CIPSI: An open chemical intellectual property service for medicinal chemists.

The availability of patent chemical data offers public access to a chemical space that is not well covered by other sources collecting small molecules from scholarly literature. However, open applications to facilitate the search and analysis of biologically-relevant molecular structures present in patents are still largely missing. We have developed CIPSI, an open Chemical Intellectual Property Service @ IMIM to assist medicinal chemists in searching and analysing molecules in SureChEMBL patents. The current version contains 6,240,500 molecules from 236,689 pharmacological patents, of which 5,949,214 are confidently assigned to core chemical structures reminiscent of the Markush structure in the patent claim. The platform includes some graphical tools to facilitate comparative patent analyses between drugs, chemical substructures, and company assignees. CIPSI is available at https://cipsi.org.

Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment.

BACKGROUND: Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. METHODS: This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. DISCUSSION: NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression.

Postoperative Nursing Care of a Deceased Donor Tracheal Transplant Recipient.

INTRODUCTION: Certain airway disorders, such as tracheal stenosis, can severely affect the ability to breathe, reduce quality of life, and increase morbidity and mortality. Treatment options for long-segment tracheal stenosis include multistage tracheal replacement with biosynthetic material, autotransplantation, and allotransplantation. These interventions have not demonstrated long-term dependable results because of lack of adequate blood supply to the organ and ciliated epithelium. A new transplant program featuring single-stage long-segment tracheal transplant addresses this concern. CLINICAL FINDINGS: The patient was a 56-year-old woman with a history of obesity, type 2 diabetes, hypertension, hyperlipidemia, liver sarcoidosis, 105-pack-year smoking history, and asthma. A severe asthma exacerbation in 2014 required prolonged intubation, and she subsequently developed long-segment cricotracheal stenosis. In 2015 she underwent an unsuccessful tracheal resection followed by failed attempts at tracheal stenting and dilation procedures. These attempts at stenting resulted in a permanent extended-length tracheostomy and ultimately ventilator dependency. INTERVENTIONS: The patient underwent a single-stage long-segment deceased donor tracheal transplant. Important nursing considerations included hemodynamic monitoring, airway management and securement, graft assessment, stoma and wound care, nutrition, medication administration, and patient education. CONCLUSION: High-quality nursing care postoperatively in the intensive care unit is critical to safe and effective treatment of the tracheal transplant recipient and success of the graft. To effectively treat these patients, nurses need relevant education and training. This article is the first documentation of postoperative nursing care following single-stage long-segment tracheal transplant.

Comammox Nitrospira bacteria outnumber canonical nitrifiers irrespective of electron donor mode and availability in biofiltration systems.

Complete ammonia oxidizing bacteria coexist with canonical ammonia and nitrite oxidizing bacteria in a wide range of environments. Whether this is due to competitive or cooperative interactions, or a result of niche separation is not yet clear. Understanding the factors driving coexistence of nitrifiers is critical to manage nitrification processes occurring in engineered and natural ecosystems. In this study, microcosm-based experiments were used to investigate the impact of nitrogen source and loading on the population dynamics of nitrifiers in drinking water biofilter media. Shotgun sequencing of DNA followed by co-assembly and reconstruction of metagenome assembled genomes revealed clade A2 comammox bacteria were likely the primary nitrifiers within microcosms and increased in abundance over Nitrosomonas-like ammonia and Nitrospira-like nitrite oxidizing bacteria irrespective of nitrogen source type or loading. Changes in comammox bacterial abundance did not correlate with either ammonia or nitrite oxidizing bacterial abundance in urea-amended systems, where metabolic reconstruction indicated potential for cross-feeding between strict ammonia and nitrite oxidizers. In contrast, comammox bacterial abundance demonstrated a negative correlation with nitrite oxidizers in ammonia-amended systems. This suggests potentially weaker synergistic relationships between strict ammonia and nitrite oxidizers might enable comammox bacteria to displace strict nitrite oxidizers from complex nitrifying communities.

Evaluating de Novo Assembly and Binning Strategies for Time Series Drinking Water Metagenomes.

Reconstructing microbial genomes from metagenomic short-read data can be challenging due to the unknown and uneven complexity of microbial communities. This complexity encompasses highly diverse populations, which often includes strain variants. Reconstructing high-quality genomes is a crucial part of the metagenomic workflow, as subsequent ecological and metabolic inferences depend on their accuracy, quality, and completeness. In contrast to microbial communities in other ecosystems, there has been no systematic assessment of genome-centric metagenomic workflows for drinking water microbiomes. In this study, we assessed the performance of a combination of assembly and binning strategies for time series drinking water metagenomes that were collected over 6 months. The goal of this study was to identify the combination of assembly and binning approaches that result in high-quality and -quantity metagenome-assembled genomes (MAGs), representing most of the sequenced metagenome. Our findings suggest that the metaSPAdes coassembly strategies had the best performance, as they resulted in larger and less fragmented assemblies, with at least 85% of the sequence data mapping to contigs greater than 1 kbp. Furthermore, a combination of metaSPAdes coassembly strategies and MetaBAT2 produced the highest number of medium-quality MAGs while capturing at least 70% of the metagenomes based on read recruitment. Utilizing different assembly/binning approaches also assists in the reconstruction of unique MAGs from closely related species that would have otherwise collapsed into a single MAG using a single workflow. Overall, our study suggests that leveraging multiple binning approaches with different metaSPAdes coassembly strategies may be required to maximize the recovery of good-quality MAGs. IMPORTANCE Drinking water contains phylogenetic diverse groups of bacteria, archaea, and eukarya that affect the esthetic quality of water, water infrastructure, and public health. Taxonomic, metabolic, and ecological inferences of the drinking water microbiome depend on the accuracy, quality, and completeness of genomes that are reconstructed through the application of genome-resolved metagenomics. Using time series metagenomic data, we present reproducible genome-centric metagenomic workflows that result in high-quality and -quantity genomes, which more accurately signifies the sequenced drinking water microbiome. These genome-centric metagenomic workflows will allow for improved taxonomic and functional potential analysis that offers enhanced insights into the stability and dynamics of drinking water microbial communities.

Spatial-temporal targeted and non-targeted surveys to assess microbiological composition of drinking water in Puerto Rico following Hurricane Maria.

Loss of basic utilities, such as drinking water and electricity distribution, were sustained for months in the aftermath of Hurricane Maria's (HM) landfall in Puerto Rico (PR) in September 2017. The goal of this study was to assess if there was deterioration in biological quality of drinking water due to these disruptions. This study characterized the microbial composition of drinking water following HM across nine drinking water systems (DWSs) in PR and utilized an extended temporal sampling campaign to determine if changes in the drinking water microbiome were indicative of HM associated disturbance followed by recovery. In addition to monitoring water chemistry, the samples were subjected to culture independent targeted and non-targeted microbial analysis including quantitative PCR (qPCR) and genome-resolved metagenomics. The qPCR results showed that residual disinfectant was the major driver of bacterial concentrations in tap water with marked decrease in concentrations from early to late sampling timepoints. While Mycobacterium avium and Pseudomonas aeruginosa were not detected in any sampling locations and timepoints, genetic material from Leptospira and Legionella pneumophila were transiently detected in a few sampling locations. The majority of metagenome assembled genomes (MAGs) recovered from these samples were not associated with pathogens and were consistent with bacterial community members routinely detected in DWSs. Further, whole metagenome-level comparisons between drinking water samples collected in this study with samples from other full-scale DWS indicated no significant deviation from expected community membership of the drinking water microbiome. Overall, our results suggest that disruptions due to HM did not result in significant and sustained deterioration of biological quality of drinking water at our study sites.

Prone Team: A Large-Scale Prone Position Initiative During COVID-19 Pandemic.

AIM: To identify strategies to improve time to prone in ICUs during the coronavirus disease 2019 (COVID-19) pandemic for patients meeting the criteria for prone position ventilation. BACKGROUND: Healthcare systems worldwide experienced an influx of COVID-19 patients, especially in critical care. COVID-19 patients are at risk of acute respiratory distress syndrome (ARDS). Prone position ventilation is the standard of care for mechanically ventilated patients with moderate to severe ARDS. Prone maneuvers in and of itself are time-consuming and labor-intensive, posing additional risks to patients. APPROACH: Our academic medical center developed a travel proning team to address the rapid increase in COVID-19 patients with ARDS necessitating prone positioning. EVALUATION: Over a period of 30 days, 420 ICU patients were intubated, 131 had moderate to severe ARDS and underwent prone positioning. Patients were placed in prone position or returned to supine position more than 834 times over 38 days. At the highest point, 37 procedures were done in 24 hours. CONCLUSION: This quality initiative demonstrated that utilization of a traveling proning team provides efficiency in time to prone. Developing a travel prone team allowed for efficiency in time to prone, supported the ICU clinical teams, and enhanced interdisciplinary collaboration, which is essential during times of crisis.

Differential prevalence and host-association of antimicrobial resistance traits in disinfected and non-disinfected drinking water systems.

Antimicrobial resistance (AMR) in drinking water has received less attention than its counterparts in the urban water cycle. While culture-based techniques or gene-centric PCR have been used to probe the impact of treatment approaches (e.g., disinfection) on AMR in drinking water, to our knowledge there is no systematic comparison of AMR trait distribution and prevalence between disinfected and disinfectant residual-free drinking water systems. We used metagenomics to assess the associations between disinfectant residuals and AMR prevalence and its host association in full-scale drinking water distribution systems (DWDSs) with and without disinfectant residuals. While the differences in AMR profiles between DWDSs were associated with the presence or absence of disinfectant, they were also associated with overall water chemistry and more importantly with microbial community structure. AMR genes and mechanisms differentially abundant in disinfected systems were primarily associated with nontuberculous mycobacteria (NTM). Finally, evaluation of metagenome assembled genomes (MAGs) also suggests that NTM possessing AMR genes conferring intrinsic resistance to key antibiotics were prevalent in disinfected systems, whereas such NTM genomes were not detected in disinfectant residual free DWDSs. Altogether, our findings provide insights into the drinking water resistome and its association with potential opportunistic pathogens, particularly in systems with disinfectant residual.

Implementing Automated Prone Ventilation for Acute Respiratory Distress Syndrome via Simulation-Based Training.

BACKGROUND: Prone position ventilation (PPV) is recommended for patients with severe acute respiratory distress syndrome, but it remains underused. Interprofessional simulation-based training for PPV has not been described. OBJECTIVES: To evaluate the impact of a novel interprofessional simulation-based training program on providers' perception of and comfort with PPV and the program's ability to help identify unrecognized safety issues ("latent safety threats") before implementation. METHODS: A prospective observational quality improvement study was done in the medical intensive care unit of an academic medical center. Registered nurses, physicians, and respiratory therapists were trained via a didactic session, simulations, and structured debriefings during which latent safety threats were identified. Participants completed anonymous surveys before and after training. RESULTS: A total of 73 providers (37 nurses, 18 physicians, 18 respiratory therapists) underwent training and completed surveys. Before training, only 39% of nurses agreed that PPV would be beneficial to patients with severe acute respiratory distress syndrome, compared with 96% of physicians and 70% of respiratory therapists (P < .001). Less than half of both nurses and physicians felt comfortable taking care of prone patients. After training, perceived benefit increased among all providers. Comfort taking care of proned patients and managing cardiac arrest increased significantly among nurses and physicians. Twenty novel latent safety threats were identified. CONCLUSION: Interprofessional simulation-based training may improve providers' perception of and comfort with PPV and can help identify latent safety threats before implementation.

Anticoagulantes de Acción Directa en Atención Primaria / Direct Action Anticoagulants in Primary Care

No disponible

Conflictos de interés y Medicina de Familia-SEMERGEN / Conflicts of Interest and Family Medicine-SEMERGEN

No disponible

Innovative therapies in Ewing Sarcoma.

Ewing Sarcoma is a developmental tumor characterized by balanced chromosomal translocations and formation of new fusion genes, which are the main hallmark of this rare entity. Despite the vast knowledge regarding the molecular aspects of this rare malignancy obtained in the last few years, including the discovery of new therapeutic targets, many questions still remain open. In this review we focus on the research on targeted therapies in this malignancy, and discussed some bottlenecks related to this such as the possible role of pathologists, the availability of samples, the lack of appropriate animal models, and the resources needed to carry out preclinical and clinical research.

PVC biodeterioration and DEHP leaching by DEHP-degrading bacteria.

Newly isolated, not previously reported, di-(2-ethylhexyl) phthalate (DEHP)-degraders were augmented to assess their role in polyvinyl chloride (PVC) shower curtain deterioration and DEHP leaching. The biofilms that developed on the surfaces of the bioaugmented shower curtains with Gram-positive strains LHM1 and LHM2 were thicker than those of the biostimulated and Gram-negative strain LHM3-augmented shower curtains. The first derivative thermogravimetric (DTG) peaks of the bioaugmented shower curtains with the Gram-positive bacteria were observed at ~287°C, whereas the control and Gram-negative strain LHM3-augmented shower curtains were detected at ~283°C. This slight delay in the first DTG peak temperature is indicative of lower plasticizer concentrations in the shower curtains that were bioaugmented with Gram positive bacteria. Despite bioaugmentation with DEHP-degraders, aqueous solutions of the bioaugmentation reactors were not DEHP-free due probably to the presence of co-solutes that must have supported microbial growth. Generally, the bioaugmented reactors with the Gram-positive strains LHM1 and LHM2 had greater aqueous DEHP concentrations in the first-half (<3 wk) of the biodeterioration experiment than the biostimulated and strain LHM3-augmented reactors. Therefore, strains LHM1 and LHM2 may play an important role in DEHP leaching to the environment and PVC biodeterioration.

PITASOR epidemiological study: prevalence, incidence and treatment of anaemia in radiation therapy oncology departments in Spain.

INTRODUCTION: Anemia is the most common haematological complication in cancer patients. OBJECTIVE: Analysis of the incidence, prevalence and treatment of anemia in oncologic patients treated in Radiation Oncology Departments in Spain (ROD) and monitoring of the existing recommendations for the treatment of anemia. MATERIAL AND METHODS: Observational, prospective, multicenter study which involved 19 Spanish ROD. The study was approved by the CEIC Central Defense Hospital. 477 patients with solid tumors, subsidiary of RT with radical intent referred to such centers within a period of one month (5/5/09 to 5/6/09) and gave their consent to participate in the study. We gathered the main characteristics of patients and their oncologic disease. All patients underwent a determination of Hb levels before RT, upon reaching 25-35 Gy and at the end treatment. In patients with anemia we assessed the existence of related symptoms and its treatment. RESULTS: Basal situation: The prevalence of anemia was 34.8% (166 patients). Mean Hb in patients with anemia was 11.17 ± 1.07 g/dl. Anemia-related symptoms were present in 34% of the patients. Anemia predisposing factors were: stage of the disease, previously received chemotherapy, and hormonal therapy. 39% (66 patients) received anemia treatment, with a mean Hb of 10.43 ± 1.04 g/dl. During RT: The prevalence of anemia was 38.9% (182 patients) with a mean Hb of 11.24 ± 1.21 g/dl. Predisposing factors for anemia during RT treatment were: age, male sex, chemotherapy prior to RT, basal anemia and chemotherapy during RT. 36.3% (66 patients) had anemia-related symptoms. 34.6% (63 patients) with a mean Hb of 10.5 ± 1.37 g/dl received treatment for anemia. The prevalence of anemia at the end of the RT was 38.1% (177 patients) with a mean Hb of 11.19 ± 1.18 g/dl. The predisposing factors for the appearance of anemia at the end of RT were: male sex, anemia at basal situation and during treatment and chemotherapy during RT. 34% (61 patients) had anemia-related symptoms and 73 patients (41.2%) with a mean Hb of 10.5 ± 1.22 g/dl received treatment for anemia. The presence of anemia-related symptoms was significantly correlated with the beginning of treatment for anemia. The incidence of anemia (new cases) during radiotherapy was 17.5%. CONCLUSION: The prevalence of anemia in basal situation, during RT and at the end of RT is 34.8%, 38.9% and 38.1%. During RT the incidence of anemia is 17.5%. 39.8%-41.2% of patients with anemia and 64.2%-68% of patients with anemia-related symptoms received treatment. Treatment of anemia starts with Hb<11 g/dl and the goal is to achieve Hb 12 g/dl. In our Radiotherapy Oncology Departments, the treatment of anemia complies with the current recommendations and guidelines in use.

The clinical relevance of molecular genetics in soft tissue sarcomas.

Bone and soft tissue sarcomas are an infrequent and heterogeneous group of mesenchymal tumors including more than a hundred different entities attending to histologic patterns. Research into the molecular aspects of sarcomas has increased greatly in the last few years. This enormous amount of knowledge has allowed, for instance, to refine the classification of sarcomas, improve the diagnosis, and increase the number of therapeutical targets available, most of them under preclinical evaluation. However, other important key issues, such as sarcomagenesis and the cell of origin of sarcomas, remain unresolved. From a molecular point of view, these neoplasias are grouped into 2 main types: (a) sarcomas showing relatively simple karyotypes and translocations, which originate gene fusions (eg, EWS-FLI1 in Ewing sarcoma) or point mutations (eg, c-kit in the gastrointestinal tumors) and (b) sarcomas showing unspecific gene alterations, very complex karyotypes, and no translocations. The discovery of the early mechanisms involved in the genesis of sarcomas, the more relevant signaling pathways, and the development of genetically engineered mouse models could also provide a new individualized therapeutic strategy against these tumors. This review describes the clinical application of some of the molecular alterations found in sarcomas, some advances in the field of sarcomagenesis, and the development of animal models.

Differences in metal and metalloid content in the hair of normo- and hypertensive postmenopausal women.

This study was performed on scalp hair samples from postmenopausal women (n=26; 12 normotensives and 14 hypertensives) to determine the relationship between blood pressure and metal and metalloids in hair samples. Hair concentrations of Al, Ba, Cd, Co, Cr, Mn, Mo, Ni, Pb, Sb, Se, Sr and V were measured using inductively coupled plasma mass spectrometry, whereas Ca, Cu, Fe, K, Mg, Na and Zn concentrations were measured by inductively coupled plasma optical emission spectrometry. Methods were optimized and then validated using certified reference material GBW 09101 human hair. Although Cd, Co and Mo levels in hypertensive volunteers were significantly higher than in normotensive individuals (P<0.05), the concentrations of Fe, Mn, Na (all P<0.05) and K (P<0.001) were significantly lower. Concentrations of K (P<0.001; P<0.001) were negatively correlated with systolic and diastolic blood pressure. The concentration of Co (P=0.004; P<0.001) displayed a positive correlation with both types of pressure, whereas Cu (P=0.013) and Ni (P<0.001) concentrations correlated significantly with diastolic blood pressure and Mn negatively correlated with systolic blood pressure (P=0.031). Overweight and hypertension concurred in 27% of volunteers. This concurrence did not modify differences in hair mineral levels attributed to hypertension. The present results indicate that scalp hair concentrations of certain metals and metalloids can be used as biomarkers for hypertension in postmenopausal women.

Prevalence of Parkinson's disease in Cantalejo, Spain: a door-to-door survey.

We assessed the prevalence of Parkinson's disease in Cantalejo, Spain. In 1994, we screened 1,579 persons (age > or = 40 years) using a high-sensitivity method. Cases fulfilling established clinical criteria were followed for a minimum of 3 years. Prevalences were compared with those from other door-to-door surveys. We detected 27 individuals with parkinsonism, 20 of whom had Parkinson's disease. The prevalence of Parkinson's disease increased with age and, when age-adjusted to European standards, was 9.01 per 1,000 (age 40 years and over; 10.78 in men and 5.23 in women). Of the 11 men, three were in Hoehn & Yahr grades III-IV, but six of the nine women were more severely affected. Overall, we found 18 newly diagnosed cases of parkinsonism, 13 of which were Parkinson's disease, and the majority of which were in men aged 80 years or older with a mean duration of illness of 5 years. Our prevalence figures are the highest reported, apparently because of the inclusion of several very elderly men. Parkinson's disease in Cantalejo is less severe in men than in women, particularly in those newly diagnosed. Despite the low numbers, the high prevalence and sex-related pattern are unexplained but they probably relate to the high sensitivity of the screening method.

Field validation of a method for population screening of parkinsonism.

We sought to validate an instrument and two application procedures for screening for prevalence of parkinsonism in conjunction with a door-to-door survey in Cantalejo, Spain. Residents in Cantalejo aged 40 years or older were assigned to three groups specifically designed to optimise case-finding and cost/efficiency. A nine-item questionnaire aimed at identifying parkinsonism-related symptoms was administered and collected door-to-door by laymen and repeated by specialists at a medical facility before neurological examination. Diagnoses were then established and confirmed after a 3-year follow-up. Different indices for and concordance of answers were studied for both applications in groups of 25 individuals with parkinsonism. The scoring procedure was updated using the prevalence community sample of parkinsonism. Whereas the application administered by laymen showed, using the same cut-off scores, a higher sensitivity for parkinsonism than that administered by trained personnel, it yielded a lower positive predictive value for parkinsonism diagnosed during the study, i.e., at a 30-point cut-off (96% vs. 80% and 15% vs. 76%, respectively). Concordance was > or =64% with kappa >or=0.316 and P