Elevated pulmonary capillary wedge pressure, higher blood pressure, and lower cardiac index in infants with bronchopulmonary dysplasia.

BACKGROUND: Left ventricular diastolic dysfunction indicated by elevated pulmonary capillary wedge pressure (ePCWP) may worsen cardiorespiratory status in bronchopulmonary dysplasia (BPD), but the scope of ePCWP by cardiac catheterization is not well described. METHODS: This single-center retrospective cohort study included infants with BPD without congenital heart disease, significant intracardiac shunts, or pulmonary vein stenosis who underwent cardiac catheterization from 2010 to 2021. ePCWP was defined as >10 mmHg. Quantitative measures of ventricular systolic and diastolic function were performed on existing echocardiograms. Patients with and without ePCWP were compared using the Chi-squared or Wilcoxon rank-sum tests. Associations between catheterization hemodynamics and echocardiographic parameters were assessed by simple linear regression. RESULTS: Seventy-one infants (93% Grade 2 or 3 BPD) met inclusion criteria, and 30 (42%) had ePCWP. Patients with ePCWP were older at catheterization (6.7 vs. 4.5 months, p < 0.001), more commonly underwent tracheostomy (66.7% vs. 29.3%, p = 0.003), and had higher mean systemic blood pressure [64.5 (56.0, 75.0) vs. 47.0 (43.0, 55.0) mm Hg, p < 0.001], higher systemic vascular resistance [11.9 (10.4, 15.6) vs. 8.7 (6.7, 11.2) WU*m2, p < 0.001), and lower cardiac index [3.9 (3.8, 4.9) vs. 4.7 (4.0, 6.3) L/min/m2, p = 0.03] at catheterization. Mean pulmonary artery pressure, pulmonary vascular resistance, and mortality were similar between the groups. Echocardiographic indices of left ventricular diastolic dysfunction did not correlate with PCWP. CONCLUSIONS: ePCWP was common in infants with severe BPD who underwent cardiac catheterization in this cohort. The association between ePCWP and higher systemic blood pressure supports further study of afterload reduction in this population.

Single proxy control.

Negative control variables are sometimes used in nonexperimental studies to detect the presence of confounding by hidden factors. A negative control outcome (NCO) is an outcome that is influenced by unobserved confounders of the exposure effects on the outcome in view, but is not causally impacted by the exposure. Tchetgen Tchetgen (2013) introduced the Control Outcome Calibration Approach (COCA) as a formal NCO counterfactual method to detect and correct for residual confounding bias. For identification, COCA treats the NCO as an error-prone proxy of the treatment-free counterfactual outcome of interest, and involves regressing the NCO on the treatment-free counterfactual, together with a rank-preserving structural model, which assumes a constant individual-level causal effect. In this work, we establish nonparametric COCA identification for the average causal effect for the treated, without requiring rank-preservation, therefore accommodating unrestricted effect heterogeneity across units. This nonparametric identification result has important practical implications, as it provides single-proxy confounding control, in contrast to recently proposed proximal causal inference, which relies for identification on a pair of confounding proxies. For COCA estimation we propose 3 separate strategies: (i) an extended propensity score approach, (ii) an outcome bridge function approach, and (iii) a doubly-robust approach. Finally, we illustrate the proposed methods in an application evaluating the causal impact of a Zika virus outbreak on birth rate in Brazil.

Immunological imprinting shapes the specificity of human antibody responses against SARS-CoV-2 variants.

The spike glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) continues to accumulate substitutions, leading to breakthrough infections of vaccinated individuals and prompting the development of updated booster vaccines. Here, we determined the specificity and functionality of antibody and B cell responses following exposure to BA.5 and XBB variants in individuals who received ancestral SARS-CoV-2 mRNA vaccines. BA.5 exposures elicited antibody responses that primarily targeted epitopes conserved between the BA.5 and ancestral spike, with poor reactivity to the XBB.1.5 variant. XBB exposures also elicited antibody responses that targeted epitopes conserved between the XBB.1.5 and ancestral spike. However, unlike BA.5, a single XBB exposure elicited low levels of XBB.1.5-specific antibodies and B cells in some individuals. Pre-existing cross-reactive B cells and antibodies were correlated with stronger overall responses to XBB but weaker XBB-specific responses, suggesting that baseline immunity influences the activation of variant-specific SARS-CoV-2 responses.

Differential content of leaf and fruit pigment in tomatoes culminate in a complex metabolic reprogramming without growth impacts.

Although significant efforts to produce carotenoid-enriched foods either by biotechnology or traditional breeding strategies have been carried out, our understanding of how changes in the carotenoid biosynthesis might affect overall plant performance remains limited. Here, we investigate how the metabolic machinery of well characterized tomato carotenoid mutant plants [namely crimson (old gold-og), Delta carotene (Del) and tangerine (t)] adjusts itself to varying carotenoid biosynthesis and whether these adjustments are supported by a reprogramming of photosynthetic and central metabolism in the source organs (leaves). We observed that mutations og, Del and t did not greatly affect vegetative growth, leaf anatomy and gas exchange parameters. However, an exquisite metabolic reprogramming was recorded on the leaves, with an increase in levels of amino acids and reduction of organic acids. Taken together, our results show that despite minor impacts on growth and gas exchange, carbon flux is extensively affected, leading to adjustments in tomato leaves metabolism to support changes in carotenoid biosynthesis on fruits (sinks). We discuss these data in the context of our current understanding of metabolic adjustments and carotenoid biosynthesis as well as regarding to improving human nutrition.

Understanding transmission risk and predicting environmental suitability for Mayaro Virus in Central and South America.

Mayaro virus (MAYV) is a mosquito-borne Alphavirus that is widespread in South America. MAYV infection often presents with non-specific febrile symptoms but may progress to debilitating chronic arthritis or arthralgia. Despite the pandemic threat of MAYV, its true distribution remains unknown. The objective of this study was to clarify the geographic distribution of MAYV using an established risk mapping framework. This consisted of generating evidence consensus scores for MAYV presence, modeling the potential distribution of MAYV in select countries across Central and South America, and estimating the population residing in areas suitable for MAYV transmission. We compiled a georeferenced compendium of MAYV occurrence in humans, animals, and arthropods. Based on an established evidence consensus framework, we integrated multiple information sources to assess the total evidence supporting ongoing transmission of MAYV within each country in our study region. We then developed high resolution maps of the disease's estimated distribution using a boosted regression tree approach. Models were developed using nine climatic and environmental covariates that are related to the MAYV transmission cycle. Using the output of our boosted regression tree models, we estimated the total population living in regions suitable for MAYV transmission. The evidence consensus scores revealed high or very high evidence of MAYV transmission in several countries including Brazil (especially the states of Mato Grosso and Goiás), Venezuela, Peru, Trinidad and Tobago, and French Guiana. According to the boosted regression tree models, a substantial region of South America is suitable for MAYV transmission, including north and central Brazil, French Guiana, and Suriname. Some regions (e.g., Guyana) with only moderate evidence of known transmission were identified as highly suitable for MAYV. We estimate that approximately 58.9 million people (95% CI: 21.4-100.4) in Central and South America live in areas that may be suitable for MAYV transmission, including 46.2 million people (95% CI: 17.6-68.9) in Brazil. Our results may assist in prioritizing high-risk areas for vector control, human disease surveillance and ecological studies.

Interpersonal and Community-Level Influences Across the PrEP Cascade Among Young Adult Latinx Men who Have Sex with Men Living in a US-Mexico Border Region: A Qualitative Study.

Latinx men who have sex with men (MSM) are an at-risk population for new HIV diagnoses. Pre-exposure prophylaxis (PrEP) is a suite of biomedical approaches to prevent HIV infection. Latinx MSM are less likely to take PrEP compared to non-Latinx White MSM. This qualitative study identified interpersonal- and community-level barriers and facilitators of PrEP among young adult Latinx MSM. Using stratified purposeful sampling, 27 Latinx men, ages 19-29 years and living in a US-Mexico border region, completed self-report demographic surveys and participated in semi-structured in-depth interviews assessing barriers and facilitators to PrEP. Directed content analysis was used to identify both a priori and emerging themes. Most participants reported that other people, including peers, friends, partners, and health care providers were both supportive and discouraging of PrEP use. Participants' intersectional identities as members of both Latinx and LGBTQ+ (Lesbian, Gay, Bisexual, Transgender, Queer) communities both hindered and facilitated PrEP use.

Risk Factors for Admission Hyperthermia and Associated Outcomes in Infants Born Preterm.

Maternal, placental, and neonatal factors were compared between infants born at ≤29 weeks of gestational age with admission hyperthermia (>37.5○C) and euthermia (36.5-37.5○C). Admission hyperthermia was associated with longer duration of face-mask positive-pressure ventilation and infant's temperature ≥37.5○C in the delivery room. Infants born preterm with admission hyperthermia had greater odds of developing necrotizing enterocolitis and neurodevelopmental impairment.

Universal Difference-in-Differences for Causal Inference in Epidemiology.

Difference-in-differences is undoubtedly one of the most widely used methods for evaluating the causal effect of an intervention in observational (i.e., nonrandomized) settings. The approach is typically used when pre- and postexposure outcome measurements are available, and one can reasonably assume that the association of the unobserved confounder with the outcome has the same absolute magnitude in the two exposure arms and is constant over time; a so-called parallel trends assumption. The parallel trends assumption may not be credible in many practical settings, for example, if the outcome is binary, a count, or polytomous, as well as when an uncontrolled confounder exhibits nonadditive effects on the distribution of the outcome, even if such effects are constant over time. We introduce an alternative approach that replaces the parallel trends assumption with an odds ratio equi-confounding assumption under which an association between treatment and the potential outcome under no treatment is identified with a well-specified generalized linear model relating the pre-exposure outcome and the exposure. Because the proposed method identifies any causal effect that is conceivably identified in the absence of confounding bias, including nonlinear effects such as quantile treatment effects, the approach is aptly called universal difference-in-differences. We describe and illustrate both fully parametric and more robust semiparametric universal difference-in-differences estimators in a real-world application concerning the causal effects of a Zika virus outbreak on birth rate in Brazil. A supplementary digital video is available at: http://links.lww.com/EDE/C90.

Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Long-term outcomes among stable post-acute myocardial infarction patients living in rural versus urban areas: insights from the prospective, observational TIGRIS registry.

BACKGROUND: Insights on the differences in clinical outcomes, quality of life (QoL) and health resource utilisation (HRU) with different levels of care available to post-acute myocardial infarction (AMI) populations in rural and urban settings are limited. METHODS: The long-Term rIsk, clinical manaGement, and healthcare Resource utilisation of stable coronary artery dISease (TIGRIS), a prospective, observational registry, enrolled 8452 patients aged ≥50 years 1-3 years post-AMI from June 2013 to November 2014 from 24 countries in Asia Pacific/Australia, Europe, North America and South America. Differences in QoL (measured using the EuroQol Research Foundation instrument) and HRU between patients in rural and urban settings were evaluated in this post hoc analysis. The incidence of clinical endpoints (cardiovascular (CV) death, AMI, unstable angina with urgent revascularisation and stroke; bleeding; and all-cause mortality) was analysed. Data were collected at baseline and every 6 months for 24 months. RESULTS: There were fewer hospitalisations and visits to general practitioners (GPs) and cardiologists in the rural versus urban populations (adjusted event rate ratio (ERR)=0.90 (95% CI, 0.82 to 1.00, p=0.04); ERR=0.84 (95% CI, 0.78 to 0.92, p<0.001); ERR=0.86 (95% CI, 0.81 to 0.92, p<0.001), respectively). No statistically significant differences were observed between rural and urban populations in all-cause death, AMI, unstable angina with urgent revascularisation, CV death, stroke, major bleeding events and health-related QoL. The adjusted incidence rate ratio was 0.92 (95% CI, 0.74 to 1.15) for the composite of CV death, AMI and stroke. CONCLUSIONS: Living in rural areas was associated with fewer GP/cardiologist visits and hospitalisations; no significant differences in clinical outcomes and QoL were observed. TRIAL REGISTRATION NUMBER: NCT01866904.

Nonmedical Prescription Drug Use Among Female Adolescents: The Relative Influence of Maternal Factors, Social Norms, and Perceptions of Risk and Availability.

Increasing understanding of the risk and protective factors for adolescent nonmedical use of prescription drugs (NMUPD) could inform prevention efforts. Several correlates have been identified, including parental factors, perceptions about use and accessibility, social norms, and age. However, these constructs have rarely been simultaneously examined using paired data from parents and adolescents. We aimed to examine the relative influence of these correlates among dyads (N=349) of mothers and adolescent daughters. Using multiple logistic regression, daughters' past NMUPD and inclination for future NMUPD were regressed onto descriptive norms for friend use, perceived drug accessibility and risk of harm from use, daughter age, mothers' disapproval about use, mothers' past NMUPD and inclination for future NMUPD, and the mother-daughter relationship quality. Akaike weights and lasso regressions were also estimated to evaluate the relative importance of each correlate. Higher descriptive norms for friend use, older age, and mothers' inclination for NMUPD were risk factors for daughters' NMUPD, while a closer mother-daughter relationship and mothers' disapproving attitudes towards NMUPD were protective factors. The three analysis approaches were corroborative. Results suggest friend descriptive norms, mother-daughter relationship quality, and mothers' attitudes about NMUPD are important prevention targets.

The interplay between autophagy and chloroplast vesiculation pathways under dark-induced senescence.

In cellular circumstances where carbohydrates are scarce, plants can use alternative substrates for cellular energetic maintenance. In plants, the main protein reserve is present in the chloroplast, which contains most of the total leaf proteins and represents a rich source of nitrogen and amino acids. Autophagy plays a key role in chloroplast breakdown, a well-recognised symptom of both natural and stress-induced plant senescence. Remarkably, an autophagic-independent route of chloroplast degradation associated with chloroplast vesiculation (CV) gene was previously demonstrated. During extended darkness, CV is highly induced in the absence of autophagy, contributing to the early senescence phenotype of atg mutants. To further investigate the role of CV under dark-induced senescence conditions, mutants with low expression of CV (amircv) and double mutants amircv1xatg5 were characterised. Following darkness treatment, no aberrant phenotypes were observed in amircv single mutants; however, amircv1xatg5 double mutants displayed early senescence and altered dismantling of chloroplast and membrane structures under these conditions. Metabolic characterisation revealed that the functional lack of both CV and autophagy leads to higher impairment of amino acid release and differential organic acid accumulation during starvation conditions. The data obtained are discussed in the context of the role of CV and autophagy, both in terms of cellular metabolism and the regulation of chloroplast degradation.

Prophylactic Administration of Vasopressors Prior to Emergency Intubation in Critically Ill Patients: A Secondary Analysis of Two Multicenter Clinical Trials.

Hypotension affects approximately 40% of critically ill patients undergoing emergency intubation and is associated with an increased risk of death. The objective of this study was to examine the association between prophylactic vasopressor administration and the incidence of peri-intubation hypotension and other clinical outcomes. DESIGN: A secondary analysis of two multicenter randomized clinical trials. The clinical effect of prophylactic vasopressor administration was estimated using a one-to-one propensity-matched cohort of patients with and without prophylactic vasopressors. SETTING: Seven emergency departments and 17 ICUs across the United States. PATIENTS: One thousand seven hundred ninety-eight critically ill patients who underwent emergency intubation at the study sites between February 1, 2019, and May 24, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was peri-intubation hypotension defined as a systolic blood pressure less than 90 mm Hg occurring between induction and 2 minutes after tracheal intubation. A total of 187 patients (10%) received prophylactic vasopressors prior to intubation. Compared with patients who did not receive prophylactic vasopressors, those who did were older, had higher Acute Physiology and Chronic Health Evaluation II scores, were more likely to have a diagnosis of sepsis, had lower pre-induction systolic blood pressures, and were more likely to be on continuous vasopressor infusions prior to intubation. In our propensity-matched cohort, prophylactic vasopressor administration was not associated with reduced risk of peri-intubation hypotension (41% vs 32%; p = 0.08) or change in systolic blood pressure from baseline (-12 vs -11 mm Hg; p = 0.66). CONCLUSIONS: The administration of prophylactic vasopressors was not associated with a lower incidence of peri-intubation hypotension in our propensity-matched analysis. To address potential residual confounding, randomized clinical trials should examine the effect of prophylactic vasopressor administration on peri-intubation outcomes.

Unveiling the dark side of guard cell metabolism.

Evidence suggests that guard cells have higher rate of phosphoenolpyruvate carboxylase (PEPc)-mediated dark CO2 assimilation than mesophyll cells. However, it is unknown which metabolic pathways are activated following dark CO2 assimilation in guard cells. Furthermore, it remains unclear how the metabolic fluxes throughout the tricarboxylic acid (TCA) cycle and associated pathways are regulated in illuminated guard cells. Here we carried out a13C-HCO3 labelling experiment in tobacco guard cells harvested under continuous dark or during the dark-to-light transition to elucidate principles of metabolic dynamics downstream of CO2 assimilation. Most metabolic changes were similar between dark-exposed and illuminated guard cells. However, illumination altered the metabolic network structure of guard cells and increased the 13C-enrichment in sugars and metabolites associated to the TCA cycle. Sucrose was labelled in the dark, but light exposure increased the 13C-labelling and leads to more drastic reductions in the content of this metabolite. Fumarate was strongly labelled under both dark and light conditions, while illumination increased the 13C-enrichment in pyruvate, succinate and glutamate. Only one 13C was incorporated into malate and citrate in either dark or light conditions. Our results indicate that several metabolic pathways are redirected following PEPc-mediated CO2 assimilation in the dark, including gluconeogenesis and the TCA cycle. We further showed that the PEPc-mediated CO2 assimilation provides carbons for gluconeogenesis, the TCA cycle and glutamate synthesis and that previously stored malate and citrate are used to underpin the specific metabolic requirements of illuminated guard cells.

Quantitative Measures of Right Ventricular Size and Function by Echocardiogram Correlate with Cardiac Catheterization Hemodynamics in Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate associations between cardiac catheterization (cath) hemodynamics, quantitative measures of right ventricular (RV) function by echocardiogram, and survival in patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN: This single-center retrospective cohort study enrolled patients with CDH who underwent index cath from 2003 to 2022. Tricuspid annular plane systolic excursion z score, RV fractional area change, RV free wall and global longitudinal strain, left ventricular (LV) eccentricity index, RV/LV ratio, and pulmonary artery acceleration time were measured from preprocedure echocardiograms. Associations between hemodynamic values, echocardiographic measures, and survival were evaluated by Spearman correlation and Wilcoxon rank sum test, respectively. RESULTS: Fifty-three patients (68% left-sided, 74% liver herniation, 57% extracorporeal membrane oxygenation, 93% survival) underwent cath (39 during index hospitalization, 14 later) including device closure of a patent ductus arteriosus in 5. Most patients (n = 31, 58%) were on pulmonary hypertension treatment at cath, most commonly sildenafil (n = 24, 45%) and/or intravenous treprostinil (n = 16, 30%). Overall, hemodynamics were consistent with precapillary pulmonary hypertension. Pulmonary capillary wedge pressure was >15 mm Hg in 2 patients (4%). Lower fractional area change and worse ventricular strain were associated with higher pulmonary artery pressure while higher LV eccentricity index and higher RV/LV ratio were associated with both higher pulmonary artery pressure and higher pulmonary vascular resistance. Hemodynamics did not differ based on survival status. CONCLUSIONS: Worse RV dilation and dysfunction by echocardiogram correlate with higher pulmonary artery pressure and pulmonary vascular resistance on cath in this CDH cohort. These measures may represent novel, noninvasive clinical trial targets in this population.

Physician Burnout and Medical Errors: Exploring the Relationship, Cost, and Solutions.

Physician burnout has demonstrated risks to providers and patients through medical errors. This review aims to synthesize current data surrounding burnout and its impacts on quality to inform targeted interventions that benefit providers and patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses scoping review methodology was utilized to identify studies of quantitative metrics for burnout and medical errors. Three independent reviewers conducted screening, study selection, and data extraction. Of 1096 identified articles, 21 were analyzed. Overall, 80.9% used the Maslach Burnout Inventory to evaluate for burnout. Moreover, 71.4% used self-reported medical errors as their primary outcome measure. Other outcome measures included observed/identified clinical practice errors and medication errors. Ultimately, 14 of 21 studies found links between burnout and clinically significant errors. Significant associations exist between burnout and medical errors. Physician demographics, including psychological factors, well-being, and training level, modulate this relationship. Better metrics are necessary to quantify errors and their impacts on outcomes. These findings may inform novel interventions that target burnout and improve experiences.