MicroRNAs control the apoptotic threshold in primed pluripotent stem cells through regulation of BIM.

Mammalian primed pluripotent stem cells have been shown to be highly susceptible to cell death stimuli due to their low apoptotic threshold, but how this threshold is regulated remains largely unknown. Here we identify microRNA (miRNA)-mediated regulation as a key mechanism controlling apoptosis in the post-implantation epiblast. Moreover, we found that three miRNA families, miR-20, miR-92, and miR-302, control the mitochondrial apoptotic machinery by fine-tuning the levels of expression of the proapoptotic protein BIM. These families therefore represent an essential buffer needed to maintain cell survival in stem cells that are primed for not only differentiation but also cell death.

Vaccination status and outcomes in critical COVID-19 patients.

OBJECTIVE: To analyze the clinical characteristics and outcomes of patients with COVID-19-related acute respiratory failure on the basis of their vaccination status at the time of ICU admission. METHODS: We conducted a retrospective observational study using a prospective database of patients admitted to the ICU of a university hospital in the city of Murcia, in Spain, between January 1, 2021 and September 1, 2022. Clinical, analytical, and sociodemographic data were collected and analyzed on the basis of patient vaccination status. We adjusted for confounding variables using propensity score matching and calculated adjusted ORs and 95% CIs. RESULTS: A total of 276 patients were included in the study. Of those, 8.3% were fully vaccinated, 12% were partially vaccinated, and 79.7% were unvaccinated. Although fully vaccinated patients had more comorbidities, partially vaccinated patients had higher disease severity. The proportion of patients with severe acute respiratory failure was higher in the unvaccinated group, followed by the partially vaccinated group. No significant differences were found among the different groups regarding complications, duration of ventilatory support, or length of ICU/hospital stay. In the sample selected by propensity score matching, the number of patients with severe complications and the in-hospital mortality rate were higher in unvaccinated patients, but the differences were not significant. CONCLUSIONS: This study failed to show a significant improvement in outcomes in critically ill COVID-19 patients vaccinated against SARS-CoV-2. However, the CIs were wide and the mortality point estimates favored patients who received at least one dose of COVID-19 vaccine.

Diffuse pulmonary meningotheliomatosis diagnosed by transbronchial lung biopsy.

Minute pulmonary meningothelial-like nodules (MPMNs) are usually unique lesions in the lung parenchyma. Diffuse pulmonary meningotheliomatosis, which is presented as multiple MPMNs, has been less frequently described. MPMNs are mainly asymptomatic and are diagnosed after lung surgery or during autopsy. We report on a patient with multiple and bilateral pulmonary nodules, some of which were cavitated, diagnosed with diffuse pulmonary meningotheliomatosis by transbronchial lung biopsy. Diffuse pulmonary meningotheliomatosis should be included in the differential diagnosis of bilateral lung nodules.

MicroRNAs Regulate Ca2+ Homeostasis in Murine Embryonic Stem Cells.

MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis of gene pathways differently expressed in the absence of miRNAs due to the deletion of Dicer, which encodes an RNase that is essential for the synthesis of miRNAs. One pathway that stood out was Ca2+ signaling. Interestingly, we found that Dicer-/- ESCs had no difference in basal cytoplasmic Ca2+ levels but were hyperresponsive when Ca2+ import into the endoplasmic reticulum (ER) was blocked by thapsigargin. Remarkably, the increased Ca2+ response to thapsigargin in ESCs resulted in almost no increase in apoptosis and no differences in stress response pathways, despite the importance of miRNAs in the stress response of other cell types. The increased Ca2+ response in Dicer-/- ESCs was also observed during purinergic receptor activation, demonstrating a physiological role for the miRNA regulation of Ca2+ signaling pathways. In examining the mechanism of increased Ca2+ responsiveness to thapsigargin, neither store-operated Ca2+ entry nor Ca2+ clearance mechanisms from the cytoplasm appeared to be involved. Rather, it appeared to involve an increase in the expression of one isoform of the IP3 receptors (Itpr2). miRNA regulation of Itpr2 expression primarily appeared to be indirect, with transcriptional regulation playing a major role. Therefore, the miRNA regulation of Itpr2 expression offers a unique mechanism to regulate Ca2+ signaling pathways in the physiology of pluripotent stem cells.

Analysis of combined non-invasive respiratory support in the first six waves of the COVID-19 pandemic. Outcome according to the first respiratory support.

Introduction: COVID-19 can lead to acute respiratory failure (ARF) requiring admission to intensive care unit (ICU). This study analyzes COVID-19 patients admitted to the ICU, according to the initial respiratory support. Its main aim is to determine if the use of combination therapy: high-flow oxygen system with nasal cannula (HFNC) and non-invasive ventilation (NIV), is effective and safe in the treatment of these patients. Methods: Retrospective observational study with a prospective database. All COVID-19 patients, admitted to the ICU, between March 11, 2020, and February 12, 2022, and who required HFNC, NIV, or endotracheal intubation with invasive mechanical ventilation (ETI-IMV) were analyzed. HFNC failure was defined as therapeutic escalation to NIV, and NIV failure as the need for ETI-IMV or death in the ICU. The management of patients with non-invasive respiratory support included the use of combined therapy with different devices. The study period included the first six waves of the pandemic in Spain. Results: 424 patients were analyzed, of whom 12 (2.8%) received HFNC, 397 (93.7%) NIV and 15 (3.5%) ETI-IMV as first respiratory support. PaO2/FiO2 was 145 ± 30, 119 ± 26 and 117 ± 29 mmHg, respectively (p = 0.003). HFNC failed in 11 patients (91.7%), who then received NIV. Of the 408 patients treated with NIV, 353 (86.5%) received combination therapy with HFNC. In patients treated with NIV, there were 114 failures (27.9%). Only the value of SAPS II index (p = 0.001) and PaO2/FiO2 (p < 0.001) differed between the six analyzed waves, being the most altered values in the 3rd and 6th waves. Hospital mortality was 18.7%, not differing between the different waves (p = 0.713). Conclusions: Severe COVID-19 ARF can be effectively and safely treated with NIV combined with HFNC. The clinical characteristics of the patients did not change between the different waves, only showing a slight increase in severity in the 3rd and 6th waves, with no difference in the outcome.

DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.

The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response.

Outcome of patients with acute heart failure secondary to acute myocardial infarction treated with noninvasive mechanical ventilation.

INTRODUCTION AND OBJECTIVES: Noninvasive ventilation (NIV) has been shown to reduce the rate of endotracheal intubation and mortality in patients with acute heart failure (AHF). However, patients with AHF secondary to acute coronary syndrome/acute myocardial infarction (ACS-AMI) have been excluded from many clinical trials. The purpose of this study was to compare the effectiveness of NIV between patients with AHF triggered by ACS-AMI and by other etiologies. METHODS: Prospective cohort study of all patients with AHF treated with NIV admitted to the intensive care unit for a period of 20 years. Patients were divided according to whether they had ACS-AMI as the cause of the AHF episode. NIV failure was defined as the need for endotracheal intubation or death. RESULTS: A total of 1009 patients were analyzed, 403 (40%) showed ACS-AMI and 606 (60%) other etiologies. NIV failure occurred in 61 (15.1%) in the ACS-AMI group and in 64 (10.6%) in the other group (P=.031), without differences in in-hospital mortality (16.6% and 14.9%, respectively; P=.478). CONCLUSIONS: The presence of ACS-AMI as the triggering cause of AHF did not influence patients with acute respiratory failure requiring noninvasive respiratory support.

Effectiveness of individualized inhaler technique training on low adherence (LowAd) in ambulatory patients with COPD and asthma.

To analyze whether there is improvement in adherence to inhaled treatment in patients with COPD and asthma after an educational intervention based on the teach-to-goal method. This is a prospective, non-randomized, single-group study, with intervention and before-after evaluation. The study population included 120 patients (67 females and 53 males) diagnosed with asthma (70.8%) and COPD (29.1%). The level of adherence (low and optimal) and the noncompliance behavior pattern (erratic, deliberate and unwitting) were determined by the Test of the adherence to Inhalers (TAI). This questionnaire allows you to determine the level of adherence and the types of noncompliance. Low Adherence (LowAd) was defined as a score less than 49 points. All patients received individualized educational inhaler technique intervention (IEITI). Before the IEITI, 67.5% of the patients had LowAd. Following IEITI, on week 24, LowAd was 55% (p = 0.024). Each patient can present one or more types of noncompliance. The most frequent type was forgetting to use the inhaler (erratic), 65.8%. The other types were deliberate: 43.3%, and unwitting: 57.5%. All of them had decreased on the final visit: 51.7% (p = 0.009), 25.8% (p = 0.002), 39.2% (p = 0.002). There were no significant differences in adherence between asthma and COPD patients at the start of the study. The only predicting factor of LowAd was the female gender. An individualized educational intervention, in ambulatory patients with COPD and asthma, in real-world clinical practice conditions, improves adherence to the inhaled treatment.

Effectiveness of Non-Presential Individualized Exercise Training PrOgram(NIETO) in Lower Limb Physical Performance in Advanced COPD.

Muscle training, a component of pulmonary rehabilitation (PR), improves the physical performance of patients with chronic obstructive pulmonary disease (COPD). Despite the existing evidence, the traditional center-based PR model is applied to a small percentage of patients and presents numerous problems of accessibility, adherence, and costs. This study presents a home model of simple muscle training, non-presential, monitored by telephone and individualized, according to the severity of the COPD. In addition, to evaluate the results, simple tests associated with the physical performance of the lower limbs, previously validated in COPD, have been used, such as the four-meter walk, speed test (4MGS) and the five-repetition test sitting and standing (5STS). The objective was to evaluate whether the Individualized Non-Presential Exercise Training PrOgram (NIETO) induces improvements in the 4MGS, 5STS and quadriceps muscle strength (QMS) tests in outpatients with advanced COPD (FEV1 ≤ 50%). After one year, the QMS was significantly higher in the intervention group (IG) than in the control group (CG) (2.44 ± 4.07 vs. 0.05 ± 4.26 kg; p = 0.009). The 4MGS and 5STS tests were significantly shorter in IG than in CG (-0.39 ± 0.86 vs. 0.37 ± 0.96 s; p = 0.001) and (-1.55 ± 2.83 vs. 0.60 ± 2.06 s; p = 0.001), respectively. A home model of simple muscle training monitored by telephone such as NIETO, can improve 4MGS, 5STS, and quadriceps strength tests in outpatients with advanced COPD.

Vaccination status and outcomes in critical COVID-19 patients / Situação vacinal e desfechos em pacientes com COVID-19 em estado crítico

ABSTRACT Objective: To analyze the clinical characteristics and outcomes of patients with COVID-19-related acute respiratory failure on the basis of their vaccination status at the time of ICU admission. Methods: We conducted a retrospective observational study using a prospective database of patients admitted to the ICU of a university hospital in the city of Murcia, in Spain, between January 1, 2021 and September 1, 2022. Clinical, analytical, and sociodemographic data were collected and analyzed on the basis of patient vaccination status. We adjusted for confounding variables using propensity score matching and calculated adjusted ORs and 95% CIs. Results: A total of 276 patients were included in the study. Of those, 8.3% were fully vaccinated, 12% were partially vaccinated, and 79.7% were unvaccinated. Although fully vaccinated patients had more comorbidities, partially vaccinated patients had higher disease severity. The proportion of patients with severe acute respiratory failure was higher in the unvaccinated group, followed by the partially vaccinated group. No significant differences were found among the different groups regarding complications, duration of ventilatory support, or length of ICU/hospital stay. In the sample selected by propensity score matching, the number of patients with severe complications and the in-hospital mortality rate were higher in unvaccinated patients, but the differences were not significant. Conclusions: This study failed to show a significant improvement in outcomes in critically ill COVID-19 patients vaccinated against SARS-CoV-2. However, the CIs were wide and the mortality point estimates favored patients who received at least one dose of COVID-19 vaccine.

RESUMO Objetivo: Analisar as características clínicas e desfechos de pacientes com insuficiência respiratória aguda por COVID-19 com base na situação vacinal no momento da admissão na UTI. Métodos: Estudo observacional retrospectivo com um banco de dados prospectivo de pacientes admitidos na UTI de um hospital universitário em Múrcia, na Espanha, entre 1º de janeiro de 2021 e 1º de setembro de 2022. Dados clínicos, analíticos e sociodemográficos foram coletados e analisados com base na situação vacinal dos pacientes. Por meio de pareamento por escore de propensão, foram realizados ajustes de modo a levar em conta as variáveis de confusão. Além disso, foram calculadas as OR ajustadas e IC95%. Resultados: Foram incluídos no estudo 276 pacientes. Destes, 8,3% apresentavam vacinação completa, 12% apresentavam vacinação incompleta e 79,7% não haviam sido vacinados. Embora os pacientes com vacinação completa apresentassem mais comorbidades, os com vacinação incompleta apresentavam doença mais grave. A proporção de pacientes com insuficiência respiratória aguda grave foi maior nos não vacinados, seguidos daqueles com vacinação incompleta. Não foram observadas diferenças significativas entre os diferentes grupos quanto a complicações, tempo de suporte ventilatório ou tempo de internação na UTI/hospital. Na amostra selecionada pelo pareamento por escore de propensão, o número de pacientes com complicações graves e a taxa de mortalidade hospitalar foram maiores em pacientes não vacinados, mas as diferenças não foram significativas. Conclusões: Este estudo não conseguiu demonstrar uma melhoria significativa dos desfechos em pacientes com COVID-19 em estado crítico e vacinados contra o SARS-CoV-2. No entanto, os IC foram amplos e as estimativas pontuais de mortalidade favoreceram os pacientes que receberam pelo menos uma dose de vacina contra a COVID-19.

Efficacy of a self-management plan in exacerbations for patients with advanced COPD.

BACKGROUND: Self-management interventions improve different outcome variables in various chronic diseases. Their role in COPD has not been clearly established. We assessed the efficacy of an intervention called the self-management program on the need for hospital care due to disease exacerbation in patients with advanced COPD. METHODS: Multicenter, randomized study in two hospitals with follow-up of 1 year. All the patients had severe or very severe COPD, and had gone to either an accident and emergency (A&E) department or had been admitted to a hospital at least once in the previous year due to exacerbation of COPD. The intervention consisted of a group education session on the main characteristics of the disease, an individual training session on inhalation techniques, at the start and during the 3rd month, and a written action plan containing instructions for physical activity and treatment for stable phases and exacerbations. We determined the combined number of COPD-related hospitalizations and emergency visits per patient per year. Secondary endpoints were number of patients with visits to A&E and the number of patients hospitalized because of exacerbations, use of antibiotics and corticosteroids, length of hospital stay, and all-cause mortality. RESULTS: After 1 year, the rate of COPD exacerbations with visits to A&E or hospitalization had decreased from 1.37 to 0.89 (P=0.04) and the number of exacerbations dropped from 52 to 42 in the group of patients who received the intervention. The numbers of patients hospitalized, at 19 (40.4%) versus 20 (52.6%) (P=0.26), and those who went to A&E, at 9 (19.1%) versus 14 (36.8%) (P=0.06), due to exacerbation of COPD were also lower in this group. Intake of antibiotics was higher in the intervention group, whereas use of glucocorticoids was slightly lower, though there were no significant differences (P=0.30). There were also no differences between groups in the length of hospital stay (P=0.154) or overall mortality (P=0.191). CONCLUSION: The implementation of a self-management program for patients with advanced COPD reduced exacerbations that required hospital care.

Antimicrobial chemotherapy for Legionnaires disease: levofloxacin versus macrolides.

BACKGROUND: The community outbreak of legionnaires disease that occurred in Murcia, Spain, in July 2001--to our knowledge, the largest such outbreak ever reported--afforded an unusual opportunity to compare the clinical response of patients with Legionella pneumonia treated with levofloxacin with that of patients treated with macrolides and to determine the role of rifampicin combined with levofloxacin in treating severe legionellosis. METHODS: An observational, prospective, nonrandomized study was conducted involving 292 patients seen at our hospital (Hospital "J. M. Morales Meseguer"; Murcia, Spain) who received a diagnosis of Legionella pneumonia during the Murcia outbreak. To compare both antibiotic regimens (macrolides vs. levofloxacin), patients were stratified by the severity of pneumonia. Duration of fever, clinical outcome, complications, side effects, and length of hospital stay were recorded. To assess the potential effects of adjuvant therapy with rifampicin, 45 case patients treated with levofloxacin plus rifampicin were evaluated and compared with 45 control pairs who were treated with levofloxacin alone. RESULTS: With the exception of 2 patients who died, all patients were cured. There were no significant differences between treatment groups in clinical outcome for patients with mild-to-moderate pneumonia. Nevertheless, in patients with severe pneumonia, levofloxacin exerted superior activity; it was associated with fewer complications (3.4% of patients receiving levofloxacin experienced complications, compared with 27.2% of patients receiving macrolides; P=.02) and shorter mean hospital stays (5.5 vs. 11.3 days; P=.04). Addition of rifampicin to the treatment regimen for patients receiveing levofloxacin for severe pneumonia provides no additional benefit. CONCLUSIONS: Our findings strongly suggest that monotherapy with levofloxacin is a safe and effective treatment for legionnaires disease, including in patients with severe disease. In these patients, levofloxacin appears to be more effective than clarithromycin.

The Short Physical Performance Battery is a discriminative tool for identifying patients with COPD at risk of disability.

BACKGROUND: Limited mobility is a risk factor for developing chronic obstructive pulmonary disease (COPD)-related disabilities. Little is known about the validity of the Short Physical Performance Battery (SPPB) for identifying mobility limitations in patients with COPD. OBJECTIVE: To determine the clinical validity of the SPPB summary score and its three components (standing balance, 4-meter gait speed, and five-repetition sit-to-stand) for identifying mobility limitations in patients with COPD. METHODS: This cross-sectional study included 137 patients with COPD, recruited from a hospital in Spain. Muscle strength tests and SPPB were measured; then, patients were surveyed for self-reported mobility limitations. The validity of SPPB scores was analyzed by developing receiver operating characteristic curves to analyze the sensitivity and specificity for identifying patients with mobility limitations; by examining group differences in SPPB scores across categories of mobility activities; and by correlating SPPB scores to strength tests. RESULTS: Only the SPPB summary score and the five-repetition sit-to-stand components showed good discriminative capabilities; both showed areas under the receiver operating characteristic curves greater than 0.7. Patients with limitations had significantly lower SPPB scores than patients without limitations in nine different mobility activities. SPPB scores were moderately correlated with the quadriceps test (r>0.40), and less correlated with the handgrip test (r<0.30), which reinforced convergent and divergent validities. A SPPB summary score cutoff of 10 provided the best accuracy for identifying mobility limitations. CONCLUSION: This study provided evidence for the validity of the SPPB summary score and the five-repetition sit-to-stand test for assessing mobility in patients with COPD. These tests also showed potential as a screening test for identifying patients with COPD that have mobility limitations.

Clinical audit of COPD patients requiring hospital admissions in Spain: AUDIPOC study.

BACKGROUNDS: AUDIPOC is a nationwide clinical audit that describes the characteristics, interventions and outcomes of patients admitted to Spanish hospitals because of an exacerbation of chronic obstructive pulmonary disease (ECOPD), assessing the compliance of these parameters with current international guidelines. The present study describes hospital resources, hospital factors related to case recruitment variability, patients' characteristics, and adherence to guidelines. METHODOLOGY/PRINCIPAL FINDINGS: An organisational database was completed by all participant hospitals recording resources and organisation. Over an 8-week period 11,564 consecutive ECOPD admissions to 129 Spanish hospitals covering 70% of the Spanish population were prospectively identified. At hospital discharge, 5,178 patients (45% of eligible) were finally included, and thus constituted the audited population. Audited patients were reassessed 90 days after admission for survival and readmission rates. A wide variability was observed in relation to most variables, hospital adherence to guidelines, and readmissions and death. Median inpatient mortality was 5% (across-hospital range 0-35%). Among discharged patients, 37% required readmission (0-62%) and 6.5% died (0-35%). The overall mortality rate was 11.6% (0-50%). Hospital size and complexity and aspects related to hospital COPD awareness were significantly associated with case recruitment. Clinical management most often complied with diagnosis and treatment recommendations but rarely (<50%) addressed guidance on healthy life-styles. CONCLUSIONS/SIGNIFICANCE: The AUDIPOC study highlights the large across-hospital variability in resources and organization of hospitals, patient characteristics, process of care, and outcomes. The study also identifies resources and organizational characteristics associated with the admission of COPD cases, as well as aspects of daily clinical care amenable to improvement.

Bilateral pulmonary nodules as a manifestation of primary pulmonary T-cell lymphoma.

Primary pulmonary lymphoma (PPL) is an uncommon pathology and is usually of the B-cell type, originating in lymphoid tissue associated with the bronchial mucosa (MALT/BALT lymphoma). Very few cases of T-cell PPL, the majority diagnosed by open lung biopsy, have been described in medical literature. We report a case of an immunocompetent patient with fever and bilateral pulmonary nodules, diagnosed with T-cell PPL by transbronchial biopsy. The patient's condition deteriorated and she responded poorly to chemotherapy. PPL should be included in the differential diagnosis of patients with fever and bilateral pulmonary nodules.