Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end-expiratory pressures (PEEPs) can improve survival in ...patients with the acute respiratory distress syndrome (ARDS), but the relative importance of each of these components is uncertain. Because respiratory-system compliance (CRS) is strongly related to the volume of aerated remaining functional lung during disease (termed functional lung size), we hypothesized that driving pressure (ΔP=VT/CRS), in which VT is intrinsically normalized to functional lung size (instead of predicted lung size in healthy persons), would be an index more strongly associated with survival than VT or PEEP in patients who are not actively breathing.
Using a statistical tool known as multilevel mediation analysis to analyze individual data from 3562 patients with ARDS enrolled in nine previously reported randomized trials, we examined ΔP as an independent variable associated with survival. In the mediation analysis, we estimated the isolated effects of changes in ΔP resulting from randomized ventilator settings while minimizing confounding due to the baseline severity of lung disease.
Among ventilation variables, ΔP was most strongly associated with survival. A 1-SD increment in ΔP (approximately 7 cm of water) was associated with increased mortality (relative risk, 1.41; 95% confidence interval CI, 1.31 to 1.51; P<0.001), even in patients receiving "protective" plateau pressures and VT (relative risk, 1.36; 95% CI, 1.17 to 1.58; P<0.001). Individual changes in VT or PEEP after randomization were not independently associated with survival; they were associated only if they were among the changes that led to reductions in ΔP (mediation effects of ΔP, P=0.004 and P=0.001, respectively).
We found that ΔP was the ventilation variable that best stratified risk. Decreases in ΔP owing to changes in ventilator settings were strongly associated with increased survival. (Funded by Fundação de Amparo e Pesquisa do Estado de São Paulo and others.).
The demographic transition can affect the equilibrium real interest rate through three channels. An increase in longevity—or expectations thereof—puts downward pressure on the real interest rate, as ...agents build up their savings in anticipation of a longer retirement period. A reduction in the population growth rate has two counteracting effects. On the one hand, capital per-worker rises, thus inducing lower real interest rates through a reduction in the marginal product of capital. On the other hand, the decline in population growth eventually leads to a higher dependency ratio (the fraction of retirees to workers). Because retirees save less than workers, this compositional effect lowers the aggregate savings rate and pushes real rates up. We calibrate a tractable life-cycle model to capture salient features of the demographic transition in developed economies, and find that its overall effect is a reduction of the equilibrium interest rate by at least one and a half percentage points between 1990 and 2014. Demographic trends have important implications for the conduct of monetary policy, especially in light of the zero lower bound on nominal interest rates. Other policies can offset the negative effects of the demographic transition on real rates with different degrees of success.
Objective
Systemic sclerosis (SSc)–related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a ...prospective cohort of patients with SSc‐related ILD and to compare it with that in control lungs and with 2 prospective clinical parameters in order to understand the molecular pathways implicated in progressive lung disease.
Methods
Lung tissue was obtained by open lung biopsy in 28 consecutive patients with SSc‐related ILD and in 4 controls. High‐resolution computed tomography (HRCT) and pulmonary function testing (PFT) were performed at baseline and 2–3 years after treatment based on lung histologic classification. Microarray analysis was performed, and the results were correlated with changes in the HRCT score (FibMax) and PFT values. Quantitative polymerase chain reaction (qPCR) and immunohistochemistry were used to confirm differential levels of messenger RNA and protein.
Results
Lung microarray data distinguished patients with SSc‐related ILD from healthy controls. In the lungs of patients with SSc‐related ILD who had nonspecific interstitial pneumonia (NSIP), expressed genes included macrophage markers, chemokines, collagen, and transforming growth factor β (TGFβ)– and interferon (IFN)–regulated genes. Expression of these genes correlated with progressive lung fibrosis defined by the change in FibMax. Immunohistochemistry confirmed increased markers of collagen (COL1A1), IFN (OAS1 and IFI44), and macrophages (CCL18 and CD163), and the positive correlation with the change in FibMax was confirmed by qPCR in a larger group of SSc patients with NSIP. Several genes correlated with both the change in FibMax (r > 0.4) and the change in % predicted forced vital capacity (r < −0.1), including IFN and macrophage markers, chemokines, and heat‐shock proteins.
Conclusion
These results highlight major pathogenic pathways relevant to progressive pulmonary fibrosis in SSc‐related ILD: macrophage emigration and activation, and up‐regulated expression of TGFβ‐ and IFN‐regulated genes.
We combine questions from the Michigan Survey about future inflation, unemployment, and interest rates to investigate whether households are aware of the basic features of U.S. monetary policy. Our ...findings provide evidence that some households form their expectations in a way that is consistent with a Taylor (1993)-type rule. We also document a large degree of variation in the pattern of responses over the business cycle. In particular, the negative relationship between unemployment and interest rates that is apparent in the data only shows up in households׳ answers during periods of labor market weakness.
•We use Michigan Survey data to test if households are aware of U.S. monetary policy.•Some households seem to form expectations in accordance with a Taylor (1993) rule.•The pattern of household responses varies markedly over the business cycle.•Households seem to be more aware of monetary policy in times of weak labor markets.
Selecting a subset of variables for linear models remains an active area of research. This article reviews many of the recent contributions to the Bayesian model selection and shrinkage prior ...literature. A posterior variable selection summary is proposed, which distills a full posterior distribution over regression coefficients into a sequence of sparse linear predictors.
Summary For patients with high-risk stage II or stage III colon cancer, adjuvant chemotherapy with fluoropyrimidine monotherapy reduces the risk of recurrence and death by approximately 20–30%. ...Additional improvements have been reported in three phase 3 colon cancer trials when oxaliplatin was added to the chemoradiation regimen, although the effect was mainly on disease-free survival. However, patients with rectal cancer were specifically excluded from these landmark studies because of potential toxicity and the confounding impact of radiotherapy and chemoradiation. Hence, despite evidence from smaller individual postoperative adjuvant phase 3 trials, meta-analyses, retrospective analyses, reviews, and population studies, the precise benefit of adjuvant chemotherapy for patients with rectal cancer following radiotherapy or chemoradiation remains unclear. Consequently, clinical guidelines offer inconsistent recommendations for the management of this patient population. In this Review, we suggest that the available data do not robustly support the routine use of postoperative adjuvant chemotherapy for patients with rectal cancer treated with preoperative chemoradiation. We discuss sources of bias and offer potential reasons to explain this observation, as well as propose a recommended schema for a randomised phase 3 trial that might potentially answer this question definitively.
We consider a new, flexible and easy-to-implement method to estimate thecausal effects of an intervention on a single treated unit when a control group is not available and which nests previous ...proposals in the literature. It is a two-step methodology where in the first stage, a counterfactual is estimated based on a large-dimensional set of variables from a pool of untreated units by means of shrinkage methods, such as the least absolute shrinkage and selection operator (LASSO). In the second stage, we estimate the average intervention effect on a vector of variables, which is consistent and asymptotically normal. Our results are valid uniformly over a wide class of probability laws. We show that these results hold even when the exact date of the intervention is unknown. Tests for multiple interventions and for contamination effects are derived. By a simple transformation of the variables, it is possible to test for multivariate intervention effects on several moments of the variables of interest. Existing methods in the literature usually test for intervention effects on a single variable and assume that the time of the intervention is known. In addition, high-dimensionality is frequently ignored and inference is either conducted under a set of more stringent hypotheses and/or by permutation tests. A Monte Carlo experiment evaluates the properties of the method in finite samples and compares it with other alternatives. As an application, we evaluate the effects on inflation, GDP growth, retail sales and credit of an anti tax-evasion program.
This study investigated the physiological and molecular responses of Wistar Hannover rats, submitted to three 5-week chronic training models, with similar training loads. Twenty-four Wistar Hanover ...rats were randomly divided into four groups: control (n = 6), low-intensity training (Z1; n = 6), moderate-intensity training (Z2; n = 6) and high-intensity training (Z3; n = 6). The three exercise groups performed a 5-week running training three times a week, with the same prescribed workload but the intensity and the volume were different between groups. An increase in maximal speed was observed after four weeks of training for the three groups that trained, with no difference between groups. Higher rest glycogen was also observed in the soleus muscle after training for the exercise groups compared to the control group. We also found that the Z2 group had a higher protein content of total and phosphorylated GSK3-β compared to the control group after five weeks of training. In conclusion, the present study shows that five weeks of treadmill training based on intensity zones 1, 2, and 3 improved performance and increased resting glycogen in the soleus muscle, therefore intensity modulation does not change the training program adaptation since the different program loads are equalized.
Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ...ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1β-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.
Background
Approximately 5% of COVID-19 patients develop respiratory failure and need ventilatory support, yet little is known about the impact of mechanical ventilation strategy in COVID-19. Our ...objective was to describe baseline characteristics, ventilatory parameters, and outcomes of critically ill patients in the largest referral center for COVID-19 in Sao Paulo, Brazil, during the first surge of the pandemic.
Methods
This cohort included COVID-19 patients admitted to the intensive care units (ICUs) of an academic hospital with 94 ICU beds, a number expanded to 300 during the pandemic as part of a state preparedness plan. Data included demographics, advanced life support therapies, and ventilator parameters. The main outcome was 28-day survival. We used a multivariate Cox model to test the association between protective ventilation and survival, adjusting for PF ratio, pH, compliance, and PEEP.
Results
We included 1503 patients from March 30 to June 30, 2020. The mean age was 60 ± 15 years, and 59% were male. During 28-day follow-up, 1180 (79%) patients needed invasive ventilation and 666 (44%) died. For the 984 patients who were receiving mechanical ventilation in the first 24 h of ICU stay, mean tidal volume was 6.5 ± 1.3 mL/kg of ideal body weight, plateau pressure was 24 ± 5 cmH
2
O, respiratory system compliance was 31.9 (24.4–40.9) mL/cmH
2
O, and 82% of patients were ventilated with protective ventilation. Noninvasive ventilation was used in 21% of patients, and prone, in 36%. Compliance was associated with survival and did not show a bimodal pattern that would support the presence of two phenotypes. In the multivariable model, protective ventilation (aHR 0.73 95%CI 0.57–0.94), adjusted for PF ratio, compliance, PEEP, and arterial pH, was independently associated with survival.
Conclusions
During the peak of the epidemic in Sao Paulo, critically ill patients with COVID-19 often required mechanical ventilation and mortality was high. Our findings revealed an association between mechanical ventilation strategy and mortality, highlighting the importance of protective ventilation for patients with COVID-19.
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