Small airways morphological alterations associated with functional impairment in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare neoplastic and cystic pulmonary disease characterized by abnormal proliferation of the so-called LAM cells. Despite the functional obstructive pattern observed in most patients, few studies investigated the morphological changes in the small airways, most of them in patients with severe and advanced LAM undergoing lung transplantation. Understanding the morphological changes in the airways that may occur early in the disease can help us understand the pathophysiology of disease progression and understand the rationale for possible therapeutic approaches, such as the use of bronchodilators. Our study aimed to characterize the morphological alterations of the small airways in patients with LAM with different severities compared to controls, and their association with variables at the pulmonary function test and with LAM Histological Score (LHS). METHODS: Thirty-nine women with LAM who had undergone open lung biopsy or lung transplantation, and nine controls were evaluated. The histological severity of the disease was assessed as LHS, based on the percentage of tissue involvement by cysts and infiltration by LAM cells. The following morphometric parameters were obtained: airway thickness, airway closure index, collagen and airway smooth muscle content, airway epithelial TGF-ß expression, and infiltration of LAM cells and inflammatory cells within the small airway walls. RESULTS: The age of patients with LAM was 39 ± 8 years, with FEV1 and DLCO of 62 ± 30% predicted and 62 ± 32% predicted, respectively. Patients with LAM had increased small airway closure index, collagen and smooth muscle content, and epithelial TGF-beta expression compared with controls. Patients with LAM with the more severe LHS and with greater functional severity (FEV1 ≤ 30%) presented higher thicknesses of the airways. Bronchiolar inflammation was mild; infiltration of the small airway walls by LAM cells was rare. LHS was associated with an obstructive pattern, air trapping, and reduced DLCO, whereas small airway wall thickness was associated with FEV1, FVC, and collagen content. CONCLUSION: LAM is associated with small airway remodelling and partial airway closure, with structural alterations observed at different airway compartments. Functional impairment in LAM is associated with airway remodelling and, most importantly, with histological severity (LHS).

Implementation and Results of a Dedicated Telemedicine Program (TeleTrachea) for Patients with Tracheal Diseases.

Background: Central airway diseases requiring frequent outpatient visits to a specialized medical center due to tracheal devices. Many of these patients have mobility and cognition restrictions or require specialized transport due to the need for supplemental oxygen. This study describes the implementation and results of a telemedicine program dedicated to patients with central airway diseases based in a Brazilian public health system. Methods: A retrospective study of telemedicine consultation for patients with central airway diseases referred to a public academic hospital between August 1, 2020 and August 1, 2022. The consultations occurred in a telemedicine department using the hospital's proprietary platform. Data retrieved consisted of demographics, disease characteristics, and the treatment modalities of the patients. The analysis included the savings in kilometers not traveled, the carbon footprint based on reducing CO2 emissions, and the cost savings in transportation. Results: A total of 1,153 telemedicine visits conducted in 516 patients (median age of 31.5 years). Two hundred ninety patients (56.2%) had a tracheal device (129 silicone T-Tube, 128 tracheostomy, and 33 endoprosthesis) and 159 patients (30.8%) had difficulties in transportation to the specialized medical center. Patients were served from 147 Brazilian cities from 22 states. The savings in kilometers traveled was 1,224,108.54 km, corresponding to a 250.14 ton reduction in CO2 emissions. The costs savings in transportation for the municipalities was BRL$ 1,272,283.78. Conclusions: Telemedicine consultations for patients with central airway diseases are feasible and safe. Cost savings and the possibility of disseminating specialized care make telemedicine a fundamental tool in current medical practice.

Tracking the time course of pathological patterns of lung injury in severe COVID-19.

BACKGROUND: Pulmonary involvement in COVID-19 is characterized pathologically by diffuse alveolar damage (DAD) and thrombosis, leading to the clinical picture of Acute Respiratory Distress Syndrome. The direct action of SARS-CoV-2 in lung cells and the dysregulated immuno-coagulative pathways activated in ARDS influence pulmonary involvement in severe COVID, that might be modulated by disease duration and individual factors. In this study we assessed the proportions of different lung pathology patterns in severe COVID-19 patients along the disease evolution and individual characteristics. METHODS: We analysed lung tissue from 41 COVID-19 patients that died in the period March-June 2020 and were submitted to a minimally invasive autopsy. Eight pulmonary regions were sampled. Pulmonary pathologists analysed the H&E stained slides, performing semiquantitative scores on the following parameters: exudative, intermediate or advanced DAD, bronchopneumonia, alveolar haemorrhage, infarct (%), arteriolar (number) or capillary thrombosis (yes/no). Histopathological data were correlated with demographic-clinical variables and periods of symptoms-hospital stay. RESULTS: Patient´s age varied from 22 to 88 years (18f/23 m), with hospital admission varying from 0 to 40 days. All patients had different proportions of DAD in their biopsies. Ninety percent of the patients presented pulmonary microthrombosis. The proportion of exudative DAD was higher in the period 0-8 days of hospital admission till death, whereas advanced DAD was higher after 17 days of hospital admission. In the group of patients that died within eight days of hospital admission, elderly patients had less proportion of the exudative pattern and increased proportions of the intermediate patterns. Obese patients had lower proportion of advanced DAD pattern in their biopsies, and lower than patients with overweight. Clustering analysis showed that patterns of vascular lesions (microthrombosis, infarction) clustered together, but not the other patterns. The vascular pattern was not influenced by demographic or clinical parameters, including time of disease progression. CONCLUSION: Patients with severe COVID-19 present different proportions of DAD patterns over time, with advanced DAD being more prevalent after 17 days, which seems to be influenced by age and weight. Vascular involvement is present in a large proportion of patients, occurs early in disease progression, and does not change over time.

COVID-19 convalescent plasma cohort study: Evaluation of the association between both donor and recipient neutralizing antibody titers and patient outcomes.

BACKGROUND: Current evidence regarding COVID-19 convalescent plasma (CCP) transfusion practices is limited and heterogeneous. We aimed to determine the impact of the use of CCP transfusion in patients with previous circulating neutralizing antibodies (nAbs) in COVID-19. METHODS: Prospective cohort including 102 patients with COVID-19 transfused with ABO compatible CCP on days 0-2 after enrollment. Clinical status of patients was assessed using the adapted World Health Organization (WHO) ordinal scale on days 0, 5, and 14. The nAbs titration was performed using the cytopathic effect-based virus neutralization test with SARS-CoV-2 (GenBank MT126808.1). The primary outcome was clinical improvement on day 14, defined as a reduction of at least two points on the adapted WHO ordinal scale. Secondary outcomes were the number of intensive care unit (ICU)-free days and the number of invasive mechanical ventilation-free days. RESULTS: Both nAbs of CCP units transfused (p < 0.001) and nAbs of patients before CCP transfusions (p = 0.028) were associated with clinical improvements by day 14. No significant associations between nAbs of patients or CCP units transfused were observed in the number of ICU or mechanical ventilation-free days. Administration of CCP units after 10 days of symptom onset resulted in a decrease in ICU-free days (p < 0.001) and mechanical ventilation-free days (p < 0.001). CONCLUSION: Transfusion of high titer nAbs CCP units may be a determinant in clinical strategies against COVID-19. We consider these data as useful parameters to guide future CCP transfusion practices.

Thoracoabdominal asynchrony associates with exercise intolerance in fibrotic interstitial lung diseases.

BACKGROUND AND OBJECTIVE: The precise coordination of respiratory muscles during exercise minimizes work of breathing and avoids exercise intolerance. Fibrotic interstitial lung disease (f-ILD) patients are exercise-intolerant. We assessed whether respiratory muscle incoordination and thoracoabdominal asynchrony (TAA) occur in f-ILD during exercise, and their relationship with pulmonary function and exercise performance. METHODS: We compared breathing pattern, respiratory mechanics, TAA and respiratory muscle recruitment in 31 f-ILD patients and 31 healthy subjects at rest and during incremental cycle exercise. TAA was defined as phase angle (PhAng) >20°. RESULTS: During exercise, when compared with controls, f-ILD patients presented increased and early recruitment of inspiratory rib cage muscle (p < 0.05), and an increase in PhAng, indicating TAA. TAA was more frequent in f-ILD patients than in controls, both at 50% of the maximum workload (42.3% vs. 10.7%, p = 0.01) and at the peak (53.8% vs. 23%, p = 0.02). Compared with f-ILD patients without TAA, f-ILD patients with TAA had lower lung volumes (forced vital capacity, p < 0.01), greater dyspnoea (Medical Research Council > 2 in 64.3%, p = 0.02), worse exercise performance (lower maximal work rate % predicted, p = 0.03; lower tidal volume, p = 0.03; greater desaturation and dyspnoea, p < 0.01) and presented higher oesophageal inspiratory pressures with lower gastric inspiratory pressures and higher recruitment of scalene (p < 0.05). CONCLUSION: Exercise induces TAA and higher recruitment of inspiratory accessory muscle in ILD patients. TAA during exercise occurred in more severely restricted ILD patients and was associated with exertional dyspnoea, desaturation and limited exercise performance.

Concentration of Serum Vascular Endothelial Growth Factor (VEGF-D) and Its Correlation with Functional and Clinical Parameters in Patients with Lymphangioleiomyomatosis from a Brazilian Reference Center.

INTRODUCTION: Serum vascular endothelial growth factor-D (VEGF-D) is a lymphangiogenic growth factor that is considered a valuable tool in the diagnosis of lymphangioleiomyomatosis (LAM). Previous studies have reported a wide variability in VEGF-D serum levels in LAM patients and it seems to be associated with pulmonary impairment and lymphatic involvement. METHODS: We conducted a cross-sectional study from 2009 to 2017 that evaluated VEGF-D serum levels in a cohort of LAM patients who were never treated with mTOR inhibitors and compared them to healthy age-matched volunteers. Clinical and functional parameters were assessed and correlated with their respective serum VEGF-D levels. RESULTS: One hundred and four patients were included in the analysis. Serum VEGF-D levels were higher in LAM patients compared to healthy controls: 796 (404-1588) versus 162 (117-232) pg/mL, respectively (p < 0.001). Patients with tuberous sclerosis complex-LAM, TSC-LAM (20%), had higher levels of VEGF-D when compared to patients with sporadic LAM (80%) [1005 (641-2732) vs. 772 (370-1383), p = 0.05]. Serum VEGF-D levels were weakly correlated with DLCO (r = - 0.26, p = 0.001) and lymphatic involvement was more frequent in those with serum VEGF-D levels equal or above 800 pg/mL (35% vs. 13%, p = 0.02). CONCLUSIONS: In LAM, serum VEGF-D is weakly associated with lung function impairment and strongly associated with lymphatic involvement. VEGF-D is validated for use in Brazilian patients with LAM whose characteristics must be accounted for when evaluating their serum VEGF-D levels.

Diaphragmatic ultrasound findings correlate with dyspnea, exercise tolerance, health-related quality of life and lung function in patients with fibrotic interstitial lung disease.

BACKGROUND: Fibrotic interstitial lung disease (FILD) patients are typically dyspneic and exercise-intolerant with consequent impairment of health-related quality of life (HRQoL). Respiratory muscle dysfunction is among the underlying mechanisms of dyspnea and exercise intolerance in FILD but may be difficult to diagnose. Using ultrasound, we compared diaphragmatic mobility and thickening in FILD cases and healthy controls and correlated these findings with dyspnea, exercise tolerance, HRQoL and lung function. METHODS: We measured diaphragmatic mobility and thickness during quiet (QB) and deep breathing (DB) and calculated thickening fraction (TF) in 30 FILD cases and 30 healthy controls. We correlated FILD cases' diaphragmatic findings with dyspnea, exercise tolerance (six-minute walk test), lung function and HRQoL (St. George's Respiratory Questionnaire). RESULTS: Diaphragmatic mobility was similar between groups during QB but was lower in FILD cases during DB when compared to healthy controls (3.99 cm vs 7.02 cm; p <  0.01). FILD cases showed higher diaphragm thickness during QB but TF was lower in FILD when compared to healthy controls (70% vs 188%, p <  0.01). During DB, diaphragmatic mobility and thickness correlated with lung function, exercise tolerance and HRQoL, but inversely correlated with dyspnea. Most FILD cases (70%) presented reduced TF, and these patients had higher dyspnea and exercise desaturation, lower HRQoL and lung function. CONCLUSION: Compared to healthy controls, FILD cases present with lower diaphragmatic mobility and thickening during DB that correlate to increased dyspnea, decreased exercise tolerance, worse HRQoL and worse lung function. FILD cases with reduced diaphragmatic thickening are more dyspneic and exercise-intolerant, have lower HRQoL and lung function.

Accuracy of Invasive and Noninvasive Parameters for Diagnosing Ventilatory Overassistance During Pressure Support Ventilation.

OBJECTIVE: Evaluate the accuracy of criteria for diagnosing pressure overassistance during pressure support ventilation. DESIGN: Prospective clinical study. SETTING: Medical-surgical ICU. PATIENTS: Adults under mechanical ventilation for 48 hours or more using pressure support ventilation and without any sedative for 6 hours or more. Overassistance was defined as the occurrence of work of breathing less than 0.3 J/L or 10% or more of ineffective inspiratory effort. Two alternative overassistance definitions were based on the occurrence of inspiratory esophageal pressure-time product of less than 50 cm H2O s/min or esophageal occlusion pressure of less than 1.5 cm H2O. INTERVENTIONS: The pressure support was set to 20 cm H2O and decreased in 3-cm H2O steps down to 2 cm H2O. MEASUREMENTS AND MAIN RESULTS: The following parameters were evaluated to diagnose overassistance: respiratory rate, tidal volume, minute ventilation, peripheral arterial oxygen saturation, rapid shallow breathing index, heart rate, mean arterial pressure, change in esophageal pressure during inspiration, and esophageal and airway occlusion pressure. In all definitions, the respiratory rate had the greatest accuracy for diagnosing overassistance (receiver operating characteristic area = 0.92; 0.91 and 0.76 for work of breathing, pressure-time product and esophageal occlusion pressure in definition, respectively) and always with a cutoff of 17 incursions per minute. In all definitions, a respiratory rate of less than or equal to 12 confirmed overassistance (100% specificity), whereas a respiratory rate of greater than or equal to 30 excluded overassistance (100% sensitivity). CONCLUSION: A respiratory rate of 17 breaths/min is the parameter with the greatest accuracy for diagnosing overassistance. Respiratory rates of less than or equal to 12 or greater than or equal to 30 are useful clinical references to confirm or exclude pressure support overassistance.

Immunohistological features related to functional impairment in lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm characterized by the pulmonary infiltration of smooth muscle-like cells (LAM cells) and cystic destruction. Patients usually present with airway obstruction in pulmonary function tests (PFTs). Previous studies have shown correlations among histological parameters, lung function abnormalities and prognosis in LAM. We investigated the lung tissue expression of proteins related to the mTOR pathway, angiogenesis and enzymatic activity and its correlation with functional parameters in LAM patients. METHODS: We analyzed morphological and functional parameters of thirty-three patients. Two groups of disease severity were identified according to FEV1 values. Lung tissue from open biopsies or lung transplants was immunostained for SMA, HMB-45, mTOR, VEGF-D, MMP-9 and D2-40. Density of cysts, density of nodules and protein expression were measured by image analysis and correlated with PFT parameters. RESULTS: There was no difference in the expression of D2-40 between the more severe and the less severe groups. All other immunohistological parameters showed significantly higher values in the more severe group (p ≤ 0.002). The expression of VEGF-D, MMP-9 and mTOR in LAM cells was associated with the density of both cysts and nodules. The density of cysts and nodules as well as the expression of MMP-9 and VEGF-D were associated with the impairment of PFT parameters. CONCLUSIONS: Severe LAM represents an active phase of the disease with high expression of VEGF-D, mTOR, and MMP-9, as well as LAM cell infiltration. Our findings suggest that the tissue expression levels of VEGF-D and MMP-9 are important parameters associated with the loss of pulmonary function and could be considered as potential severity markers in open lung biopsies of LAM patients.

Unilateral diaphragm paralysis: a dysfunction restricted not just to one hemidiaphragm.

BACKGROUND: Most patients with unilateral diaphragm paralysis (UDP) have unexplained dyspnea, exercise limitations, and reduction in inspiratory muscle capacity. We aimed to evaluate the generation of pressure in each hemidiaphragm separately and its contribution to overall inspiratory strength. METHODS: Twenty-seven patients, 9 in right paralysis group (RP) and 18 in left paralysis group (LP), with forced vital capacity (FVC) < 80% pred, and 20 healthy controls (CG), with forced expiratory volume in 1 s (FEV1) > 80% pred and FVC > 80% pred, were evaluated for lung function, maximal inspiratory (MIP) and expiratory (MEP) pressure measurements, diaphragm ultrasound, and transdiaphragmatic pressure during magnetic phrenic nerve stimulation (PdiTw). RESULTS: RP and LP had significant inspiratory muscle weakness compared to controls, detected by MIP (- 57.4 ± 16.9 for RP; - 67.1 ± 28.5 for LP and - 103.1 ± 30.4 cmH2O for CG) and also by PdiTW (5.7 ± 4 for RP; 4.8 ± 2.3 for LP and 15.3 ± 5.7 cmH2O for CG). The PdiTw was reduced even when the non-paralyzed hemidiaphragm was stimulated, mainly due to the low contribution of gastric pressure (around 30%), regardless of whether the paralysis was in the right or left hemidiaphragm. On the other hand, in CG, esophagic and gastric pressures had similar contribution to the overall Pdi (around 50%). Comparing both paralyzed and non-paralyzed hemidiaphragms, the mobility during quiet and deep breathing, and thickness at functional residual capacity (FRC) and total lung capacity (TLC), were significantly reduced in paralyzed hemidiaphragm. In addition, thickness fraction was extremely diminished when contrasted with the non-paralyzed hemidiaphragm. CONCLUSIONS: In symptomatic patients with UDP, global inspiratory strength is reduced not only due to weakness in the paralyzed hemidiaphragm but also to impairment in the pressure generated by the non-paralyzed hemidiaphragm.

Experience of Lung Transplantation in Patients with Lymphangioleiomyomatosis at a Brazilian Reference Centre.

INTRODUCTION: Lung transplantation (LT) is the standard of care for patients with advanced lung diseases, including lymphangioleiomyomatosis (LAM). LAM accounts for only 1% of all LTs performed in the international registry. As a result, the global experience, including the use of mechanistic target of rapamycin (mTOR) inhibitors before and after LT in LAM, is still limited. METHODS: We conducted a retrospective review of all LAM patients who underwent LT at our centre between 2003 and 2016. Pre- and post-transplant data were assessed. RESULTS: Eleven women with LAM underwent LT, representing 3.3% of all procedures. Ten (91%) patients underwent double-LT. The mean age at diagnosis was 39 ± 6 years and the mean FEV1 before LT was 28 ± 14%. Only one patient underwent pleurodesis for recurrent pneumothorax. Pulmonary hypertension was confirmed in 3 (27%) patients. Four (36%) patients received sirolimus preoperatively; three of them received it until the day of LT, and there was no occurrence of bronchial anastomotic dehiscence after the procedure. Four patients (36%) received mTOR inhibitors post-transplant. The median follow-up from LT was 44 months. There were 3 deaths (27%) during the study and survival probabilities at 1, 3, and 5 years after LT were, 90, 90, and 77%, respectively. CONCLUSIONS: This data reinforces the role of LT for LAM patients with end-stage disease. The use of sirolimus seems to be safe before LT and the occurrence of complications after LT, including those LAM-related, should be continuously monitored.

Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01374022.

The polyploidy and its key role in plant breeding.

MAIN CONCLUSION: This article provides an up-to-date review concerning from basic issues of polyploidy to aspects regarding the relevance and role of both natural and artificial polyploids in plant breeding programs. Polyploidy is a major force in the evolution of both wild and cultivated plants. Polyploid organisms often exhibit increased vigor and, in some cases, outperform their diploid relatives in several aspects. This remarkable superiority of polyploids has been the target of many plant breeders in the last century, who have induced polyploidy and/or used natural polyploids in many ways to obtain increasingly improved plant cultivars. Some of the most important consequences of polyploidy for plant breeding are the increment in plant organs ("gigas" effect), buffering of deleterious mutations, increased heterozygosity, and heterosis (hybrid vigor). Regarding such features as tools, cultivars have been generated with higher yield levels, improving the product quality and increasing the tolerance to both biotic and abiotic stresses. In some cases, when the crossing between two species is not possible because of differences in ploidy level, polyploids can be used as a bridge for gene transferring between them. In addition, polyploidy often results in reduced fertility due to meiotic errors, allowing the production of seedless varieties. On the other hand, the genome doubling in a newly formed sterile hybrid allows the restoration of its fertility. Based on these aspects, the present review initially concerns the origin, frequency and classification of the polyploids, progressing to show the revolution promoted by the discovery of natural polyploids and polyploidization induction in the breeding program status of distinct crops.

Development of an algorithm to aid triage decisions for intensive care unit admission: a clinical vignette and retrospective cohort study.

BACKGROUND: Intensive care unit (ICU) admission triage is performed routinely and is often based solely on clinical judgment, which could mask biases. A computerized algorithm to aid ICU triage decisions was developed to classify patients into the Society of Critical Care Medicine's prioritization system. In this study, we sought to evaluate the reliability and validity of this algorithm. METHODS: Nine senior physicians evaluated forty clinical vignettes based on real patients. The reference standard was defined as the priorities ascribed by two investigators with full access to patients' records. Agreement of algorithm-based priorities with the reference standard and with intuitive priorities provided by the physicians were evaluated. Correlations between algorithm prioritization and physicians' judgment of the appropriateness of ICU admissions in scarcity and nonscarcity settings were also evaluated. Validity was further assessed by retrospectively applying this algorithm to 603 patients with requests for ICU admission for association with clinical outcomes. RESULTS: Agreement between algorithm-based priorities and the reference standard was substantial, with a median κ of 0.72 (interquartile range [IQR] 0.52-0.77). Algorithm-based priorities demonstrated higher interrater reliability (overall κ 0.61, 95% confidence interval [CI] 0.57-0.65; median percentage agreement 0.64, IQR 0.59-0.70) than physicians' intuitive prioritization (overall κ 0.51, 95% CI 0.47-0.55; median percentage agreement 0.49, IQR 0.44-0.56) (p = 0.001). Algorithm-based priorities were also associated with physicians' judgment of appropriateness of ICU admission (priorities 1, 2, 3, and 4 vignettes would be admitted to the last ICU bed in 83.7%, 61.2%, 45.2%, and 16.8% of the scenarios, respectively; p < 0.001) and with actual ICU admission, palliative care consultation, and hospital mortality in the retrospective cohort. CONCLUSIONS: This ICU admission triage algorithm demonstrated good reliability and validity. However, more studies are needed to evaluate a difference in benefit of ICU admission justifying the admission of one priority stratum over the others.

Effects of the open lung concept following ARDSnet ventilation in patients with early ARDS.

BACKGROUND: Ventilation with low tidal volume (VT) is well recognized as a protective approach to patients with acute respiratory distress syndrome (ARDS), but the optimal level of positive end-expiratory pressure (PEEP) remains uncertain. This study aims to evaluate two protective ventilatory strategies sequentially applied in patients with early ARDS. METHODS: In this prospective cohort study, fifteen patients were ventilated during 24 h with positive end-expiratory pressure (PEEP) adjusted according to the ARDSnet low-PEEP table (ARDSnet-24 h). During the next 24 h, nine patients with PaO2/FIO2 ratio below 350 mmHg were ventilated with PEEP titrated according to the Open Lung Concept protocol (ARDSnet + OLC). In the other six patients, regardless of their PaO2/FIO2 ratio, the ARDSnet remained for a further 24 h (ARDSnet-48 h). Ventilatory variables, arterial blood-gas and cytokine were obtained at baseline, 24 and 48 h. Additionally, whole-lung-computed tomography was acquired at 24 and 48 h. RESULTS: A sustained improvement in PaO2/FIO2 ratio (P = 0.008) with a decrease in collapsed regions (P = 0.008) was observed in the ARDSnet + OLC group compared with the ARDSnet-24 h group. A reduction in IL-6 in plasma (P < 0.02) was observed throughout the protocol in the ARDSnet + OLC group. Compared with the ARDSnet-48 h group, the ARDSnet + OLC presented smaller amounts of collapsed areas (P = 0.018) without significant differences in hyperinflated regions and in driving and plateau pressures. CONCLUSIONS: In this set of patients with early ARDS, mechanical ventilation with an individually tailored PEEP sustained improved pulmonary function with better aeration, without significant increase in hyperinflated areas". TRIAL REGISTRATION: Brazilian Clinical Trials Registry (ReBec). RBR-5zm9pr. 04th November 2015.

The genome of Anopheles darlingi, the main neotropical malaria vector.

Anopheles darlingi is the principal neotropical malaria vector, responsible for more than a million cases of malaria per year on the American continent. Anopheles darlingi diverged from the African and Asian malaria vectors ∼100 million years ago (mya) and successfully adapted to the New World environment. Here we present an annotated reference A. darlingi genome, sequenced from a wild population of males and females collected in the Brazilian Amazon. A total of 10 481 predicted protein-coding genes were annotated, 72% of which have their closest counterpart in Anopheles gambiae and 21% have highest similarity with other mosquito species. In spite of a long period of divergent evolution, conserved gene synteny was observed between A. darlingi and A. gambiae. More than 10 million single nucleotide polymorphisms and short indels with potential use as genetic markers were identified. Transposable elements correspond to 2.3% of the A. darlingi genome. Genes associated with hematophagy, immunity and insecticide resistance, directly involved in vector-human and vector-parasite interactions, were identified and discussed. This study represents the first effort to sequence the genome of a neotropical malaria vector, and opens a new window through which we can contemplate the evolutionary history of anopheline mosquitoes. It also provides valuable information that may lead to novel strategies to reduce malaria transmission on the South American continent. The A. darlingi genome is accessible at www.labinfo.lncc.br/index.php/anopheles-darlingi.

Evaluation of the extent of pulmonary cysts and their association with functional variables and serum markers in lymphangioleiomyomatosis (LAM).

PURPOSE: Although computed tomography (CT) has been used previously to assess disease severity in lymphangioleiomyomatosis (LAM), the associations between the extent of pulmonary cysts on CT and six-minute walk test (6MWT), matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF-D) are not well established. We performed a cross-sectional study to quantify the extent of pulmonary cysts in CT and to establish their correlations with pulmonary function tests (PFTs), 6MWT results, including a composite index (desaturation-distance ratio, DDR), and levels of VEGF-D and MMPs in LAM. METHODS: Twenty-three LAM patients underwent CT scanning to automatically quantify the extent of pulmonary cysts and performed PFTs and 6MWT. Serum levels of MMP-2, MMP-9, and VEGF-D were also measured. RESULTS: The severity of pulmonary cystic involvement was mild (the extent of cysts was 6.8 %) and correlated best with FEV1/FVC (r = -0.84), residual volume (r = 0.66), DLCO (r = -0.82), the DDR index (r = 0.77), and desaturation during the 6MWT (r = -0.81). There was a weak correlation with VEGF-D (r = 0.45), but no association was found with MMP-2 and MMP-9. CONCLUSIONS: The severity of pulmonary cystic involvement was mild in this sample of LAM patients and correlated best with airway obstruction, air trapping, reduced DLCO, the DDR index, and desaturation during the 6MWT. Serum VEGF-D cannot be completely defined as a valuable marker of disease severity and there may be a mechanism independent of MMPs to explain the formation of pulmonary cysts.

Clinical, tomographic and functional comparison of sporadic and tuberous sclerosis complex-associated forms of lymphangioleiomyomatosis: a retrospective cohort study.

Background: Lymphangioleiomyomatosis (LAM) is a rare disease that can occur sporadically (S-LAM) or associated with the tuberous sclerosis complex (TSC-LAM). The natural history of LAM is not completely understood, including whether there is a difference between the clinical courses of the two forms. This study aimed to compare the clinical, functional and tomographic features between S-LAM and TSC-LAM, and evaluate the annual rates of change in lung function. Methods: This retrospective cohort study included patients with LAM followed up between 1994 and 2019. Clinical, functional and imaging variables were evaluated, and the lung cysts were automatically quantified. Quality of life and predictors of lung function impairment were accessed, and the annual rate of lung function decline was compared between S-LAM and TSC-LAM. Results: Of the 107 patients included, 77 had S-LAM and 30 had TSC-LAM. Although patients with TSC-LAM had a higher prevalence of renal angiomyolipomas and neurological and dermatological manifestations, pulmonary function tests were similar. Patients with S-LAM had a greater rate of forced expiratory volume in 1 s decline and a higher extent of cysts. Pneumothorax, desaturation in the 6-minute walking test and a higher extent of lung cysts were predictors of functional impairment. A greater impact on vitality and emotional health was observed in the TSC-LAM. Conclusion: Greater functional decline and a higher cystic extension were found in patients with S-LAM. Our study provides a broad clinical, functional and tomographic characterisation of patients with LAM, adding valuable information to the existing evidence to better understand the two forms of the disease.

A comprehensive physical functional assessment of survivors of critical care unit stay due to COVID-19.

OBJECTIVE: To examine the physical function and respiratory muscle strength of patients - who recovered from critical COVID-19 - after intensive care unit discharge to the ward on Days one (D1) and seven (D7), and to investigate variables associated with functional impairment. METHODS: This was a prospective cohort study of adult patients with COVID-19 who needed invasive mechanical ventilation, non-invasive ventilation or high-flow nasal cannula and were discharged from the intensive care unit to the ward. Participants were submitted to Medical Research Council sum-score, handgrip strength, maximal inspiratory pressure, maximal expiratory pressure, and short physical performance battery tests. Participants were grouped into two groups according to their need for invasive ventilation: the Invasive Mechanical Ventilation Group (IMV Group) and the Non-Invasive Mechanical Ventilation Group (Non-IMV Group). RESULTS: Patients in the IMV Group (n = 31) were younger and had higher Sequential Organ Failure Assessment scores than those in the Non-IMV Group (n = 33). The short physical performance battery scores (range 0 - 12) on D1 and D7 were 6.1 ± 4.3 and 7.3 ± 3.8, respectively for the Non-Invasive Mechanical Ventilation Group, and 1.3 ± 2.5 and 2.6 ± 3.7, respectively for the IMV Group. The prevalence of intensive care unit-acquired weakness on D7 was 13% for the Non-IMV Group and 72% for the IMV Group. The maximal inspiratory pressure, maximal expiratory pressure, and handgrip strength increased on D7 in both groups, but the maximal expiratory pressure and handgrip strength were still weak. Only maximal inspiratory pressure was recovered (i.e., > 80% of the predicted value) in the Non-IMV Group. Female sex, and the need and duration of invasive mechanical were independently and negatively associated with the short physical performance battery score and handgrip strength. CONCLUSION: Patients who recovered from critical COVID-19 and who received invasive mechanical ventilation presented greater disability than those who were not invasively ventilated. However, they both showed marginal functional improvement during early recovery, regardless of the need for invasive mechanical ventilation. This might highlight the severity of disability caused by SARS-CoV-2.