Dysphagia, dysarthria and aphasia following a first acute ischaemic stroke: incidence and associated factors.

BACKGROUND AND PURPOSE: Dysphagia, dysarthria and aphasia are common symptoms following acute stroke; however, limited data are available from recent prospective clinical trials. The aim of this study was to determine the incidence and associated factors of dysphagia, dysarthria and aphasia following a first acute ischaemic stroke in patients admitted to a comprehensive stroke center. METHODS: All first ischaemic stroke patients admitted to the Stroke Unit of Ghent University Hospital within 48 h after symptom onset were enrolled in this prospective study between March 2018 and October 2019. Dysphagia and communication screenings were performed within 3 days after admission. When dysphagia, dysarthria and/or aphasia were assumed, standardized assessments were performed. Incidence rates were calculated as point estimates (%) with 95% confidence intervals (CI). Associated factors were calculated via multivariate binary logistic regression analyses. RESULTS: Dysphagia, dysarthria and aphasia were present in 23% (95% CI, 17-31), 44% (95% CI, 37-52) and 23% (95% CI, 17-30), respectively of 151 first ischaemic stroke patients [67 female, mean age 67 (SD 14) years]. Separate multivariate binary logistic regression analyses showed that dysphagia, dysarthria and aphasia were significantly associated with age-adjusted stroke severity at baseline [odds ratio (OR), 1.16; 95% CI, 1.09-1.23; OR, 1.13; 95% CI, 1.07-1.20 and OR, 1.11; 95% CI, 1.05-1.17 respectively]. Corrected for stroke severity, the risk for aphasia increased by 4% per year of age (OR, 1.04; 95% CI, 1.00-1.07). Adjusted for age and stroke severity, aphasia was significantly associated with large artery atherosclerosis as stroke etiology (OR, 3.91; 95% CI, 1.18-12.98). CONCLUSIONS: This trial showed a high incidence of dysphagia, dysarthria and aphasia following acute ischaemic stroke. Stroke severity was an associated factor for all three symptoms.

Measuring the cost of a pediatric vaccine administration in the UK.

The administration of a vaccine dose involves a series of activities prior to and on the day of vaccine delivery. Total vaccination cost should include the cost of each activity, which is often not done or poorly reported. To calculate those costs a field study was performed in 6 United Kingdom (UK) sites (General Practitioner (GP) practices) during a 4-month period (April-June 2015). First, a workflow map of all the relevant vaccine-related activities per site was obtained through interviews. Second, time estimates for activities happening prior to the vaccination day were obtained through interviews and associated costs were calculated. A prospective, non-interventional study using Time & Motion (T&M) methodology was used to measure time for activities happening on the day of vaccination. Consumables, wastage, and guardian time were also collected. Third, the time for each task and for all tasks combined during the T&M study was analyzed using a random intercept model to account for site effect. Hundred and twenty-three T&M observations with approximately 20 per site were collected and were equally stratified by vaccination visit during the first year of a baby's life. Total cost per visit was £11.9 (site range: £8.6-£17.0) when supply cost and time for activities prior to the vaccination day were included. Time per dose administrated was 7.1 min (site range: 5.7-9.2) and the associated cost was £4.3 (site range: £3.1-£6.2). The study demonstrates an accurate reflection of the time and cost involved in a vaccine dose administration in a pediatric setting in the UK. The amount measured is consistent with the current National Health Services fee schedule.

An unusual neoplasm of the pancreas: Pancreatic metastasis of a Merkel cell carcinoma. Case report and review of the literature.

Isolated pancreatic metastases are rare. The differential diagnosis of pancreatic neoplasms can be difficult, especially it can be troublesome to obtain tissue diagnosis. However, pancreatic lesions in patients with a history of a malignancy must be considered to be metastases. We present a case of a patient with a history of a Merkel cell carcinoma (MCC) in the neck. Twelve months after this diagnosis a follow-up CT shows a large isolated tumor in the head of the pancreas. Histological and immunohistochemical studies of specimen obtained through ultrasound-guided transabdominal biopsy, show similar characteristics as the primary MCC. To our knowledge twelve cases of a pancreatic metastasis of a MCC have been reported in English literature. A review of the literature was performed.

The novel ADAMTS13-p.D187H mutation impairs ADAMTS13 activity and secretion and contributes to thrombotic thrombocytopenic purpura in mice.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) is characterized by mutations in the ADAMTS13 gene, which either impair protein secretion or influence ADAMTS13 (A Disintegrin-like And Metalloprotease domain with ThromboSpondin type-1 motif, member 13) activity. Phenotypic consequences of these mutations have not yet been evaluated in animal models for TTP. OBJECTIVES: To identify the in vitro effect of a novel ADAMTS13 mutation and to investigate whether this mutation induces TTP in vivo. METHODS: All 29 ADAMTS13 exons with exon-intron boundaries of a patient with pregnancy-onset TTP were sequenced. Wild-type and mutant ADAMTS13 proteins were both transiently and stably expressed in human embryonic kidney cells, and their activity was evaluated in vitro using fluorescence resonance energy transfer and flow assays. Molecular dynamics simulations were performed to study Ca(2+) stability. Adamts13(-/-) mice were hydrodynamically injected with wild-type and mutant expression plasmids and triggered with recombinant human von Willebrand factor. RESULTS: We identified a novel heterozygous c.559G>C mutation in exon 6 of the proposita's ADAMTS13 gene. This mutation resulted in a p.Asp187His substitution (p.D187H), which was located in the high affinity Ca(2+) -binding site in the metalloprotease domain of ADAMTS13. The homozygous p.D187H mutation down-regulated ADAMTS13 activity in vitro. Impaired proteolytic activity was linked to unstable Ca(2+) binding as visualized using a molecular dynamics simulation. In addition, the p.D187H mutation affects protein secretion in vitro. In Adamts13(-/-) mice, the homozygous p.D187H mutation reduced ADAMTS13 secretion and activity and contributed to TTP when these mice were triggered with recombinant human von Willebrand factor. CONCLUSIONS: Our data indicate that the p.D187H mutation impairs ADAMTS13 activity and secretion and is responsible for TTP onset in mice.

Cost-effectiveness of linezolid vs vancomycin in suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Germany.

BACKGROUND: The oxazolidinone antibiotic linezolid has demonstrated efficacy in treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In a retrospective analysis of two prospective randomized clinical trials in patients with nosocomial pneumonia (NP), initial therapy with linezolid produced significantly better clinical cure and survival rates than vancomycin in the subset of patients with documented MRSA infection. This study was designed to evaluate the economic impact of these clinical outcomes from the perspective of the German health care system to determine the use of these regimens in the light of limited resources and rising costs. METHODS: A decision-analytic model using clinical trial data was developed to examine the costs and outcomes of treatment with linezolid or vancomycin in hospitalized patients with NP caused by suspected MRSA. The model followed an average patient from initiation of empiric treatment until treatment success, death, or second-line treatment failure. Local treatment patterns and resource use were obtained from a Delphi panel. Costs were taken from published sources. Outcomes included total cost per patient, cost per additional cure, cost per death avoided, and cost per life-year gained. RESULTS: The model calculated that linezolid was associated with an 8.7% higher cure rate compared with vancomycin (73.6% vs 64.9%, respectively). Average total costs per episode for linezolid- and vancomycin-treated patients were 12,829 and 12,409, respectively. Death rates were 13.2% lower with linezolid than with vancomycin (20.7% vs 33.9%), resulting in an average of 2.3 life-years gained per linezolid-treated patient in a 65-year-old cohort (14.0 life-years vs 11.7 life-years). With linezolid, incremental costs per death avoided and per patient cured were 3,171 and 4,813, respectively. The base case estimated a similar mean length of stay for both drugs (11.2 vs 10.8 days). One-way sensitivity analyses did not change the overall results. CONCLUSION: The model estimated a higher clinical cure (+8.7%) and survival (+13.2%) for linezolid compared with vancomycin at an incremental cost of 420 per treatment episode. The cost-benefit profile suggests that linezolid could be considered a cost-effective alternative to vancomycin in the treatment of patients with NP caused by suspected MRSA in Germany.

Cost-effectiveness of linezolid versus vancomycin for hospitalized patients with complicated skin and soft-tissue infections in France.

UNLABELLED: Studies have shown similar clinical cure rates and shorter length of hospitalization when using linezolid compared to vancomycin in patients with complicated skin and soft-tissue infections due to suspected or proven methicillin-resistant Staphylococcus aureus (MRSA). OBJECTIVE: This study had for aim to compare the cost-effectiveness of linezolid versus vancomycin in French healthcare settings. METHOD: A decision-analytic model followed an average patient from the initiation of an empiric treatment until cure, death or second-line treatment failure. A clinical data probability was obtained from clinical trials, resource utilization data (including treatment duration and length of hospitalization) and prevalence of MRSA was obtained from a Delphi panel, and costs from published sources. RESULTS: First-line cure rate for linezolid-treated patients was 90.7% versus 85.5% for vancomycin; the total cure rates after two lines of treatment were 98.5% and 98.0%, respectively. The average total cost was 7,778euro for linezolid versus 8,777euro for vancomycin. The mean estimated length of hospitalization after two lines of treatment was 10.7 days for linezolid versus 13.3 days for vancomycin. The increased effectiveness and reduced cost lead to more frequent prescription. This did not change after one-way sensitivity analyses. CONCLUSION: Linezolid may be considered as a cost-effective treatment for patients with complicated skin and soft-tissue infections suspected to be MRSA related in France.

Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy.

BACKGROUND: Ibandronate is the first third-generation bisphosphonate to have both oral and intravenous (i.v.) efficacy. An incremental cost-effectiveness model compared oral ibandronate with i.v. zoledronic acid and i.v. generic pamidronate in female breast cancer patients with metastatic bone disease, undergoing i.v. chemotherapy. METHODS: A global economic model was adapted to the UK National Health Service (NHS), with primary outcomes of direct healthcare costs and quality-adjusted life years (QALYs). Efficacy, measured as relative risk reduction of skeletal-related events (SREs), was obtained from clinical trials. Resource use data for i.v. bisphosphonates and the cost of managing SREs were obtained from published studies. Hospital management and SRE treatment costs were taken from unit cost databases. Monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with/without an SRE to adjust survival for quality of life. Model design and inputs were validated through expert UK clinician review. RESULTS: Total cost, including drug acquisition, was pound 386 less per patient with oral ibandronate vs. i.v. zoledronic acid and pound 224 less vs. i.v. generic pamidronate. Oral ibandronate gained 0.019 and 0.02 QALYs vs. i.v. zoledronic acid and i.v. pamidronate, respectively, making it the economically dominant option. At a threshold of pound 30,000 per QALY, oral ibandronate was cost-effective vs. zoledronic acid in 85% of simulations and vs. pamidronate in 79%. CONCLUSIONS: Oral ibandronate is a cost-effective treatment for metastatic bone disease from breast cancer due to reduced SREs, bone pain, and cost savings from avoidance of resource use commonly associated with bisphosphonate infusions.

One year comparison of costs of coronary surgery versus percutaneous coronary intervention in the stent or surgery trial.

OBJECTIVES: To compare initial and one year costs of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in the stent or surgery trial. DESIGN: Prospective, unblinded, randomised trial. SETTING: Multicentre study. PATIENTS: 988 patients with multivessel disease. INTERVENTIONS: CABG and stent assisted PCI. MAIN OUTCOME MEASURES: Initial hospitalisation and one year follow up costs. RESULTS: At one year mortality was 2.5% in the PCI arm and 0.8% in the CABG arm (p = 0.05). There was no difference in the composite of death or Q wave myocardial infarction (6.9% for PCI v 8.1% for CABG, p = 0.49). There were more repeat revascularisations with PCI (17.2% v 4.2% for CABG). There was no significant difference in utility between arms at six months or at one year. Quality adjusted life years were similar 0.6938 for PCI v 0.6954 for PCI, Delta = 0.00154, 95% confidence interval (CI) -0.0242 to 0.0273). Initial length of stay was longer with CABG (12.2 v 5.4 days with PCI, p < 0.0001) and initial hospitalisation costs were higher (7321 pounds sterling v 3884 pounds sterling for PCI, Delta = 3437 pounds sterling, 95% CI 3040 pounds sterling to 3848 pounds sterling). At one year the cost difference narrowed but costs remained higher for CABG (8905 pounds sterling v 6296 pounds sterling for PCI, Delta = 2609 pounds sterling, 95% CI 1769 pounds sterling to 3314 pounds sterling). CONCLUSIONS: Over one year, CABG was more expensive and offered greater survival than PCI but little added benefit in terms of quality adjusted life years. The additional cost of CABG can be justified only if it offers continuing benefit at no further increase in cost relative to PCI over several years.

Mutations that alter initiation codon discrimination by Escherichia coli initiation factor IF3.

This work describes the isolation of mutations in infC, the structural gene for IF3, using different genetic screens. Among 21 mutants characterised, seven were shown to produce stable variant IF3 proteins unable to fully complement a strain carrying a chromosomal deletion of the infC gene. The mutants were also shown to be unable to normally discriminate against several non-canonical initiation codons such as AUU and ACG. The two mutants with the strongest complementation or discrimination defects carry changes in the C-terminal domain of IF3, which is responsible for the binding of the factor to the 30 S ribosomal subunit. We show that the first mutant has an expected decreased but the second an unexpected increased capacity to bind the 30 S subunit. The in vivo defects of the second mutant are explained by its capacity to bind unspecifically to other targets, as shown by its increased affinity for the 50 S subunit, which is normally not recognised by the factor. Interestingly, this mutant corresponds to a change of an acidic residue that might play a negative discriminatory role in preventing interactions with non-cognate RNAs, as has been reported for acidic residues of aminoacyl-tRNA synthetases shown to be involved in tRNA recognition.

The interdomain linker of Escherichia coli initiation factor IF3: a possible trigger of translation initiation specificity.

Initiation factor IF3 is responsible for the accuracy of translation initiation in bacteria, by destabilizing complexes involving non-initiator tRNA and/or nonstart codons. This proofreading is performed on the 30S subunit to which IF3 binds selectively. IF3 has an unusual architecture, with two globular domains connected by a mobile, positively charged linker. Here, we have investigated the function of this flexible tether by probing its conformation when IF3 is bound to the ribosomal RNA. Using site-directed mutagenesis of the linker region, we have also selectively modified its length, its flexibility and its chemical composition. The function of the mutant genes was assayed in vivo, and the structural and biochemical properties of some of the corresponding variant proteins were characterized in vitro. The two isolated domains of IF3 were also co-expressed in order to test the requirement for their covalent attachment. The results indicate that the physical link between the two domains of IF3 is essential for the function of this protein, but that the exact length and chemical composition of the linker can be varied to a large extent. A model is presented in which the extended linker would act as a 'strap', triggering a conformational change in the 30S subunit, which would then ensure initiator tRNA selection.

Heteronuclear NMR studies of E. coli translation initiation factor IF3. Evidence that the inter-domain region is disordered in solution.

Initiation factor IF3 from Escherichia coli plays a critical role in the selection of the correct initiation codon. This protein is composed of two domains, connected by a lysin-rich hydrophilic linker. The conformation of native IF3 was investigated by heteronuclear NMR spectroscopy. The two domains are independent and show little or no interaction. Heteronuclear relaxation studies of a sample selectively labelled on lysine residues demonstrates that the inter-domain linker is highly flexible, exhibiting increased 15N T2 values and negative 1H[15N] nuclear Overhause effects over a length of at least eight residues. Analysis of the rotational correlation times further shows that the motions of the two domains are most likely uncorrelated. The inter-domain linker thus displays almost totally unrestricted motions. Accordingly, the amide protons in the central region are shown to be in fast exchange with water. Such a high degree of flexibility of the inter-domain linker might be required for IF3 domains to interact with distant regions of the ribosome.

Synthesis and conformational study of two L-prolyl-L-leucyl-glycinamide analogues with a reduced peptide bond.

The peptide bond between Pro-Leu or Leu-Gly in Pro-Leu-Gly-NH2 was replaced by a CH2-NH function. The 1H and 13C n.m.r. studies demonstrated that HCl X Pro-Leu psi (CH2-NH)Gly-NH2 10 adopted a conformation in DMSO that is similar to the previously postulated beta-turn for the natural hormone. This was not the case for the other analogue. In vivo tests on 10 revealed an activity approximately equal to the natural compound and an increased toxicity.