUND: Attempted joint salvage of infected primary arthroplasty traditionally has utilized joint washouts in combination with costly long-term inpatient parenteral antibiotic regimens. Outpatient and home parenteral antibiotic therapy (OHPAT) represents a potential alternative. However, there is a lack of published data on its value for primary deep arthroplasty infection. This paper describes the surgical and microbiologic outcomes of a cohort of patients with deep arthroplasty infections treated with OHPAT after surgical washout and debridement. METHODS: Local OHPAT records identified all patients who underwent attempted joint salvage of a primary hip or knee replacement complicated by a deep post-operative infection between February 2006 and February 2009. Minimum follow-up for all patients was 24 mos. For each patient, hospital records were reviewed to ascertain the effectiveness of treatment. RESULTS: In total, 14 patients (10 total knee replacements; four total hip replacements) were identified from the records. Eleven joints (79%) were salvaged. There was a trend toward a higher salvage rate with early infection (<6 mos after primary surgery), with eight of nine joints (89%) being salvaged, versus 60% (three of five) for later presentation. Methicillin-sensitive Staphylococcus aureus was the most common organism identified (43% of cases), and 57% of infections were polymicrobial. The average duration of OHPAT was 58 days. Two patients were readmitted because of clinical deterioration, both of whom later required revision. All patients, regardless of their outcomes, stated they were satisfied with the OHPAT service and believed it was more convenient than inpatient treatment. We estimate OHPAT saved approximately £13,000 per patient episode. CONCLUSIONS: Use of OHPAT for deep infection after primary arthroplasty has a high success rate. It is effective at identifying patients failing treatment, is cost-effective, and has a high level of patient satisfaction.