This study aims to establish the relative effectiveness and safety of low molecular weight heparin in elderly patients with venous thrombosis in order to find an alternative to oral anticoagulant ...therapy with less bleeding complications in the long-term treatment of deep venous thrombosis (DVT). One hundred consecutive elderly patients (>75 years old) with venographically demonstrated proximal DVT were included in a randomized trial. All patients were treated for ten days with adjusted doses of intravenous heparin. Informed consent was obtained and on the eight day, patients were randomly allocated to receive acenocoumarol (INR 2.0-3.0) or subcutaneous enoxaparin (4000 anti-Xa units once a day) for three months. All patients were followed-up clinically and venographically for a one year period. The results were analyzed with Fisher's exact test or chi-square test as appropriate. During the treatment and surveillance period, 6 of the 50 patients (12%) who received acenocoumarol and 8 of the 50 patients (16%) who received enoxaparin had new episodes of venous thromboembolism confirmed by objective testing (p = 0.6; 95% CI for the difference: -19.5 to 11.5). Hemorrhagic complications occurred in six of the 50 patients (12%) who received acenocoumarol and in one (2%) of those on enoxaparin (p = 0.1; 95% CI for the difference: -1.8 to 21.8). Vertebral fractures developed in 2 patients (4%) in the enoxaparin group (p = 0.5; 95% CI for the difference: -11.4 to 3.4). These results show that fixed dose enoxaparin seems to be effective and safe in the long-term treatment of proximal DVT in the elderly. In comparison with oral anticoagulants, the findings are inconclusive due to the wide confidence intervals for differences between outcomes, however they suggest that the former may have less bleeding complications with similar efficacy.
•Molecular genetic and clinical findings of 64 genetically confirmed CMS patients.•Overview on relative frequencies of different subtypes in Spanish population.•Thirty-six different mutations were ...identified, with 6 of them not reported so far.•Phenotypes associated with the different CMS genes are described.
Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management.
This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian ...cancer (OC).
Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75).
The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP).
This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities.
ClinicalTrials.gov, number NCT01379989.
Bacterial type VII secretion systems secrete a wide range of extracellular proteins that play important roles in bacterial viability and in interactions of pathogenic mycobacteria with their hosts. ...Mycobacterial type VII secretion systems consist of five subtypes, ESX-1–5, and have four substrate classes, namely, Esx, PE, PPE, and Esp proteins. At least some of these substrates are secreted as heterodimers. Each ESX system mediates the secretion of a specific set of Esx, PE, and PPE proteins, raising the question of how these substrates are recognized in a system-specific fashion. For the PE/PPE heterodimers, it has been shown that they interact with their cognate EspG chaperone and that this chaperone determines the designated secretion pathway. However, both structural and pulldown analyses have suggested that EspG cannot interact with the Esx proteins. Therefore, the determining factor for system specificity of the Esx proteins remains unknown. Here, we investigated the secretion specificity of the ESX-1 substrate pair EsxB_1/EsxA_1 in Mycobacterium marinum. Although this substrate pair was hardly secreted when homologously expressed, it was secreted when co-expressed together with the PE35/PPE68_1 pair, indicating that this pair could stimulate secretion of the EsxB_1/EsxA_1 pair. Surprisingly, co-expression of EsxB_1/EsxA_1 with a modified PE35/PPE68_1 version that carried the EspG5 chaperone-binding domain, previously shown to redirect this substrate pair to the ESX-5 system, also resulted in redirection and co-secretion of the Esx pair via ESX-5. Our results suggest a secretion model in which PE35/PPE68_1 determines the system-specific secretion of EsxB_1/EsxA_1.
•Statistically significant differences between MPN and plate count have been found.•MPN underestimates the count of some bacterial genera.•Of the plate counting methods, membrane filtration is the ...most effective.
Sewage sludge usually contains potentially polluting substances such as heavy metals, organic pollutants and various organisms including bacteria, protozoa, helminths, viruses and algae, some of which may be pathogenic. Certain of these pathogens could be transferred to the soil if the sludge is used on agricultural or land recovery applications. For its application on agricultural land, sewage sludge must comply with the limits established in the legislation, which in Europe does not include quality standards regarding microbiological parameters. Nevertheless, the presence of pathogens could limit its agricultural use, as it could pose a risk to human, animal and environmental health. This study compares 4 different methodologies used in microbiological analysis in order to identify the most efficient and reliable method on determining bacteria in sewage sludge. Escherichia coli and Enterococcus faecium are used as bacterial indicators. The results obtained in this work indicate that results obtained with three different plate count methods cannot be comparable with those obtained with the MPN method. The membrane filtration method is recommended for its high precision and sensitivity, both in low and high bacterial loads. It is also concluded that it would be necessary to establish the quality standard in concordance with the method used.
This paper presents the problem of finding the optimal harvesting strategy, maximizing the expected present value of total revenues. The problem is formulated as an optimal control problem. Combining ...the techniques of Pontryagin’s Maximum Principle and the shooting method, an algorithm has been developed that is not affected by the values of the parameter. The algorithm is able to solve conventional problems as well as cases in which the optimal solution is shown to be bang–bang with singular arcs. In addition, we present a result that characterizes the optimal steady-state in infinite-horizon, autonomous models (except in the discount factor) and does not require the solution of the dynamic optimization problem. We also present a result that, under certain additional conditions, allows us to know a priori the final state solution when the optimization interval is finite. Finally, several numerical examples are presented to illustrate the different possibilities of the method.
Heart failure (HF) and diabetes are 2 strongly associated diseases. The main objective of this work was to analyze changes in the prognosis of patients with diabetes who were admitted for heart ...failure in 2 time periods.
This work is a prospective study comparing prognosis at one year of follow-up among patients with diabetes who were hospitalized for HF in either 2008–2011 or 2018. The patients are from the Spanish Society of Internal Medicine's National Heart Failure Registry (RICA, for its initials in Spanish). The primary endpoint was to analyze the composite outcome of total mortality and/or readmission due to HF in 12 months. A multivariate Cox regression model was used to evaluate the strength of association (hazard ratio HR) between diabetes and the outcomes between both periods.
A total of 936 patients were included in the 2018 cohort, of which 446 (48%) had diabetes. The baseline characteristics of the populations from the 2 periods were similar. In patients with diabetes, the composite outcome was observed in 233 (47.5%) in the 2008–2011 cohort and 162 (36%) in the 2018 cohort HR 1.48; 95% confidence interval (95%CI) 1.18–1.85; p < .001. The proportion of readmissions (HR 1.39; 95%CI 1.07–1.80; p = .015) and total mortality (HR 1.60; 95%CI 1.20–2.14; p < .001) were also significantly higher in patients with diabetes from the 2008-2011 cohort compared to the 2018 cohort.
In 2018, an improvement was observed in the prognosis for all-cause mortality and readmissions over one year of follow-up in patients with diabetes hospitalized for HF compared to the 2008–2011 period.
La insuficiencia cardíaca (IC) y la diabetes son 2 procesos fuertemente asociados. El objetivo principal fue analizar la evolución del pronóstico de los pacientes con diabetes que ingresan por IC a lo largo de 2 períodos.
Estudio prospectivo para comparar el pronóstico a un año de seguimiento entre los pacientes con diabetes que ingresan por IC en 2008–2011 y 2018. Los pacientes proceden del Registro Nacional de Insuficiencia Cardíaca (RICA) de la Sociedad Española de Medicina Interna. El objetivo primario fue analizar el desenlace combinado de mortalidad total o ingreso por IC durante 12 meses. Se utilizó una regresión multivariante de Cox para evaluar la fuerza de asociación (hazard ratio HR) de la diabetes y los desenlaces entre ambos períodos.
Se incluyó a un total de 936 pacientes en la cohorte de 2018, de los que 446 (48%) tenían diabetes. Las características basales de la población de los 2 períodos fueron similares. En los pacientes con diabetes se observó el desenlace combinado en 233 (47,5%) en la cohorte de 2008−2011 y 162 (36%) en la cohorte de 2018 (HR 1,48; intervalo de confianza del 95% IC95% 1,18–1,85; p < 0,001). La proporción de ingresos (HR 1,39; IC95% 1,07–1,80; p = 0,015) y la mortalidad total (HR 1,60; IC95% 1,20–2,14; p < 0,001) también fueron significativamente mayores en los pacientes con diabetes de la cohorte de 2008–2011 con respecto a la del 2018.
En 2018 se observa una mejoría del pronóstico de la mortalidad total y los reingresos durante un año de seguimiento en pacientes con diabetes hospitalizados por IC con respecto al período de 2008–2011.
Assess 12-month efficacy and safety of intraocular injections of 0.3 mg or 0.5 mg ranibizumab in patients with macular edema after branch retinal vein occlusion (BRVO).
Prospective, randomized, sham ...injection-controlled, double-masked, multicenter trial.
A total of 397 patients with macular edema after BRVO.
Eligible patients were randomized 1:1:1 to 6 monthly injections of 0.3 mg or 0.5 mg ranibizumab or sham injections. After 6 months, all patients with study eye best-corrected visual acuity (BCVA) ≤20/40 or central subfield thickness ≥250 μm were to receive ranibizumab. Patients could receive rescue laser treatment once during the treatment period and once during the observation period if criteria were met.
The main efficacy outcome reported is mean change from baseline BCVA letter score at month 12. Additional visual and anatomic parameters were assessed.
Mean (95% confidence interval) change from baseline BCVA letter score at month 12 was 16.4 (14.5-18.4) and 18.3 (15.8-20.9) in the 0.3 mg and 0.5 mg groups, respectively, and 12.1 (9.6-14.6) in the sham/0.5 mg group (P<0.01, each ranibizumab group vs. sham/0.5 mg). The percentage of patients who gained ≥15 letters from baseline BCVA at month 12 was 56.0% and 60.3% in the 0.3 mg and 0.5 mg groups, respectively, and 43.9% in the sham/0.5 mg group. On average, there was a marked reduction in central foveal thickness (CFT) after the first as-needed injection of 0.5 mg ranibizumab in the sham/0.5 mg group, which was sustained through month 12. No new ocular or nonocular safety events were identified.
At month 12, treatment with ranibizumab as needed during months 6-11 maintained, on average, the benefits achieved by 6 monthly ranibizumab injections in patients with macular edema after BRVO, with low rates of ocular and nonocular safety events. In the sham/0.5 mg group, treatment with ranibizumab as needed for 6 months resulted in rapid reduction in CFT to a similar level as that in the 0.3 mg ranibizumab treatment group and an improvement in BCVA, but not to the extent of that in the 2 ranibizumab groups. Intraocular injections of ranibizumab provide an effective treatment for macular edema after BRVO.
Proprietary or commercial disclosure may be found after the references.
Abstract
Aims
The 2019 report from the European Society of Cardiology (ESC) Atlas provides a contemporary analysis of cardiovascular disease (CVD) statistics across 56 member countries, with ...particular emphasis on international inequalities in disease burden and healthcare delivery together with estimates of progress towards meeting 2025 World Health Organization (WHO) non-communicable disease targets.
Methods and results
In this report, contemporary CVD statistics are presented for member countries of the ESC. The statistics are drawn from the ESC Atlas which is a repository of CVD data from a variety of sources including the WHO, the Institute for Health Metrics and Evaluation, and the World Bank. The Atlas also includes novel ESC sponsored data on human and capital infrastructure and cardiovascular healthcare delivery obtained by annual survey of the national societies of ESC member countries. Across ESC member countries, the prevalence of obesity (body mass index ≥30 kg/m2) and diabetes has increased two- to three-fold during the last 30 years making the WHO 2025 target to halt rises in these risk factors unlikely to be achieved. More encouraging have been variable declines in hypertension, smoking, and alcohol consumption but on current trends only the reduction in smoking from 28% to 21% during the last 20 years appears sufficient for the WHO target to be achieved. The median age-standardized prevalence of major risk factors was higher in middle-income compared with high-income ESC member countries for hypertension {23.8% interquartile range (IQR) 22.5–23.1% vs. 15.7% (IQR 14.5–21.1%)}, diabetes 7.7% (IQR 7.1–10.1%) vs. 5.6% (IQR 4.8–7.0%), and among males smoking 43.8% (IQR 37.4–48.0%) vs. 26.0% (IQR 20.9–31.7%) although among females smoking was less common in middle-income countries 8.7% (IQR 3.0–10.8) vs. 16.7% (IQR 13.9–19.7%). There were associated inequalities in disease burden with disability-adjusted life years per 100 000 people due to CVD over three times as high in middle-income 7160 (IQR 5655–8115) compared with high-income 2235 (IQR 1896–3602) countries. Cardiovascular disease mortality was also higher in middle-income countries where it accounted for a greater proportion of potential years of life lost compared with high-income countries in both females (43% vs. 28%) and males (39% vs. 28%). Despite the inequalities in disease burden across ESC member countries, survey data from the National Cardiac Societies of the ESC showed that middle-income member countries remain severely under-resourced compared with high-income countries in terms of cardiological person-power and technological infrastructure. Under-resourcing in middle-income countries is associated with a severe procedural deficit compared with high-income countries in terms of coronary intervention, device implantation and cardiac surgical procedures.
Conclusion
A seemingly inexorable rise in the prevalence of obesity and diabetes currently provides the greatest challenge to achieving further reductions in CVD burden across ESC member countries. Additional challenges are provided by inequalities in disease burden that now require intensification of policy initiatives in order to reduce population risk and prioritize cardiovascular healthcare delivery, particularly in the middle-income countries of the ESC where need is greatest.
PDF
