Midwives and gynecologists: knowledge about sterile water injections for pain relief in labor

Presently, there is great interest in nonpharmacologic methods of pain relief during labor. The aim of this study was to determine whether gynecologists and midwives are aware of the use of sterile water injections for pain relief during childbirth, whether they use this pain relief method, and if not, would they do so in the future. We designed a quantitative, observational, descriptive, prospective and transversal study. Study participants were recruited from the 16th Health Department of Alicante, Spain. The data collection method used was a questionnaire of self-realization. The most relevant results indicate that those with less working experience (8.06 ± 6.82 years) used the technique most often compared with the group with more working experience (16.92 ± 11.90 years; p = .04). The results determined that women have more knowledge about the technique (79.3%), whereas only 33.3% of men are aware of it (p = .02). The results of this study showed a lack of knowledge regarding this technique, as well as educational interest in the fact that women have more knowledge than men. Increased use was observed in younger, less experienced professionals

Evaluation of interventions in people with digestive stoma through the Nursing Interventions Classification

This manuscript is part of the project "The experience of having an intestinal stoma and its relations to nursing practice. Qualitative metasynthesis and implementation of qualitative evidence through clinical pathways." This project was funded by the Ministry of Health, Junta de Andalucia, Spain (Expt: PI-2011-0564).Purpose: To determine which nursing interventions are used in individuals with a digestive stoma and the relationships between nursing interventions used and sociodemographic and clinical variables. Methods: The present study is an observational, cross-sectional, descriptive. Data from 102 individuals in the general surgery unit of a first-level hospital (University Hospital Complex of Granada, Spain) were analyzed. Data on the use of nursing interventions and sociodemographic and clinical variables were collected. Univariate, bivariate, and multivariate data analyses were conducted. Findings: Interventions: Decision-Making Support (5250) and Ostomy Care (0480) were the most prevalent interventions in the sample. The period of care (postoperative and follow-up) was the most common significant variable (p < 0.05) among the interventions observed. Anxiety Reduction (5820), Nutritional Counseling (5246), Self-Esteem Enhancement (5400), and Body Image Enhancement (5220) were also relevant findings. Conclusions: The present study contributes to determining which nursing interventions are used in individuals with a digestive stoma. Implications for nursing practice: This study could be useful in planning nursing interventions in individuals with a digestive stoma.Ministry of Health, Junta de Andalucia, Spain PI-2011-056

Incidence, hospitalization, mortality and risk factors of COVID-19 in long-term care residential homes for patients with chronic mental illness

Long-term care residential homes (LTCRH) for patients with chronic mental illness have suffered the enormous impact of COVID-19. This study aimed to estimate incidence, hospitalization, mortality, and risk factors of COVID-19 to prevent future epidemics. From March 2020 to January 2021 and before vaccination anti-SARS-CoV-2 begins, cumulate incidence rate (CIR), hospitalization rate (HR), mortality rate (MR), and risk factors of COVID-19 in the 11 LTCRH of two Health Departments of Castellon (Spain) were studied by epidemiological surveillance and an ecological design. Laboratory tests confirmed COVID-19 cases, and multilevel Poisson regression models were employed. All LTCRH participated and comprised 346 residents and 482 staff. Residents had a mean age of 47 years, 40% women, and suffered 75 cases of COVID-19 (CIR = 21.7%), five hospitalizations (HR = 1.4%), and two deaths (MR = 0.6%) with 2.5% fatality-case. Staff suffered 74 cases of the disease (CIR = 15.4%), one hospitalization (HR = 0.2%), and no deaths were reported. Risk factors associated with COVID-19 incidence in residents were private ownership, severe disability, residents be younger, CIR in municipalities where LTCRH was located, CIR in staff, and older age of the facilities. Conclusion: COVID-19 incidence could be prevented by improving infection control in residents and staff and modernizing facilities with increased public ownership

Efficacy and safety of universal (TCRKO) ARI-0001 CAR-T cells for the treatment of B-cell lymphoma

Autologous T cells expressing the Chimeric Antigen Receptor (CAR) have been approved as advanced therapy medicinal products (ATMPs) against several hematological malignancies. However, the generation of patient-specific CART products delays treatment and precludes standardization. Allogeneic off-theshelf CAR-T cells are an alternative to simplify this complex and timeconsuming process. Here we investigated safety and efficacy of knocking out the TCR molecule in ARI-0001 CAR-T cells, a second generation aCD19 CAR approved by the Spanish Agency of Medicines and Medical Devices (AEMPS) under the Hospital Exemption for treatment of patients older than 25 years with Relapsed/Refractory acute B cell lymphoblastic leukemia (B-ALL). We first analyzed the efficacy and safety issues that arise during disruption of the TCR gene using CRISPR/Cas9. We have shown that edition of TRAC locus in T cells using CRISPR as ribonuleorproteins allows a highly efficient TCR disruption (over 80%) without significant alterations on T cells phenotype and with an increased percentage of energetic mitochondria. However, we also found that efficient TCRKO can lead to on-target large and medium size deletions, indicating a potential safety risk of this procedure that needs monitoring. Importantly, TCR edition of ARI-0001 efficiently prevented allogeneic responses and did not detectably alter their phenotype, while maintaining a similar anti-tumor activity ex vivo and in vivo compared to unedited ARI-0001 CAR-T cells. In summary, we showed here that, although there are still some risks of genotoxicity due to genome editing, disruption of the TCR is a feasible strategy for the generation of functional allogeneic ARI-0001 CAR-T cells. We propose to further validate this protocol for the treatment of patients that do not fit the requirements for standard autologous CAR-T cells administration.Spanish ISCIII Health Research FundEuropean Commission PI15/02015 PI18/00337 PI21/00298Red TerAv RD21/ 0017/0004 PI18/ 00330 PI17/00672CECEyU and CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) for Andalusia 2016000073391-TRA 2016000073332-TRA PI-57069 PAIDIBio326 CARTPI-0001- 201 PECART-0031-2020 PI0014-2016 PEER-0286-2019Spanish Government 00123009/SNEO-20191072 PLEC2021-008094regional Ministry of Health 0006/2018 C2-0002-2019Spanish Government FPU16/05467 FPU17/02268 FPU17/04327Junta de Andalucia PECART-00312020Consejeria de Salud y Familias PECART-0027-2020 MCI DIN2018-010180 DIN2020-01155

Physiological lentiviral vectors for the generation of improved CAR-T cells

Anti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms.However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%–50%of the treated patients.MostCAR-Tcells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of theirmoderate andTCR-like expression profile. Compared with CAR-T cells generated with human elongation factor a (EF1a)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-a) and interferon (IFN)-ɣ after efficient destruction of CD19+ lymphoma cells, both in vitro and in vivo.Moreover, we also showed their improved efficiency using an in vitro CD19+ pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing ofAW-CAR-T cells in good manufacturing practice (GMP)-like conditions. Based on these data, we propose the use of AW-LVs for the generation of improved CAR-T products.Spanish ISCIII Health Research FundEuropean Commission PI15/02015 PI18/00337 PI21/00298 RD21/0017/0004 PI18/00330 PI17/00672CSyF of the Junta de Andalucia FEDER/European Cohesion Fund (FSE) for Andalusia 2016000073391-TRA 2016000073332-TRA PI-57069 PA IDI-Bio326 CARTPI-0001-201 PECART-0031-2020 Red RANTECAR CAR-T 2019 00400200101918 PLEC2021-008094 PI-0014-2016 PEER-0286-2019Spanish Government PLEC2021-008094 00123009/SNEO-20191072Nicolas Monardes contracts from regional Ministry of Health 0006/2018 C2-0002-2019German Research Foundation (DFG) FPU16/05467 FPU17/02268 FPU17/04327 MCI DIN2018-010180Fundacion Andaluza Progreso y SaludGerman Research Foundation (DFG) PEJ-2018-001760-AJunta de Andalucia PE-0223-2018Biomedicine Programme of the University of Granada (Spain

Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer’s disease.

Background: The complex pathophysiology of Alzheimer’s disease (AD) hampers the development of effective treatments. Attempts to prevent neurodegeneration in AD have failed so far, highlighting the need for further clarification of the underlying cellular and molecular mechanisms. Neuroinflammation seems to play a crucial role in disease progression, although its specific contribution to AD pathogenesis remains elusive. We have previously shown that the modulation of the endocannabinoid system (ECS) renders beneficial effects in a context of amyloidosis, which triggers neuroinflammation. In the 5xFAD model, the genetic inactivation of the enzyme that degrades anandamide (AEA), the fatty acid amide hydrolase (FAAH), was associated with a significant amelioration of the memory deficit. Methods: In this work, we use electrophysiology, flow cytometry and molecular analysis to evaluate the cellular and molecular mechanisms underlying the improvement associated to the increased endocannabinoid tone in the 5xFAD mouse− model. Results: We demonstrate that the chronic enhancement of the endocannabinoid tone rescues hippocampal synaptic plasticity in the 5xFAD mouse model. At the CA3–CA1 synapse, both basal synaptic transmission and longterm potentiation (LTP) of synaptic transmission are normalized upon FAAH genetic inactivation, in a CB1 receptor (CB1R)- and TRPV1 receptor-independent manner. Dendritic spine density in CA1 pyramidal neurons, which is notably decreased in 6-month-old 5xFAD animals, is also restored. Importantly, we reveal that the expression of microglial factors linked to phagocytic activity, such as TREM2 and CTSD, and other factors related to amyloid beta clearance and involved in neuron–glia crosstalk, such as complement component C3 and complement receptor C3AR, are specifically upregulated in 5xFAD/FAAH−/− animals. Conclusion: In summary, our findings support the therapeutic potential of modulating, rather than suppressing, neuroinflammation in Alzheimer’s disease. In our model, the long-term enhancement of the endocannabinoid tone triggered augmented microglial activation and amyloid beta phagocytosis, and a consequent reversal in the neuronal phenotype associated to the diseasepost-print4206 K

Lentiviral vectors for inducible, transactivator-free advanced therapy medicinal products: Application to CAR-T cells

Controlling transgene expression through an externally administered inductor is envisioned as a potent strategy to improve safety and efficacy of gene therapy approaches. Generally, inducible ON systems require a chimeric transcription factor (transactivator) that becomes activated by an inductor, which is not optimal for clinical translation due to their toxicity. We generated previously the first all-in-one, transactivator-free, doxycycline (Dox)-responsive (Lent-On-Plus or LOP) lentiviral vectors (LVs) able to control transgene expression in human stem cells. Here, we have generated new versions of the LOP LVs and have analyzed their applicability for the generation of inducible advanced therapy medicinal products (ATMPs) with special focus on primary human T cells. We have shown that, contrary to all other cell types analyzed, an Is2 insulator must be inserted into the 30 long terminal repeat of the LOP LVs in order to control transgene expression in human primary T cells. Importantly, inducible primary T cells generated by the LOPIs2 LVs are responsive to ultralow doses of Dox and have no changes in phenotype or function compared with untransduced T cells. We validated the LOPIs2 system by generating inducible CAR-T cells that selectively kill CD19+ cells in the presence of Dox. In summary, we describe here the first transactivatorfree, all-one-one system capable of generating Dox-inducible ATMPs.Spanish ISCIII Health Research FundEuropean Union (EU) PI18/00337 PI21/00298 RD21/0017/0004 PI18/00330 PI17/00672Red TerAvJunta de Andalucia FEDER/European Cohesion Fund (FSE) for AndalusiaSpanish Government PI18/00337 PI21/00298European Union-NextGenerationEU - Maria Zambrano Senior Program RD21/0017/0004 PI18/00330 PI17/00672Ministry of Health 2016000073332-TRA PI-57069 CARTPI-0001-201 PE-CART-0031-2020 PI-0014-2016 PECART-0027-2020 ProyExcel_00875 PEER-0286-2019European Cooperation in Science and Technology (COST) 00123009/SNEO-20191072MINECO - European Regional Development Fund PLEC2021-008094Spanish Government 0006/2018FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades CA21113Spanish Government SAF2015-71589-PMCI RYC-2016-21395German Research Foundation (DFG) PY20_00619 y A-CTS-28_UGR20Biomedicine Program of the University of Granada (Spain) FPU16/05467 FPU17/02268 FPU17/04327 DIN2018-010180 DIN2020-011550 PEJ-2018-001760-

Prognostic models for mortality after cardiac surgery in patients with infective endocarditis: a systematic review and aggregation of prediction models.

Background There are several prognostic models to estimate the risk of mortality after surgery for active infective endocarditis (IE). However, these models incorporate different predictors and their performance is uncertain. Objective We systematically reviewed and critically appraised all available prediction models of postoperative mortality in patients undergoing surgery for IE, and aggregated them into a meta-model. Data sources We searched Medline and EMBASE databases from inception to June 2020. Study eligibility criteria We included studies that developed or updated a prognostic model of postoperative mortality in patient with IE. Methods We assessed the risk of bias of the models using PROBAST (Prediction model Risk Of Bias ASsessment Tool) and we aggregated them into an aggregate meta-model based on stacked regressions and optimized it for a nationwide registry of IE patients. The meta-model performance was assessed using bootstrap validation methods and adjusted for optimism. Results We identified 11 prognostic models for postoperative mortality. Eight models had a high risk of bias. The meta-model included weighted predictors from the remaining three models (EndoSCORE, specific ES-I and specific ES-II), which were not rated as high risk of bias and provided full model equations. Additionally, two variables (age and infectious agent) that had been modelled differently across studies, were estimated based on the nationwide registry. The performance of the meta-model was better than the original three models, with the corresponding performance measures: C-statistics 0.79 (95% CI 0.76–0.82), calibration slope 0.98 (95% CI 0.86–1.13) and calibration-in-the-large –0.05 (95% CI –0.20 to 0.11). Conclusions The meta-model outperformed published models and showed a robust predictive capacity for predicting the individualized risk of postoperative mortality in patients with IE. Protocol registration PROSPERO (registration number CRD42020192602).pre-print270 K