Initiating Heavy-atom Based Phasing by Multi-Dimensional Molecular Replacement

To obtain an electron-density map from a macromolecular crystal the phase-problem needs to be solved, which often involves the use of heavy-atom derivative crystals and concomitantly the determination of the heavy atom substructure. This is customarily done by direct methods or Patterson-based approaches, which however may fail when only poorly diffracting derivative crystals are available, as often the case for e.g. membrane proteins. Here we present an approach for heavy atom site identification based on a Molecular Replacement Parameter Matrix (MRPM) search. It involves an n-dimensional search to test a wide spectrum of molecular replacement parameters, such as clusters of different conformations. The result is scored by the ability to identify heavy-atom positions, from anomalous difference Fourier maps, that allow meaningful phases to be determined. The strategy was successfully applied in the determination of a membrane protein structure, the CopA Cu+-ATPase, when other methods had failed to resolve the heavy atom substructure. MRPM is particularly suited for proteins undergoing large conformational changes where multiple search models should be generated, and it enables the identification of weak but correct molecular replacement solutions with maximum contrast to prime experimental phasing efforts.Comment: 19 pages total, main paper: 6 pages (2 figures), supplementary material: 13 pages (2 figures, 9 tabels

Diagnosis and Antibiotic Treatment of Urinary Tract Infections in Danish General Practice: A Quality Assessment

Rational antibiotic treatment of urinary tract infections (UTI) is important. To improve the quality of antibiotic treatment of UTI, it is essential to obtain insight into diagnostic approaches and prescribing patterns in general practice. The aim of this study was to investigate the quality of diagnostics and treatment of UTI in general practice by means of quality indicators (QIs). QIs provide a quantitative measure of quality and are defined by a numerator (the number of patients receiving a specific investigation or treatment) and a denominator (the number of patients included in the quality assessment). For adult patients with suspected UTI, practices registered the following: age, sex, risk factors, symptoms and signs, examinations, diagnosis and treatment. The levels of the QIs were compared with their corresponding standards. Half of the patients diagnosed with lower UTI or pyelonephritis fulfilled the diagnostic criteria for UTI: characteristic UTI symptoms and clear signs of bacteriuria, respectively. Urinalysis was performed for nearly all patients, including patients without characteristic symptoms of UTI. One-fourth of the patients with suspected lower UTI were treated with antibiotics despite no urinalysis and nearly half received antibiotics despite an inconclusive dipstick test. Pivmecillam was the preferred antibiotic. The findings of this study indicate that there is room for improvement in the management of UTI in Danish general practice

The Danish National Database for Asthma

AIM OF THE DATABASE: Asthma is the most prevalent chronic disease in children, adolescents, and young adults. In Denmark (with a population of 5.6 million citizens), >400,000 persons are prescribed antiasthmatic medication annually. However, undiagnosed cases, dubious diagnoses, and poor asthma management are probably common. The Danish National Database for Asthma (DNDA) was established in 2015. The aim of the DNDA was to collect the data on all patients treated for asthma in Denmark and to monitor asthma occurrence, the quality of diagnosis, and management. STUDY POPULATION: Persons above the age of 6 years, with a specific focus on 6–44 years, are included. The DNDA links three existing nationwide registries of administrative records in the Danish health care system: the National Patient Register, the National Health Insurance Services Register, and the National Prescription Registry. For each year, the inclusion criteria are a second purchase of asthma prescription medicine within a 2-year period (National Prescription Registry) or a diagnosis of asthma (National Patient Register). Patients with chronic obstructive pulmonary disease are excluded, but smokers are not excluded. DESCRIPTIVE DATA: A total of 366,471 prevalent patients with asthma have been identified (year 2014 – as a preliminary test search). This number is in agreement with the estimates of ~400,000 inhabitants that are available for patients with possible asthma in Denmark. Data encompass the following quality indicators: annual asthma control visits and pharmacological therapy. MAIN VARIABLES: The variables included are spirometry, as well as tools for diagnosis (including allergy testing), smoking status, height, weight, and acute hospital admissions and unscheduled visits. CONCLUSION: DNDA is available from January 1, 2016

How defensive medicine is defined and understood in European medical literature:protocol for a systematic review

IntroductionThe term defensive medicine, referring to actions motivated primarily by litigious concerns, originates from the USA and has been used in medical research literature since the late 1960s. Differences in medical legal systems between the US and most European countries with no tort legislation raise the question whether the US definition of defensive medicine holds true in Europe.AimTo present the protocol of a systematic review investigating variations in definitions and understandings of the term ‘defensive medicine’ in European research articles.Methods and analysisIn concordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic review of all medical research literature that investigate defensive medicine will be performed by two independent reviewers. The databases PubMed, Embase and Cochrane will be systematically searched on the basis of predetermined criteria. Data from all included European studies will systematically be extracted including the studies’ definitions and understandings of defensive medicine, especially the motives for doing medical actions that the study regards as ‘defensive’.Ethics and disseminationNo ethics clearance is required as no primary data will be collected. The results of the systematic review will be published in a peer-reviewed, international journal.PROSPERO registration numberThis review has been submitted to International Prospective Register of Systematic Reviews (PROSPERO) and is awaiting registration