PRL-3 overexpression in epithelial cells is induced by surrounding stromal fibroblasts

We isolate and culture carcinoma-associated fibroblasts (CAFs) from primary tumour (CAFpt), CAFs from corresponding synchronous liver metastasis (CAFlm) as well as normal colonic fibroblasts (NCF) from the same patient. From these cultures, conditioned media (CM) was obtained. Culture of a wide panel of colorectal and pancreatic cell lines in CM from CAFlm resulted in overexpression of mRNA PRL-3 and higher overexpression in CAFs than in non-activated fibroblasts. Moreover PRL-3 mRNA expression correlates with expression of α-SMA and deposition of collagen fibrils in the stroma. We demonstrate that products secreted by CAFs trigger PRL-3 overexpression in cancer cells. Identification of these factors may contribute to new stroma-targeted therapies for desmoplastic tumours

Long-Term Use of Tedizolid in Osteoarticular Infections: Benefits among Oxazolidinone Drugs

Background: To evaluate the efficacy and safety of long-term use of tedizolid in osteoarticular infections. Methods: Multicentric retrospective study (January 2017–March 2019) of osteoarticular infection cases treated with tedizolid. Failure: clinical worsening despite antibiotic treatment or the need of suppressive treatment. Results: Cases (n = 51; 59% women, mean age of 65 years) included osteoarthritis (n = 27, 53%), prosthetic joint infection (n = 17, 33.3%), and diabetic foot infections (n = 9, 18%); where, 59% were orthopedic device-related. Most frequent isolates were Staphylococcus spp. (65%, n = 47; S. aureus, 48%). Reasons for choosing tedizolid were potential drug-drug interaction (63%) and cytopenia (55%); median treatment duration was 29 days (interquartile range -IQR- 15–44), 24% received rifampicin (600 mg once daily) concomitantly, and adverse events were scarce (n = 3). Hemoglobin and platelet count stayed stable throughout treatment (from 108.6 g/L to 116.3 g/L, p = 0.079; and 240 × 109/L to 239 × 109/L, p = 0.942, respectively), also in the subgroup of cases with cytopenia. Among device-related infections, 33% were managed with implant retention. Median follow-up was 630 days and overall cure rate 83%; among failures (n = 8), 63% were device-related infections. Conclusions: Long-term use of tedizolid was effective, showing a better safety profile with less myelotoxicity and lower drug-drug interaction than linezolid. Confirmation of these advantages could make tedizolid the oxazolidinone of choice for most of osteoarticular infections

Individualización posológica de natalizumab en la esclerosis múltiple remitente recurrente

La esclerosis multiple (EM) es la enfermedad autoinmune, inflamatoria, cronica y degenerativa mas prevalente a nivel mundial, cuya forma mas frecuente es la EM remitente recurrente (EMRR). Para el manejo de la EMRR grave se aprobo natalizumab, un anticuerpo monoclonal IgG4 que se une a la integrina 41 de la superficie de los leucocitos, impidiendo que migren al sistema nervioso central. Con la dosis fija intravenosa aprobada, de 300 mg cada 4 semanas, se ha comprobado que mas del 90% de los pacientes alcanzan concentraciones sericas preinfusion de NTZ >10 μg/mL, cuando la eficacia se ha demostrado con unos niveles de 2,5-10 μg/mL. Una concentracion plasmatica de NTZ de 2,5 μg/mL asegura una ocupacion del 50% de la biofase y demuestra una eficacia terapeutica, mientras que tasas de ocupacion del 20-40% se han relacionado con un aumento de la actividad de la enfermedad. Palabras clave: Esclerosis multiple, natalizumab, farmacocinétic

Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes : results from the ASSESS study

Acknowledgements The authors would like to thank the study investigators at each of the participating centres for their contribution to the study. The full list of study investigators is available in Additional file 1. We would also like to thank Deborah McGregor, PhD, of Complete Medical Communications, who provided medical writing support funded by Almirall, S.A. Barcelona, Spain. This study was funded by Almirall S.A., Barcelona, Spain. The study sponsor was involved in the design of the study, analysis of the data, review of the data, and review and approval of the manuscript. The sponsors placed no restrictions on statements made in the final version of the manuscript or on the decision to submit the manuscript for publication and all authors had full access to the data.Peer reviewedPublisher PD

Multiplex real-time PCR in non-invasive respiratory samples to reduce antibiotic use in community-acquired pneumonia: a randomised trial

We assessed whether multiplex real-time PCR plus conventional microbiological testing is safe and more effective than conventional microbiological testing alone for reducing antibiotic use in community-acquired pneumonia (CAP). In this randomised trial, we recruited adults hospitalised with CAP at four Spanish hospitals. Patients were randomly assigned (1:1) to undergo either multiplex real-time PCR in non-invasive respiratory samples plus conventional microbiological testing or conventional microbiological testing alone. The primary endpoint was antibiotic use measured by days of antibiotic therapy (DOT). Between February 20, 2020, and April 24, 2023, 242 patients were enrolled; 119 were randomly assigned to multiplex real-time PCR plus conventional microbiological testing and 123 to conventional microbiological testing alone. All but one of the patients allocated to multiplex real-time PCR plus conventional microbiological testing underwent PCR, which was performed in sputum samples in 77 patients (65.2%) and in nasopharyngeal swabs in 41 (34.7%). The median DOT was 10.04 (IQR 7.98, 12.94) in the multiplex PCR plus conventional microbiological testing group and 11.33 (IQR 8.15, 16.16) in the conventional microbiological testing alone group (difference -1.04; 95% CI, -2.42 to 0.17; p = 0.093). No differences were observed in adverse events and 30-day mortality. Our findings do not support the routine implementation of multiplex real-time PCR in the initial microbiological testing in hospitalised patients with CAP

Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients. Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization. Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39-1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360-842] vs. 870 mg [IQR 364-1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00-17.5] vs. 18.5 days [3.00-53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05-2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC. Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19

People's interest in brain health testing: Findings from an international, online cross-sectional survey

Brain health entails mental wellbeing and cognitive health in the absence of brain disorders. The past decade has seen an explosion of tests, cognitive and biological, to predict various brain conditions, such as Alzheimer's Disease. In line with these current developments, we investigated people's willingness and reasons to—or not to—take a hypothetical brain health test to learn about risk of developing a brain disease, in a cross-sectional multilanguage online survey. The survey was part of the Global Brain Health Survey, open to the public from 4th June 2019 to 31st August 2020. Respondents were largely recruited via European brain councils and research organizations. 27,590 people responded aged 18 years or older and were predominantly women (71%), middle-aged or older (>40 years; 83%), and highly educated (69%). Responses were analyzed to explore the relationship between demographic variables and responses. Results: We found high public interest in brain health testing: over 91% would definitely or probably take a brain health test and 86% would do so even if it gave information about a disease that cannot be treated or prevented. The main reason for taking a test was the ability to respond if one was found to be at risk of brain disease, such as changing lifestyle, seeking counseling or starting treatment. Higher interest in brain health testing was found in men, respondents with lower education levels and those with poor self-reported cognitive health. Conclusion: High public interest in brain health and brain health testing in certain segments of society, coupled with an increase of commercial tests entering the market, is likely to put pressure on public health systems to inform the public about brain health testing in years to come.publishedVersio

Alterations in Gut Microbiome in Cirrhosis as Assessed by Quantitative Metagenomics: Relationship With Acute-on-Chronic Liver Failure and Prognosis

Background and Aims: Cirrhosis is associated with changes in gut microbiome composition. Although acute-on-chronic liver failure (ACLF) is the most severe clinical stage of cirrhosis, there is lack of information about gut microbiome alterations in ACLF using quantitative metagenomics. We investigated the gut microbiome in patients with cirrhosis encompassing the whole spectrum of disease (compensated, acutely decompensated without ACLF, and ACLF). A group of healthy subjects was used as control subjects. Methods: Stool samples were collected prospectively in 182 patients with cirrhosis. DNA library construction and sequencing were performed using the Ion Proton Sequencer (ThermoFisher Scientific, Waltham, MA). Microbial genes were grouped into clusters, denoted as metagenomic species. Results: Cirrhosis was associated with a remarkable reduction in gene and metagenomic species richness compared with healthy subjects. This loss of richness correlated with disease stages and was particularly marked in patients with ACLF and persisted after adjustment for antibiotic therapy. ACLF was associated with a significant increase of Enterococcus and Peptostreptococcus sp and a reduction of some autochthonous bacteria. Gut microbiome alterations correlated with model for end-stage liver disease and Child-Pugh scores and organ failure and was associated with some complications, particularly hepatic encephalopathy and infections. Interestingly, gut microbiome predicted 3-month survival with good stable predictors. Functional analysis showed that patients with cirrhosis had enriched pathways related to ethanol production, γ-aminobutyric acid metabolism, and endotoxin biosynthesis, among others. Conclusions: Cirrhosis is characterized by marked alterations in gut microbiome that parallel disease stages with maximal changes in ACLF. Altered gut microbiome was associated with complications of cirrhosis and survival. Gut microbiome may contribute to disease progression and poor prognosis. These results should be confirmed in future studies

PRL-3 is essentially overexpressed in primary colorectal tumours and associates with tumour aggressiveness

Phosphatase PRL-3 has been involved in different types of cancer, especially in metastases from colorectal carcinoma (CRC). In this study, we explored both isoforms of PRL-3 as a biomarker to predict the recurrence of stage IIIB-C CRC. Overexpression of PRL-3 was investigated in primary human colorectal tumours (n=20) and hepatic metastases (n=36) xenografted in nude mice, samples characterised by absence of human non-tumoral cells, showing a high degree of expression in metastases (P=0.001). In 27 cases of matched normal colonic mucosa/primary tumour/hepatic metastases, PRL-3 overexpression occurs in primary tumours vs normal mucosa (P=0.001) and in hepatic metastases vs primary tumours (P=0.045). Besides, our results in a series of 80 stage IIIB-C CRC primary tumours showed that high levels of PRL-3 were an independent predictor of metastasis (P<0.0001; OR: 9.791) in multivariate analysis of a binary logistic regression and that PRL-3 expression tightly correlates with parameters of bad outcome. Moreover, PRL-3 expression associated with poor outcome in univariate (P<0.0001) and multivariate Cox models (hazard ratio: 3.322, 95%, confidence interval: 1.405-7.852, P=0.006). In conclusion, PRL-3 is a good marker of aggressiveness of locally advanced CRS and a promising predictor of distant metastases. Nevertheless, for prognosis purposes, it is imperative to validate the cutoff value of PRL-3 expression in a larger and consecutive series and adjuvant setting

The Global Brain Health Survey: Development of a Multi-Language Survey of Public Views on Brain Health.

Background: Brain health is a multi-faceted concept used to describe brain physiology, cognitive function, mental health and well-being. Diseases of the brain account for one third of the global burden of disease and are becoming more prevalent as populations age. Diet, social interaction as well as physical and cognitive activity are lifestyle factors that can potentially influence facets of brain health. Yet, there is limited knowledge about the population's awareness of brain health and willingness to change lifestyle to maintain a healthy brain. This paper introduces the Global Brain Health Survey protocol, designed to assess people's perceptions of brain health and factors influencing brain health. Methods: The Global Brain Health Survey is an anonymous online questionnaire available in 14 languages to anyone above the age of 18 years. Questions focus on (1) willingness and motivation to maintain or improve brain health, (2) interest in learning more about individual brain health using standardized tests, and (3) interest in receiving individualized support to take care of own brain health. The survey questions were developed based on results from a qualitative interview study investigating brain health perceptions among participants in brain research studies. The survey includes 28 questions and takes 15-20 min to complete. Participants provide electronically informed consent prior to participation. The current survey wave was launched on June 4, 2019 and will close on August 31, 2020. We will provide descriptive statistics of samples distributions including analyses of differences as a function of age, gender, education, country of residence, and we will examine associations between items. The European Union funded Lifebrain project leads the survey in collaboration with national brain councils in Norway, Germany, and Belgium, Brain Foundations in the Netherlands and Sweden, the National University of Ostroh Academy and the Women's Brain Project. Discussion: Results from this survey will provide new insights in peoples' views on brain health, in particular, the extent to which the adoption of positive behaviors can be encouraged. The results will contribute to the development of policy recommendations for supporting population brain health, including measures tailored to individual needs, knowledge, motivations and life situations