Mycobacterium tuberculosis (Mtb) is an obligate human pathogen and the causative agent of tuberculosis
. Although Mtb can synthesize vitamin B
(cobalamin) de novo, uptake of cobalamin has been linked ...to pathogenesis of tuberculosis
. Mtb does not encode any characterized cobalamin transporter
; however, the gene rv1819c was found to be essential for uptake of cobalamin
. This result is difficult to reconcile with the original annotation of Rv1819c as a protein implicated in the transport of antimicrobial peptides such as bleomycin
. In addition, uptake of cobalamin seems inconsistent with the amino acid sequence, which suggests that Rv1819c has a bacterial ATP-binding cassette (ABC)-exporter fold
. Here, we present structures of Rv1819c, which reveal that the protein indeed contains the ABC-exporter fold, as well as a large water-filled cavity of about 7,700 Å
, which enables the protein to transport the unrelated hydrophilic compounds bleomycin and cobalamin. On the basis of these structures, we propose that Rv1819c is a multi-solute transporter for hydrophilic molecules, analogous to the multidrug exporters of the ABC transporter family, which pump out structurally diverse hydrophobic compounds from cells
.
Uptake of vitamin B12 is essential for many prokaryotes, but in most cases the membrane proteins involved are yet to be identified. We present the biochemical characterization and high-resolution ...crystal structure of BtuM, a predicted bacterial vitamin B12 uptake system. BtuM binds vitamin B12 in its base-off conformation, with a cysteine residue as axial ligand of the corrin cobalt ion. Spectroscopic analysis indicates that the unusual thiolate coordination allows for decyanation of vitamin B12. Chemical modification of the substrate is a property other characterized vitamin B12-transport proteins do not exhibit.
A new interprofessional model incorporating non-dispensing pharmacists in general practice teams can improve the quality of pharmaceutical care. However, results of the model are dependent on the ...context. Understanding when, why and how the model works may increase chances of successful broader implementation in other general practices. Earlier theories suggested that the results of the model are achieved by bringing pharmacotherapeutic knowledge into general practices. This mechanism may not be enough for successful implementation of the model. We wanted to understand better how establishing new interprofessional models in existing healthcare organisations takes place.
An interview study, with a realist informed evaluation was conducted. This qualitative study was part of the Pharmacotherapy Optimisation through Integration of a Non-dispensing pharmacist in primary care Teams (POINT) project. We invited the general practitioners of the 9 general practices who (had) worked closely with a non-dispensing pharmacist for an interview. Interview data were analysed through discussions about the coding with the research team where themes were developed over time.
We interviewed 2 general practitioners in each general practice (18 interviews in total). In a context where general practitioners acknowledge the need for improvement and are willing to work with a non-dispensing pharmacist as a new team member, the following mechanisms are triggered. Non-dispensing pharmacists add new knowledge to current general practice. Through everyday talk (discursive actions) both general practitioners and non-dispensing pharmacists evolve in what they consider appropriate, legitimate and imaginable in their work situations. They align their professional identities.
Not only the addition of new knowledge of non-dispensing pharmacist to the general practice team is crucial for the success of this interprofessional healthcare model, but also alignment of the general practitioners' and non-dispensing pharmacists' professional identities. This is essentially different from traditional pharmaceutical care models, in which pharmacists and GPs work in separate organisations. To induce the process of identity alignment, general practitioners need to acknowledge the need to improve the quality of pharmaceutical care interprofessionally. By acknowledging the aspect of interprofessionality, both general practitioners and non-dispensing pharmacists will explore and reflect on what they consider appropriate, legitimate and imaginable in carrying out their professional roles.
The POINT project was pre-registered in The Netherlands National Trial Register, with Trial registration number NTR-4389.
Aims
To evaluate the effect of non‐dispensing pharmacists (NDPs) integrated in general practice on medication‐related hospitalisations, drug burden index and costs in patients at high risk of ...medication problems (being 65 years or older and using 5 or more chronic medications).
Methods
This was a multicentre, nonrandomised, controlled intervention study with pre–post comparison (2013 vs June 2014 to May 2015) in 25 general practices in the Netherlands, comparing NDP‐led care (intervention) with 2 current pharmaceutical care models (usual care and usual care plus). In the intervention group, 10 specially trained NDPs were employed in general practices to take integral responsibility for the pharmaceutical care. They provided a broad range of medication therapy management services both on patient level (e.g. clinical medication review) and practice level (e.g. quality improvement projects). In the control groups, pharmaceutical care was provided as usual by general practitioners and community pharmacists, or as usual plus, when pharmacists were additionally trained in performing medication reviews.
Results
Overall, 822 medication‐related hospitalisations were identified among 11 281 high‐risk patients during the intervention period. After adjustment for clustering and potential confounders, the rate ratio of medication‐related hospitalisations in the intervention group compared to usual care was 0.68 (95% confidence interval: 0.57–0.82) and 1.05 (95% confidence interval: 0.73–1.52) compared to usual care plus. No differences in drug burden index or costs were found.
Conclusions
In general practices with an integrated NDP, the rate of medication‐related hospitalisations is lower compared to usual care. No differences with usual care plus were found.
The
Escherichia coli peptide binding protein OppA is an essential component of the oligopeptide transporter Opp. Based on studies on its orthologue from
Salmonella typhimurium, it has been proposed ...that OppA binds peptides between two and five amino acids long, with no apparent sequence selectivity. Here, we studied peptide binding to
E. coli OppA directly and show that the protein has an unexpected preference for basic peptides. OppA was expressed in the periplasm, where it bound to available peptides. The protein was purified in complex with tightly bound peptides. The crystal structure (up to 2.0 Å) of OppA liganded with the peptides indicated that the protein has a preference for peptides containing a lysine. Mass spectrometry analysis of the bound peptides showed that peptides between two and five amino acids long bind to the protein and indeed hinted at a preference for positively charged peptides. The preference of OppA for peptides with basic residues, in particular lysines, was corroborated by binding studies with peptides of defined sequence using isothermal titration calorimetry and intrinsic protein fluorescence titration. The protein bound tripeptides and tetrapeptides containing positively charged residues with high affinity, whereas related peptides without lysines/arginines were bound with low affinity. A structure of OppA in an open conformation in the absence of ligands was also determined to 2.0 Å, revealing that the initial binding site displays a negative surface charge, consistent with the observed preference for positively charged peptides. Taken together,
E. coli OppA appears to have a preference for basic peptides.
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► The
E. coli peptide binding protein OppA is part of the oligopeptide permease Opp. ► The substrate preferences of OppA have been defined. ► OppA has a preference for positively charged peptides.
Kisspeptins (KPs) and their receptor (GPR54 or KiSS1R) play a key-role in regulation of the hypothalamic-pituitary-gonadal axis and are therefore interesting targets for therapeutic interventions in ...the field of reproductive endocrinology. As dogs show a rapid and robust LH response after the administration of KP10, they can serve as a good animal model for research concerning KP signaling. The aims of the present study were to test the antagonistic properties of KP analogs p234, p271, p354, and p356 in vitro, by determining the intracellular Ca2+ response of CHEM1 cells that stably express human GPR54, and to study the in vivo effects of these peptides on basal plasma LH concentration and the KP10-induced LH response in female dogs. Exposure of the CHEM1 cells to KP-10 resulted in a clear Ca2+ response. P234, p271, p354, and p356 did not prevent or lower the KP10-induced Ca2+ response. Moreover, the in vivo studies in the dogs showed that none of these supposed antagonists lowered the basal plasma LH concentration and none of the peptides lowered the KP10-induced LH response. In conclusion, p234, p271, p354, and p356 had no antagonistic effects in vitro nor any effect on basal and kisspeptin-stimulated plasma LH concentration in female dogs.
Medication review procedures have been developed in many countries to improve rational and safe medication use. The similarities, comprehensiveness, and effectiveness of these procedures has not been ...assessed, or compared.
The aim of this study was to explore medication review practices in European countries.
An online survey was sent to 32 European countries (all 28 European Union countries and 4 other European countries) by email to one person in each country known to be aware of medication review practices in their country in May 2011. The informants were identified through Pharmaceutical Group of European Union. To complement and validate the information received through Pharmaceutical Group of European Union, medication review experts involved in Pharmaceutical Care Network Europe were contacted. The survey assessed comprehensiveness of the medication review procedures classified according to 3 types in terms of settings; access to patient clinical information; patient involvement; availability of documentation and information; collaboration with the physician; quality control, and training required.
Almost two thirds (64%) of the 25 European countries which responded (response rate 78%) indicated having at least one type of medication review procedure in their country. In the community setting prescription (type I) and adherence (type II) medication reviews were the most common (established in 9 and 11 countries, respectively). More comprehensive type III clinical medication reviews requiring access to clinical patient information were still rare, and just being established in 6 countries.
Medication review procedures are becoming common in health care throughout Europe, however improving their comprehensiveness would require better access to patient information for those professionals conducting clinical medication reviews. In addition to benchmarking, the inventory can enhance cooperation between countries and stakeholders involved in medication review practice development nationally and internationally.
Aims and Objectives
Targeting older patients with predictive factors for drug‐related problems (DRPs) could make clinical medication reviews more cost‐effective. The aim of this study was to identify ...the number, type, and potential predictive factors for DRPs in older polypharmacy patients.
Methods
Community pharmacists performed clinical medication reviews and documented DRPs, types of interventions, and their implementation in older patients.
Results
Three hundred eighty‐eight medication reviews were analyzed, 964 DRPs (average 2.5 ± 1.9), and 1022 interventions (average 2.6 ± 2.0) were identified. The overall implementation rate of interventions was 70.1%, the highest was observed in interventions aiming to resolve the lack of therapy monitoring (86.8%). Patients with ≥12 medications had an increased risk of ≥5 DRPs (P < .001). Asthma was associated with lack of adherence (P = .002), lack of aspirin, statins, and proton pump inhibitors use with additional therapy needed (P = .002‐.004). Predictive factors for drug interactions were antihypertensive medications and/or medications with narrow therapeutic index (P < .05). Lack of efficacy was associated with diabetes (P = .006). Nonsteroidal anti‐inflammatory drugs were risk factors for inappropriate drug selection (P = .002). Lack of monitoring was associated with hypertension (P = .013), whereas benzodiazepines (P < .001) and aspirin (P = .021) were overused.
Conclusion
Patients with asthma, hypertension, and diabetes and lack of statin, antithrombotic agent, and/or proton pump inhibitor use were associated with higher risks for DRPs.
Summary
What is known and objective
Limited and conflicting evidence exists on the effect of a multicomponent pharmaceutical care intervention (i.e. medication review, involving collaboration between ...general practitioners (GPs), pharmacists and patients) on medication‐related hospitalizations, survival, adverse drug events (ADEs) and quality of life. We aimed to investigate the effect of a multicomponent pharmaceutical care intervention on these outcomes.
Methods
An open controlled multicentre study was conducted within primary care settings. Patients with a high risk on medication‐related hospitalizations based on old age, use of five or more medicines, non‐adherence and type of medication used were included. The intervention consisted of a patient interview, a review of the pharmacotherapy and the execution and follow‐up evaluation of a pharmaceutical care plan. The patient's own pharmacist and GP carried out the intervention. The control group received usual care and was cared for by a GP other than the intervention GP. The primary outcome of the study was the frequency of hospital admissions related to medication within the study period of 12 months for each patient. Secondary outcomes were survival, quality of life and ADEs.
Results and discussion
364 intervention and 310 control patients were included. Less medication‐related hospital admissions were found in the intervention group (n = 6; 1·6%) than in the control group (n = 10; 3·2%) but the overall effect was not statistically significant (hazard ratio (HR) 0·50, 95% confidence interval (CI) 0·12–1·59). The secondary outcomes were not statistically significantly different either. The study was underpowered, which may explain the negative results. A post hoc analysis showed that the effect of the intervention was statistically significant for patients with five diseases or more: five diseases, HR 0·28 (95% bootstrap CI: 0·056–0·73) and eight diseases, HR 0·11 (95% CI: 0·013–0·34).
What is new and conclusion
A multicomponent pharmaceutical care intervention does not prevent medication‐related hospital admissions. Whether this is true for such interventions in general is unknown, because the PHARM study was underpowered. The intervention may significantly reduce medication‐related hospitalizations in patients with five or more comorbidities, but this is only based on a post hoc analysis and thus needs confirmation in large controlled trials.
The driving performance is easily impaired as a consequence of the use of alcohol and/or licit and illicit drugs. However, the role of drugs other than alcohol in motor vehicle accidents has not been ...well established. The objective of this study was to estimate the association between psychoactive drug use and motor vehicle accidents requiring hospitalisation.
A prospective observational case-control study was conducted in the Tilburg region of The Netherlands from May 2000 to August 2001. Cases were car or van drivers involved in road crashes needing hospitalisation. Demographic and trauma related data was collected from hospital and ambulance records. Urine and/or blood samples were collected on admission.
Controls were drivers recruited at random while driving on public roads. Sampling was conducted by researchers, in close collaboration with the Tilburg police, covering different days of the week and times of the day. Respondents were interviewed and asked for a urine sample. If no urine sample could be collected, a blood sample was requested.
All blood and urine samples were tested for alcohol and a number of licit and illicit drugs. The main outcome measures were odds ratios (OR) for injury crash associated with single or multiple use of several drugs by drivers.
The risk for road trauma was increased for single use of benzodiazepines (adjusted OR 5.1 (95% Cl: 1.8–14.0)) and alcohol (blood alcohol concentrations of 0.50–0.79
g/l, adjusted OR 5.5 (95% Cl: 1.3–23.2) and ≥0.8
g/l, adjusted OR 15.5 (95% Cl: 7.1–33.9)). High relative risks were estimated for drivers using combinations of drugs (adjusted OR 6.1 (95% Cl: 2.6–14.1)) and those using a combination of drugs and alcohol (OR 112.2 (95% Cl: 14.1–892)). Increased risks, although not statistically significantly, were assessed for drivers using amphetamines, cocaine, or opiates. No increased risk for road trauma was found for drivers exposed to cannabis.
The study concludes that drug use, especially alcohol, benzodiazepines and multiple drug use and drug–alcohol combinations, among vehicle drivers increases the risk for a road trauma accident requiring hospitalisation.
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