Recommendations for blood sampling in emergency departments from the European Society for Emergency Medicine (EUSEM), European Society for Emergency Nursing (EuSEN), and European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group for the Preanalytical Phase. Executive summary.

AIM: Blood Sampling Guidelines have been developed to target European emergency medicine-related professionals involved in the blood sampling process (e.g. physicians, nurses, phlebotomists working in the ED), as well as laboratory physicians and other related professionals. The guidelines population focus on adult patients. The development of these blood sampling guidelines for the ED setting is based on the collaboration of three European scientific societies that have a role to play in the preanalytical phase process: EuSEN, EFLM, and EUSEM. The elaboration of the questions was done using the PICO procedure, literature search and appraisal was based on the GRADE methodology. The final recommendations were reviewed by an international multidisciplinary external review group. RESULTS: The document includes the elaborated recommendations for the selected sixteen questions. Three in pre-sampling, eight regarding sampling, three post-sampling, and two focus on quality assurance. In general, the quality of the evidence is very low, and the strength of the recommendation in all the questions has been rated as weak. The working group in four questions elaborate the recommendations, based mainly on group experience, rating as good practice. CONCLUSIONS: The multidisciplinary working group was considered one of the major contributors to this guideline. The lack of quality information highlights the need for research in this area of the patient care process. The peculiarities of the emergency medical areas need specific considerations to minimise the possibility of errors in the preanalytical phase.

First Report of Rhizoctonia solani AG-4 HG-I Causing Root and Basal Stem Rot on Roselle (Hibiscus sabdariffa) in Mexico.

Roselle (Hibiscus sabdariffa L.) is a crop of economic importance, refreshing drinks are prepared from its calyces, it is also attributed to antioxidant, antibacterial, and antihypertensive properties (Da-Costa-Rocha et al. 2014). In November 2022, in municipality of Iguala (18.355592N, 99.548546W, 749 m above sea level), Guerrero, México, roselle plants of approximately 1.5 months of age with basal rot were detected under greenhouse conditions. The symptoms consisted of wilting, yellowing, and root and stem rot with constriction in the base of the stem. The symptoms were detected in approximately 15% of plants at the operation. From symptomatic tissue, cuts were made into approximately 0.5 cm pieces, sterilized with 2% NaClO, washed with sterile distilled water, transferred to PDA medium amended with 50 mg/liter of Chloramphenicol, and incubated in the dark for four days at 28 °C. Rhizoctonia-like colonies were consistently obtained, and nine isolates were selected and purified by the hyphal-tip method. After four days, isolates developed a mycelium was light-white that became brown with age. Right-angled hyphal branching was also observed, in addition to a slight constriction at the base of the branches. In some older cultures, numerous dark brown sclerotia were observed. They were multinucleate cell with three to eight nuclei and measured from 1 to 2 mm in diameter. Together these characteristics were consistent with the description of Rhizoctonia solani Kühn (Parmeter 1970). The anastomosis group (AG) was confirmed by amplifying the ITS region with the primers ITS1 and ITS4 (White et al. 1990) of the RIJAM3 and RIJAM5 strains. The sequences were deposited in GenBank (Nos. OR364496 and OR364497 for RIJAM3 and RIJAM5, respectively). BLAST analysis, both isolates indicated 99.7 identity to R. solani AG-4 HG-I (GenBank: KM013470) strain ICMP 20043 (Ireland et al. 2015). The phylogenetic analysis of AGs sequences allowed assignment of isolates RIJAM3 and RIJAM5 to the AG-4 HG-1 clade. A pathogenicity test was performed on 20 one-month-old roselle plants. Mycelium of RIJAM3 isolate was inserted into the base of the stem with a sterile toothpick. As a control, a sterile toothpick with no mycelium was inserted in ten healthy plants. Additionally, 50 eight-day-old seedlings were inoculated by placing a 5-mm diameter agar plug colonized with mycelium of RIJAM3 at the base of the stem 10 mm below the soil surface. As control treatments, uncolonized PDA plugs were deposited at the base of 25 seedlings. The inoculated plants were incubated in a greenhouse with an average temperature and relative humidity of 28°C and 85%, respectively. Following inoculation, symptoms similar to those observed in the original outbreak were observed in plants after six days and only after four days in seedlings. In both experiments, the control plants and seedlings remained asymptomatic. R. solani was re-isolated from plants and seedlings, complying with Koch's postulates. The pathogenicity testing was repeated twice, with concordant results. In Nigeria and Malaysia R. solani was reported to seedling death to cause seedling dieback in roselle (Adeniji 1970; Eslaminejad and Zakaria 2011). In México R. solani AG-4 has been previously reported in crops of potato, chili and tomato (Montero-Tavera et al. 2013; Ortega-Acosta et al. 2022; Virgen-Calleros et al. 2000). To the best of our knowledge, this is the first report of R. solani AG-4 HG-I as a causing of root and basal stem rot on roselle in Mexico. This research provides information essential for informing the management of this disease, and may help design measures to prevent the spread of the pathogen to other regions.

Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity.

BACKGROUND: Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood-brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. METHODS: Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. RESULTS: The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. CONCLUSIONS: The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB.

From contigs towards chromosomes: automatic improvement of long read assemblies (ILRA).

Recent advances in long read technologies not only enable large consortia to aim to sequence all eukaryotes on Earth, but they also allow individual laboratories to sequence their species of interest with relatively low investment. Long read technologies embody the promise of overcoming scaffolding problems associated with repeats and low complexity sequences, but the number of contigs often far exceeds the number of chromosomes and they may contain many insertion and deletion errors around homopolymer tracts. To overcome these issues, we have implemented the ILRA pipeline to correct long read-based assemblies. Contigs are first reordered, renamed, merged, circularized, or filtered if erroneous or contaminated. Illumina short reads are used subsequently to correct homopolymer errors. We successfully tested our approach by improving the genome sequences of Homo sapiens, Trypanosoma brucei, and Leptosphaeria spp., and by generating four novel Plasmodium falciparum assemblies from field samples. We found that correcting homopolymer tracts reduced the number of genes incorrectly annotated as pseudogenes, but an iterative approach seems to be required to correct more sequencing errors. In summary, we describe and benchmark the performance of our new tool, which improved the quality of novel long read assemblies up to 1 Gbp. The pipeline is available at GitHub: https://github.com/ThomasDOtto/ILRA.

Past, Present and Future of Research on Wearable Technologies for Healthcare: A Bibliometric Analysis Using Scopus.

Currently, wearable technology is present in different fields that aim to satisfy our needs in daily life, including the improvement of our health in general, the monitoring of patient health, ensuring the safety of people in the workplace or supporting athlete training. The objective of this bibliometric analysis is to examine and map the scientific advances in wearable technologies in healthcare, as well as to identify future challenges within this field and put forward some proposals to address them. In order to achieve this objective, a search of the most recent related literature was carried out in the Scopus database. Our results show that the research can be divided into two periods: before 2013, it focused on design and development of sensors and wearable systems from an engineering perspective and, since 2013, it has focused on the application of this technology to monitoring health and well-being in general, and in alignment with the Sustainable Development Goals wherever feasible. Our results reveal that the United States has been the country with the highest publication rates, with 208 articles (34.7%). The University of California, Los Angeles, is the institution with the most studies on this topic, 19 (3.1%). Sensors journal (Switzerland) is the platform with the most studies on the subject, 51 (8.5%), and has one of the highest citation rates, 1461. We put forward an analysis of keywords and, more specifically, a pennant chart to illustrate the trends in this field of research, prioritizing the area of data collection through wearable sensors, smart clothing and other forms of discrete collection of physiological data.

Predictive Model for Human Activity Recognition Based on Machine Learning and Feature Selection Techniques.

Research into assisted living environments -within the area of Ambient Assisted Living (ALL)-focuses on generating innovative technology, products, and services to provide medical treatment and rehabilitation to the elderly, with the purpose of increasing the time in which these people can live independently, whether they suffer from neurodegenerative diseases or disabilities. This key area is responsible for the development of activity recognition systems (ARS) which are a valuable tool to identify the types of activities carried out by the elderly, and to provide them with effective care that allows them to carry out daily activities normally. This article aims to review the literature to outline the evolution of the different data mining techniques applied to this health area, by showing the metrics used by researchers in this area of knowledge in recent experiments.

Effect of 10 km run on lower limb skin temperature and thermal response after a cold-stress test over the following 24 h.

Skin temperature assessment has received much attention as a possible measurement of physiological response against stress produced by exercise and research studies usually measure skin temperature 24 or 48 h after exercise. Scientific evidence about skin temperature evolution during the 24-h period immediately after exercising is, however, scarce. The aim was to assess the effect of a 10 km run at moderate intensity on baseline skin temperature and thermal response after a cold stress test during that 24 h period. Fourteen participants were measured before, immediately after, and at 2, 5, 9 and 24 h after a 10 km run at a perceived exertion rate of 11 points (max 20 points). Fourteen control participants who undertook no exercise were also measured during that day. The measurements included muscle pain and fatigue perception, reactive oxygen species, heart rate variability, skin temperature of the lower limbs, and skin temperature after cold stress test. Exercise resulted in a skin temperature increase (e.g., 0.5-1.3 °C of posterior leg 9 h after exercise) and this effect continued in some regions (0.4-0.9 °C of posterior leg) over that 24 h period. However, the thermal response to the cold stress test remained the same (p > 0.05). In conclusion, 10 km aerobic running exercise results in a skin temperature increase, peaking at between 5 and 9 h after exercise, but does not alter the thermal response to a cold stress test. This study provides a sound basis for post-exercise skin temperature response that can be used as a setting-off point for comparisons with future studies that analyze greater muscle damage.

Identification of the most vulnerable populations in the psychosocial sphere: a cross-sectional study conducted in Catalonia during the strict lockdown imposed against the COVID-19 pandemic.

DESIGN AND OBJECTIVES: A cross-sectional study to evaluate the impact of COVID-19 on the psychosocial sphere in both the general population and healthcare workers (HCWs). METHODS: The study was conducted in Catalonia (Spain) during the first wave of the COVID-19 pandemic when strict lockdown was in force. The study population included all people aged over 16 years who consented to participate in the study and completed the survey, in this case a 74-question questionnaire shared via social media using snowball sampling. A total of 56 656 completed survey questionnaires were obtained between 3 and 19 April 2020.The primary and secondary outcome measures included descriptive statistics for the non-psychological questions and the psychological impact of the pandemic, such as depression, anxiety, stress and post-traumatic stress disorder question scores. RESULTS: A n early and markedly negative impact on family finances, fear of working with COVID-19 patients and ethical issues related to COVID-19 care among HCWs was observed. A total of seven target groups at higher risk of impaired mental health and which may therefore benefit from an intervention were identified, namely women, subjects aged less than 42 years, people with a care burden, socioeconomically deprived groups, people with unskilled or unqualified jobs, patients with COVID-19 and HCWs working with patients with COVID-19. CONCLUSIONS: Active implementation of specific strategies to increase resilience and to prepare an adequate organisational response should be encouraged for the seven groups identified as high risk and susceptible to benefit from an intervention. TRIAL REGISTRATION NUMBER: NCT04378452.

Offline Solid-Phase Extraction and Separation of Mineral Oil Saturated Hydrocarbons and Mineral Oil Aromatic Hydrocarbons in Edible Oils, and Analysis via GC with a Flame Ionization Detector.

A method was developed for the determination of mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH) in edible oils, achieving similar limits of quantification than those obtained by online extraction methodologies, i.e., 0.5 mg/kg. The isolation of MOSH and MOAH was performed in a silver nitrated silica gel stationary phase prior to their analysis by gas chromatography-flame ionization detector (GC-FID). To improve the sensitivity, the simulated on-column injection method, using a suitable liner, was optimized. The method was validated at 0.5, 10.0 and 17.9 mg/kg, and recoveries ranged from 80 to 110%. Intra and inter-day precision were evaluated at the same levels, and relative standard deviation (RSD) was lower than 20%. The method was applied to a total of 27 samples of different types of oil previously analyzed in an accredited laboratory, detecting MOSH up to 79.2 mg/kg and MOAH up to 22.4 mg/kg.

Untargeted Metabolomics for the Diagnosis of Exocrine Pancreatic Insufficiency in Chronic Pancreatitis.

Background and Objectives: The clinical manifestations and course of chronic pancreatitis (CP) are often nonspecific and variable, hampering diagnosis of the risk of exocrine pancreatic insufficiency (EPI). Development of new, reproducible, and non-invasive methods to diagnose EPI is therefore a major priority. The objective of this metabolomic study was to identify novel biomarkers associated with EPI. Materials and Methods: We analyzed 53 samples from patients with CP, 32 with and 21 without EPI, using an untargeted metabolomics workflow based on hydrophilic interaction chromatography coupled to high-resolution mass spectrometry. Principal component and partial least squares-discriminant analyses showed significant between-group differentiation, and univariate and multivariate analyses identified potential candidate metabolites that significantly differed between samples from CP patients with EPI and those without EPI. Results: Excellent results were obtained using a six-metabolic panel to diagnose the presence of EPI in CP patients (area under the ROC curve = 0.785). Conclusions: This study confirms the usefulness of metabolomics in this disease setting, allowing the identification of novel biomarkers to differentiate between the presence and absence of EPI in CP patients.

Reproducibility of Skin Temperature Response after Cold Stress Test Using the Game Ready System: Preliminary Study.

The objective of this preliminary study was to determine the reproducibility of lower limbs skin temperature after cold stress test using the Game Ready system. Skin temperature of fourteen participants was measured before and after cold stress test using the Game Ready system and it was repeated the protocol in four times: at 9:00, at 11:00, at 19:00, and at 9:00 h of the posterior day. To assess skin temperature recovery after cold stress test, a logarithmic equation for each region was calculated, and constant (ß0) and slope (ß1) coefficients were obtained. Intraclass correlation coefficient (ICC), standard error (SE), and within-subject coefficient of variation (CV) were determined. No differences were observed between measurement times in any of the regions for the logarithmic coefficients (p > 0.38). Anterior thigh (ß0 ICC 0.33-0.47; ß1 ICC 0.31-0.43) and posterior knee (ß0 ICC 0.42-0.58; ß1 ICC 0.28-0.57) were the regions with the lower ICCs, and the other regions presented values with a fair and good reproducibility (ICC > 0.41). Posterior leg was the region with the better reproducibility (ß0 ICC 0.68-0.78; ß1 ICC 0.59-0.74; SE 3-4%; within-subject CV 7-12%). In conclusion, cold stress test using Game Ready system showed a fair and good reproducibility, especially when the posterior leg was the region assessed.

UJAmI Location: A Fuzzy Indoor Location System for the Elderly.

Due to the large number of elderly people with physical and cognitive issues, there is a strong need to provide indoor location systems that help caregivers monitor as many people as possible and with the best quality possible. In this paper, a fuzzy indoor location methodology is proposed in a smart environment based on mobile devices and Bluetooth Low Energy (BLE) beacons where a set of Received Signal Strength Indicators (RSSI) is received by mobile devices worn by the inhabitants. The use of fuzzy logic and a fuzzy linguistic approach is proposed to deal with the imprecise nature of the RSSI values, which are influenced by external factors such as radio waves, causing significant fluctuations. A case study carried out at the Smart Lab of the University of Jaén (UJAmI Smart Lab) is presented to demonstrate the effectiveness of the proposed methodology, where our proposal is compared with a non-fuzzy logic approach, obtaining an accuracy of 91.63%, approximately 10 points higher than the methodology without using fuzzy logic. Finally, our theoretical proposal is accompanied by a description of the UJAmI Location system, which applies the theory to the functionality of locating elderly people in indoor environments.

Novel Biomarkers to Distinguish between Type 3c and Type 2 Diabetes Mellitus by Untargeted Metabolomics.

Pancreatogenic diabetes mellitus (T3cDM) is a highly frequent complication of pancreatic disease, especially chronic pancreatitis, and it is often misdiagnosed as type 2 diabetes mellitus (T2DM). A correct diagnosis allows the appropriate treatment of these patients, improving their quality of life, and various technologies have been employed over recent years to search for specific biomarkers of each disease. The main aim of this metabolomic project was to find differential metabolites between T3cDM and T2DM. Reverse-phase liquid chromatography coupled to high-resolution mass spectrometry was performed in serum samples from patients with T3cDM and T2DM. Multivariate Principal Component and Partial Least Squares-Discriminant analyses were employed to evaluate between-group variations. Univariate and multivariate analyses were used to identify potential candidates and the area under the receiver-operating characteristic (ROC) curve was calculated to evaluate their diagnostic value. A panel of five differential metabolites obtained an area under the ROC curve of 0.946. In this study, we demonstrate the usefulness of untargeted metabolomics for the differential diagnosis between T3cDM and T2DM and propose a panel of five metabolites that appear altered in the comparison between patients with these diseases.

State of the Art in Exocrine Pancreatic Insufficiency.

Exocrine pancreatic insufficiency (EPI) is defined as the maldigestion of foods due to inadequate pancreatic secretion, which can be caused by alterations in its stimulation, production, transport, or interaction with nutrients at duodenal level. The most frequent causes are chronic pancreatitis in adults and cystic fibrosis in children. The prevalence of EPI is high, varying according to its etiology, but it is considered to be underdiagnosed and undertreated. Its importance lies in the quality of life impairment that results from the malabsorption and malnutrition and in the increased morbidity and mortality, being associated with osteoporosis and cardiovascular events. The diagnosis is based on a set of symptoms, indicators of malnutrition, and an indirect non-invasive test in at-risk patients. The treatment of choice combines non-restrictive dietary measures with pancreatic enzyme replacement therapy to correct the associated symptoms and improve the nutritional status of patients. Non-responders require the adjustment of pancreatic enzyme therapy, the association of proton pump inhibitors, and/or the evaluation of alternative diagnoses such as bacterial overgrowth. This review offers an in-depth overview of EPI in order to support the proper management of this entity based on updated and integrated knowledge of its etiopathogenesis, prevalence, diagnosis, and treatment.

Role of Exocrine and Endocrine Insufficiency in the Management of Patients with Chronic Pancreatitis.

BACKGROUND: Exocrine pancreatic insufficiency results from the destruction of the pancreatic parenchyma and is diagnosed by using direct or indirect tests, both of which have shortcomings. Chronic pancreatitis is the most frequent cause of this pathology in adults. METHODS: Patients meeting radiological or histological diagnostic criteria of chronic pancreatitis are enrolled and the stool elastase test is conducted, considering fecal elastase levels >200 µg/g to represent normal pancreatic function, and levels <200 µg/g to indicate the presence of exocrine pancreatic insufficiency. Additionally, we determine the body mass index of the patients and study their nutritional status and main biochemical and hematological variables, including their glucose and hemoglobin A1c (HbA1c) levels. RESULTS: Exocrine pancreatic insufficiency is detected in 60% of the patients. Among these, 83.3% are severe cases, and 72% of the latter also are diagnosed with endocrine pancreatic insufficiency (diabetes mellitus). During the nutritional status study, HbA1c levels are significantly higher, and magnesium and prealbumin levels are significantly lower in patients with exocrine pancreatic insufficiency than in those without this disease. CONCLUSIONS: Exocrine and endocrine pancreatic insufficiency are highly prevalent among patients with chronic pancreatitis and an early diagnosis of these diseases is vital to improve the clinical management of these patients and reduce their risk of mortality.

Efecto conjunto de la democracia y libertad económica sobre la corrupción / Efeito conjunto da democracia e da liberdade econômica sobre a corrupção / The joint effect of democracy and economic freedom on corruption

Resumen Este trabajo examina el efecto conjunto de la democracia y libertad económica sobre la corrupción. Para ello, se utilizan las bases de datos de 160 países de los años 2010 - 2016, considerando varias fuentes de información para un conjunto de variables económicas, culturales, históricas e institucionales. Las pesquisas señalan que el efecto conjunto de los niveles de libertad económica y democracia es importante para combatir la corrupción. Por lo tanto, las políticas más eficaces para los países objeto de estudio, serán aquellas enfocadas al derecho fundamental que tienen los seres humanos para controlar el fruto de su trabajo, englobando de manera integral las libertades y derechos de producción, distribución o consumo de bienes y servicios.

Resumo Este trabalho examina o efeito conjunto exercido pela democracia e pela liberdade econômica sobre a corrupção. Para tal fim, foram utilizados os bancos de dados de 160 países entre os anos de 2010 a 2016, considerando diversas fontes de informação para um conjunto de variáveis econômicas, culturais, históricas e institucionais. As pesquisas indicam que o efeito conjunto dos níveis de liberdade econômica e democracia é importante para combater a corrupção. Portanto, as políticas mais eficazes para os países analisados serão aquelas concentradas no direito fundamental dos seres humanos de controlar o resultado de seu trabalho, incluindo, de forma abrangente, as liberdades e os direitos de produção, distribuição ou consumo de bens. e serviços.

Abstract This work examines the joint effect of democracy and economic freedom on corruption. The study used a database of 160 countries from 2010 - 2016, containing information for a set of economic, cultural, historical, and institutional variables. Several researches show that the joint effect of economic freedom levels and democracy are essential to fight corruption. Therefore, the most effective public policies for countries under study are those focused on the fundamental right of human beings to control satisfying outcomes of their jobs, which holistically encompasses the freedom and rights of production, distribution, or consumption of goods and services.

Heat Stress Factors Expressed during Seed Maturation Differentially Regulate Seed Longevity and Seedling Greening.

Heat Stress Factor A9 (A9), a seed-specific transcription factor contributing to seed longevity, also enhances phytochrome-dependent seedling greening. The RNA-seq analyses of imbibed-seed transcripts here reported indicated potential additional effects of A9 on cryptochrome-mediated blue-light responses. These analyses also suggested that in contrast to the A9 effects on longevity, which require coactivation by additional factors as A4a, A9 alone might suffice for the enhancement of photomorphogenesis at the seedling stage. We found that upon its seed-specific overexpression, A9 indeed enhanced the expected blue-light responses. Comparative loss-of-function analyses of longevity and greening, performed by similar expression of dominant-negative and inactive forms of A9, not only confirmed the additional greening effects of A9, but also were consistent with A9 not requiring A4a (or additional factors) for the greening effects. Our results strongly indicate that A9 would differentially regulate seed longevity and photomorphogenesis at the seedling stage, A9 alone sufficing for both the phytochrome- and cryptochrome-dependent greening enhancement effects.

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan.

Unveiling the mechanism of action of a drug is key to understand the benefits and adverse reactions of a medication in an organism. However, in complex diseases such as heart diseases there is not a unique mechanism of action but a wide range of different responses depending on the patient. Exploring this collection of mechanisms is one of the clues for a future personalized medicine. The Therapeutic Performance Mapping System (TPMS) is a Systems Biology approach that generates multiple models of the mechanism of action of a drug. Each molecular mechanism generated could be associated to particular individuals, here defined as prototype-patients, hence the generation of models using TPMS technology may be used for detecting adverse effects to specific patients. TPMS operates by (1) modelling the responses in humans with an accurate description of a protein network and (2) applying a Multilayer Perceptron-like and sampling strategy to find all plausible solutions. In the present study, TPMS is applied to explore the diversity of mechanisms of action of the drug combination sacubitril/valsartan. We use TPMS to generate a wide range of models explaining the relationship between sacubitril/valsartan and heart failure (the indication), as well as evaluating their association with macular degeneration (a potential adverse effect). Among the models generated, we identify a set of mechanisms of action associated to a better response in terms of heart failure treatment, which could also be associated to macular degeneration development. Finally, a set of 30 potential biomarkers are proposed to identify mechanisms (or prototype-patients) more prone of suffering macular degeneration when presenting good heart failure response. All prototype-patients models generated are completely theoretical and therefore they do not necessarily involve clinical effects in real patients. Data and accession to software are available at http://sbi.upf.edu/data/tpms/.

The premature closure of ROMPA clinical trial: mortality reduction in septic shock by plasma adsorption.

OBJECTIVES: Coupled Plasma Filtration and Adsorption (CPFA) use in septic shock remains controversial. The objective is to clarify whether the application of high doses of CPFA in addition to the current clinical practice could reduce hospital mortality in septic shock patients in Intensive Care Units at 28 days and at 90 days follow-up. DESIGN: We designed a prospective randomised clinical trial, Reducción de la Mortalidad Plasma-Adsorción (ROMPA), to demonstrate an absolute mortality reduction of 20% (α=0.05; 1-ß=0.8; n=190 (95×2)). SETTING: Being aware of the pitfalls associated with previous medical device trials, we developed a training programme to improve CPFA use (especially clotting problems). The protocol was approved by the ethics committees of all participating centres. Circumstances beyond our control produced a change in recruitment conditions unacceptable to ROMPA researchers and the trial was discontinued. PARTICIPANTS: By closure, five centres from an initial 10 fulfilled the necessary trial criteria, with 49 patients included, 30 in the control group (CG) and 19 in the intervention group (IG). INTERVENTION: CPFA. MAIN OUTCOME MEASURES: Hospital mortality at 28 days and 90 days follow-up. RESULTS: After 28 days, 14 patients died (46.7%) from the CG and 11 (57.9%) from the IG, not reaching statistical significance (p=0.444). At 90 days, 19 patients had died (63.3%) from the CG and 11 patients (57.9%) from the IG, (p=0.878). The adjustment by propensity score or the use of the Kaplan-Meier technique failed to achieve statistical difference, neither by Intention to Treat nor by the Actual Intervention Received. CONCLUSION: We herewith present the results gained from the prematurely closed trial. The results are inconclusive due to low statistical power but we consider that this data is of interest for the scientific community and potentially necessary for any ensuing debate. REGISTER: NCT02357433 in clinicaltrials.gov.

Principal Criteria for Evaluating the Quality, Safety and Efficacy of hMSC-Based Products in Clinical Practice: Current Approaches and Challenges.

Human Mesenchymal Stem Cells (hMSCs) play an important role as new therapeutic alternatives in advanced therapies and regenerative medicine thanks to their regenerative and immunomodulatory properties, and ability to migrate to the exact area of injury. These properties have made hMSCs one of the more promising cellular active substances at present, particularly in terms of the development of new and innovative hMSC-based products. Currently, numerous clinical trials are being conducted to evaluate the therapeutic activity of hMSC-based products on specific targets. Given the rapidly growing number of hMSC clinical trials in recent years and the complexity of these products due to their cellular component characteristics and medicinal product status, there is a greater need to define more stringent, specific, and harmonized requirements to characterize the quality of the hMSCs and enhance the analysis of their safety and efficacy in final products to be administered to patients. These requirements should be implemented throughout the manufacturing process to guarantee the function and integrity of hMSCs and to ensure that the hMSC-based final product consistently meets its specifications across batches. This paper describes the principal phases involved in the design of the manufacturing process and updates the specific technical requirements needed to address the appropriate clinical use of hMSC-based products. The challenges and limitations to evaluating the safety, efficacy, and quality of hMSCs have been also reviewed and discussed.