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OBJECTIVE: To describe the safety and effectiveness of treating pediatric patients who have pulmonary arterial hypertension (PAH) with selexipag in a real-world, multicenter cohort, given that data supporting its use in pediatric PAH are sparse. STUDY DESIGN: We report a multicenter, retrospective, cohort study of children with PAH treated with selexipag. Demographic and clinical variables were extracted from the medical records. Clinical parameters were analyzed at 3 timepoints: before selexipag, 3-12 months after selexipag, and >12 months follow-up. RESULTS: Eighty-seven patients were included, 32 received selexipag as add-on to background therapy, and 55 transitioned from another prostanoid. The median starting and final doses were 4.7 and 28.5 µg/kg/dose twice daily, respectively. Add-on patients demonstrated improved indexed pulmonary to systemic vascular resistance ratio after selexipag initiation (PVRi/SVRi, 0.62v0.53; P = .034) with a lower average mean pulmonary artery pressure (46 vs 39 mm Hg; P = NS), and oxygen consumption (maximal oxygen consumption during cardiopulmonary exercise testing [VO2 max] 27.8 mL/kg/min vs 30.9 mL/kg/min; P = NS). Transition patients demonstrated stable mean pulmonary artery pressure (47 mm Hg vs 45 mm Hg; P = NS) and a lower mean indexed pulmonary vascular resistance (10.9 Wood units∗m2 vs 8.2 Wood units∗m2; P = NS) but late functional worsening in some with VO2 max decreased at follow-up (26.0 mL/kg/min vs 19.5 mL/kg/min). Side effects were noted in 40% of the cohort, but prompted discontinuation in only 2%. CONCLUSIONS: In a large, multicenter cohort, the oral prostacyclin agonist selexipag demonstrates favorable tolerability and effectiveness. Add-on patients demonstrated early hemodynamic improvement. Transition patients demonstrated early stability with risk of late functional worsening, highlighting the importance of ongoing monitoring.

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Negative density dependence (NDD) in biotic interactions of interference such as plant-plant competition, granivory and herbivory are well-documented mechanisms that promote species' coexistence in diverse plant communities worldwide. Here, we investigated the generality of a novel type of NDD mechanism that operates through the mutualistic interactions of frugivory and seed dispersal among fruit-eating birds and plants. By sampling community-wide frugivory interactions at high spatial and temporal resolution in Pennsylvania, Puerto Rico, Peru, Brazil and Argentina, we evaluated whether interaction frequencies between birds and fruit resources occurred more often (selection), as expected, or below expectations (under-utilization) set by the relative fruit abundance of the fruit resources of each plant species. Our models considered the influence of temporal scales of fruit availability and bird phylogeny and diets, revealing that NDD characterizes frugivory across communities. Irrespective of taxa or dietary guild, birds tended to select fruits of plant species that were proportionally rare in their communities, or that became rare following phenological fluctuations, while they mostly under-utilized abundant fruit resources. Our results demonstrate that negative density-dependence in frugivore-plant interactions provides a strong equalizing mechanism for the dispersal processes of fleshy-fruited plant species in temperate and tropical communities, likely contributing to building and sustaining plant diversity. This article is part of the theme issue 'Diversitydependence of dispersal: interspecific interactions determine spatial dynamics'.

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OBJECTIVES: Quantify the relationship between perioperative anaerobic lactate production, microcirculatory blood flow, and mitochondrial respiration in patients after cardiovascular surgery with cardiopulmonary bypass. DESIGN: Serial measurements of lactate-pyruvate ratio (LPR), microcirculatory blood flow, plasma tricarboxylic acid cycle cycle intermediates, and mitochondrial respiration were compared between patients with a normal peak lactate (≤ 2 mmol/L) and a high peak lactate (≥ 4 mmol/L) in the first 6 hours after surgery. Regression analysis was performed to quantify the relationship between clinically relevant hemodynamic variables, lactate, LPR, and microcirculatory blood flow. SETTING: This was a single-center, prospective observational study conducted in an academic cardiovascular ICU. PATIENTS: One hundred thirty-two patients undergoing elective cardiovascular surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with a high postoperative lactate were found to have a higher LPR compared with patients with a normal postoperative lactate (14.4 ± 2.5 vs. 11.7 ± 3.4; p = 0.005). Linear regression analysis found a significant, negative relationship between LPR and microcirculatory flow index ( r = -0.225; ß = -0.037; p = 0.001 and proportion of perfused vessels: r = -0.17; ß = -0.468; p = 0.009). There was not a significant relationship between absolute plasma lactate and microcirculation variables. Last, mitochondrial complex I and complex II oxidative phosphorylation were reduced in patients with high postoperative lactate levels compared with patients with normal lactate (22.6 ± 6.2 vs. 14.5 ± 7.4 pmol O 2 /s/10 6 cells; p = 0.002). CONCLUSIONS: Increased anaerobic lactate production, estimated by LPR, has a negative relationship with microcirculatory blood flow after cardiovascular surgery. This relationship does not persist when measuring lactate alone. In addition, decreased mitochondrial respiration is associated with increased lactate after cardiovascular surgery. These findings suggest that high lactate levels after cardiovascular surgery, even in the setting of normal hemodynamics, are not simply a type B phenomenon as previously suggested.

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OBJECTIVE: To describe parents' motivations for and against participation in neonatal research, including the views of those who declined participation. STUDY DESIGN: We performed 44 semi-structured, qualitative interviews of parents approached for neonatal research. Here we describe their motivations for and against participation. RESULTS: Altruism was an important reason parents chose to participate. Some hoped participation in research would benefit their infant. Burdens of participation to the family, such as transportation to follow up (distinct from risks/burdens to the infant), were often deciding factors among those who declined participation. Perceived risks to the infant were reasons against participation, but parents often did not differentiate between baseline risks and incremental risk of study participation. Concerns regarding their infant being treated like a "guinea pig" were common among those who declined. Finally, historical abuses and institutional racism were reported as important concerns by some research decliners from minoritized populations. CONCLUSIONS: Within a diverse sample of parents approached to enroll their infant in neonatal research, motivations for and against participation emerged, which may be targets of future interventions. These motivations included reasons for participation which we may hope to encourage, such as altruism. They also included reasons against participation, which we may hope to, as feasible, eliminate, mitigate, or at least acknowledge. These findings can help clinical trialists, regulators, and funders attempting to improve neonatal research recruitment processes.

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We examined postnatal echocardiograms for 62 infants with congenital diaphragmatic hernia born from 2014 through 2020. Left and right ventricular dysfunction on D0 were sensitive, whereas persistent dysfunction on D2 was specific for extracorporeal membrane oxygenation requirement. Biventricular dysfunction had the strongest association with extracorporeal membrane oxygenation. Serial echocardiography may inform prognosis in congenital diaphragmatic hernia.

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Arapaima scales possess a hierarchical structure capable of absorbing a considerable amount of energy before fracture. These natural dermal armors present significant potential in the sustainable development of cost-effective composites. This work aimed, for the first time, to analyze the impact resistance and ballistic performance of arapaima scale-reinforced epoxy composites and their potential application in multilayered armor systems (MAS). Composite plates were prepared with 20%, 30%, and 40 vol% of arapaima scales. Composite specimens were subjected to notched Izod impact and residual velocity stand-alone tests and their MAS through backface signature (BFS) tests, with their fracture surfaces studied using SEM. The Izod tests confirmed the effect of scales' volume fraction on the energy absorbed by the composites, showing an increase with volume fraction. Residual velocity tests showed that composites with 30 vol% of scales resulted in the most significant improvement in absorbed energy. All MAS formulations presented BFS depths lower than the trauma limit specified by the NIJ standard. Fractographic analysis showed that the scales' toughening mechanisms improved the composites' energy absorption capacity. The experimental results substantiate the potential use of arapaima scales as a reinforcement agent in polymeric composites, with 30 vol% being the optimal volume fraction for energy-absorbing applications.

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An environmentally responsive root system is crucial for plant growth and crop yield, especially in suboptimal soil conditions. This responsiveness enables the plant to exploit regions of high nutrient density while simultaneously minimizing abiotic stress. Despite the vital importance of root systems in regulating plant growth, significant gaps of knowledge exist in the mechanisms that regulate their architecture. Auxin defines both the frequency of lateral root (LR) initiation and the rate of LR outgrowth. Here, we describe a search for proteins that regulate root system architecture (RSA) by interacting directly with a key auxin transporter, PIN1. The native separation of Arabidopsis plasma membrane protein complexes identified several PIN1 co-purifying proteins. Among them, AZG1 was subsequently confirmed as a PIN1 interactor. Here, we show that, in Arabidopsis, AZG1 is a cytokinin (CK) import protein that co-localizes with and stabilizes PIN1, linking auxin and CK transport streams. AZG1 expression in LR primordia is sensitive to NaCl, and the frequency of LRs is AZG1-dependent under salt stress. This report therefore identifies a potential point for auxin:cytokinin crosstalk, which shapes RSA in response to NaCl.

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We examined the results of cardiac catheterization in infants with congenital diaphragmatic hernia (CDH) from 2009 to 2020. Catheterization confirmed pulmonary arterial hypertension in all cases (n =  17) and identified left ventricular (LV) diastolic dysfunction (LVDD) in 53%. LVDD was associated with greater respiratory morbidity. Preprocedural noninvasive assessment showed inconsistent agreement with catheterization results.

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Clinical deterioration of hospitalized patients is common and can lead to critical illness and death. Rapid response teams (RRTs) assess and treat high-risk patients with signs of clinical deterioration to prevent further worsening and subsequent adverse outcomes. Whether activation of the RRT early in the course of clinical deterioration impacts outcomes, however, remains unclear. We sought to characterize the relationship between increasing time to RRT activation after physiologic deterioration and short-term patient outcomes. DESIGN: Retrospective multicenter cohort study. SETTING: Three academic hospitals in Pennsylvania. PATIENTS: We included the RRT activation of a hospitalization for non-ICU inpatients greater than or equal to 18 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary exposure was time to RRT activation after physiologic deterioration. We selected four Cardiac Arrest Risk Triage (CART) score thresholds a priori from which to measure time to RRT activation (CART score ≥ 12, ≥ 16, ≥ 20, and ≥ 24). The primary outcome was 7-day mortality-death or discharge to hospice care within 7 days of RRT activation. For each CART threshold, we modeled the association of time to RRT activation duration with 7-day mortality using multivariable fractional polynomial regression. Increased time from clinical decompensation to RRT activation was associated with higher risk of 7-day mortality. This relationship was nonlinear, with odds of mortality increasing rapidly as time to RRT activation increased from 0 to 4 hours and then plateauing. This pattern was observed across several thresholds of physiologic derangement. CONCLUSIONS: Increasing time to RRT activation was associated in a nonlinear fashion with increased 7-day mortality. This relationship appeared most marked when using a CART score greater than 20 threshold from which to measure time to RRT activation. We suggest that these empirical findings could be used to inform RRT delay definitions in further studies to determine the clinical impact of interventions focused on timely RRT activation.

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OBJECTIVES: Physiological decompensation of hospitalized patients is common and is associated with substantial morbidity and mortality. Research surrounding patient decompensation has been hampered by the absence of a robust definition of decompensation and lack of standardized clinical criteria with which to identify patients who have decompensated. We aimed to: 1) develop a consensus definition of physiological decompensation and 2) to develop clinical criteria to identify patients who have decompensated. DESIGN: We utilized a three-phase, modified electronic Delphi (eDelphi) process, followed by a discussion round to generate consensus on the definition of physiological decompensation and on criteria to identify decompensation. We then validated the criteria using a retrospective cohort study of adult patients admitted to the Hospital of the University of Pennsylvania. SETTING: Quaternary academic medical center. PATIENTS: Adult patients admitted to the Hospital of the University of Pennsylvania who had triggered a rapid response team (RRT) response between January 1, 2019, and December 31, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-nine experts participated in the eDelphi. Participation was high across the three survey rounds (first round: 93%, second round: 94%, and third round: 98%). The expert panel arrived at a consensus definition of physiological decompensation, "An acute worsening of a patient's clinical status that poses a substantial increase to an individual's short-term risk of death or serious harm." Consensus was also reached on criteria for physiological decompensation. Invasive mechanical ventilation, severe hypoxemia, and use of vasopressor or inotrope medication were bundled as criteria for our novel decompensation metric: the adult inpatient decompensation event (AIDE). Patients who met greater than one AIDE criteria within 24 hours of an RRT call had increased adjusted odds of 7-day mortality (adjusted odds ratio [aOR], 4.1 [95% CI, 2.5-6.7]) and intensive care unit transfer (aOR, 20.6 [95% CI, 14.2-30.0]). CONCLUSIONS: Through the eDelphi process, we have reached a consensus definition of physiological decompensation and proposed clinical criteria with which to identify patients who have decompensated using data easily available from the electronic medical record, the AIDE criteria.

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Peroxide has been considered a chemical agent that can be used to tune the properties of polymeric materials. This research evaluated the influence of different concentrations of dialkyl peroxides on the mechanical, thermal, and morphological properties of linear low-density polyethylene (LLDPE) and ultra-high molecular weight polyethylene (UHMWPE). The neat polymer, as well as those with the addition of 1% and 2% by mass of dialkyl peroxides, were subjected to compression molding and immersion in water for 1 h, under controlled temperatures of 90 °C. The values of the gel content found in the samples indicated that the addition of peroxide to the LLDPE and to the UHMWPE promoted the formation of a reticulated network. The structure obtained by the crosslinking led to less reorganization of the chains during the crystallization process, resulting in the formation of imperfect crystals and, consequently, in the reduction in melting temperatures, crystallization and enthalpy. The mechanical properties were altered with the presence of the crosslinker. The polymers presented had predominant characteristics of a ductile material, with the occurrence of crazing with an increased peroxide content.

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Brazilian Jiu-Jitsu (BJJ) is a popular martial art that exposes participants to recurrent intermittent asphyxiation due to controlled application of neck chokes. To what extent the sport impacts the regulation of cerebral blood flow (CBF) and cognition has not been examined. This study compared eleven elite Brazilian Jiu-Jitsu athletes (aged 30 ± 8 y) who trained 12 ± 6 hours/week for 8 ± 4 years against eleven cardiorespiratory fitness (CRF)- and age-matched controls. Internal carotid (ICA) and vertebral artery (VA) blood flow were measured via duplex ultrasound to determine global cerebral blood flow (gCBF). Mild cognitive impairment and sub-domains of memory, attention/concentration/visual motor coordination, and executive function were determined by psychometric testing. There was no evidence of mild cognitive impairment in the athletes, and cognitive function was comparable between groups (all p > 0.05). In contrast, resting gCBF was selectively elevated in the athletes (741 ± 186 mL∙min-1 vs. 573 ± 166 mL∙min-1 , p = 0.037) due to combined differences in ICA (+65 mL∙min-1 , p = 0.079) and VA (+19 mL∙min-1 , p = 0.277) flow. In conclusion, the sustained elevation in resting cerebral perfusion provides preliminary evidence for adaptive neuroprotection that is independent of CRF and likely mediated by choke-induced cerebral preconditioning and/or lifelong exposure to BJJ-specific high-intensity interval training.

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OBJECTIVE: To describe the parental experience of recruitment and assess differences between parents who participated and those who declined to enroll in a neonatal clinical trial. STUDY DESIGN: This was a survey conducted at 12 US neonatal intensive care units of parents of infants who enrolled in the High-dose Erythropoietin for Asphyxia and encephaLopathy (HEAL) trial or who were eligible but declined enrollment. Questions assessed 6 factors of the parental experience of recruitment: (1) interactions with research staff; (2) the consent experience; (3) perceptions of the study; (4) decisional conflict; (5) reasons for/against participation; and (6) timing of making the enrollment decision. RESULTS: In total, 269 of 387 eligible parents, including 183 of 242 (75.6%) of those who enrolled their children in HEAL and 86 of 145 (59.3%) parents who declined to enroll their children in HEAL, were included in analysis. Parents who declined to enroll more preferred to be approached by clinical team members rather than by research team members (72.9% vs 49.2%, P = .005). Enrolled parents more frequently reported positive initial impressions (54.9% vs 10.5%, P < .001). Many parents in both groups made their decision early in the recruitment process. Considerations of reasons for/against participation differed by enrollment status. CONCLUSIONS: Understanding how parents experience recruitment, and how this differs by enrollment status, may help researchers improve recruitment processes for families and increase enrollment. The parental experience of recruitment varied by enrollment status. These findings can guide future work aiming to inform optimal recruitment strategies for neonatal clinical trials.

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To measure the frequency of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis among decedents in hospitals of different sizes and teaching statuses. DESIGN: We performed a multicenter, retrospective cohort study. SETTING: Four large teaching hospitals, four affiliated small teaching hospitals, and nine affiliated nonteaching hospitals in the United States. PATIENTS: We included a sample of all adult inpatient decedents between August 2017 and August 2019. MEASUREMENTS AND MAIN RESULTS: We reviewed inpatient notes and categorized the immediately preceding circumstances as withdrawal of life-sustaining therapy for perceived poor neurologic prognosis, withdrawal of life-sustaining therapy for nonneurologic reasons, limitations or withholding of life support or resuscitation, cardiac death despite full treatment, or brain death. Of 2,100 patients, median age was 71 years (interquartile range, 60-81 yr), median hospital length of stay was 5 days (interquartile range, 2-11 d), and 1,326 (63%) were treated at four large teaching hospitals. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis occurred in 516 patients (25%) and was the sole contributing factor to death in 331 (15%). Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis was common in all hospitals: 30% of deaths at large teaching hospitals, 19% of deaths in small teaching hospitals, and 15% of deaths at nonteaching hospitals. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis happened frequently across all hospital units. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis contributed to one in 12 deaths in patients without a primary neurologic diagnosis. After accounting for patient and hospital characteristics, significant between-hospital variability in the odds of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis persisted. CONCLUSIONS: A quarter of inpatient deaths in this cohort occurred after withdrawal of life-sustaining therapy for perceived poor neurologic prognosis. The rate of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis occurred commonly in all type of hospital settings. We observed significant unexplained variation in the odds of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis across participating hospitals.

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OBJECTIVE: To understand what considerations drive family decisions for, and against, pediatric home ventilation. STUDY DESIGN: Qualitative interviews with parents of children who faced a decision about home ventilation in the previous 5 years at 3 geographically dispersed institutions. RESULTS: In total, 38 families (42 parents) were interviewed; 20 families opted for pediatric home ventilation, and 18 families opted against. Approximately one-quarter of children had isolated chronic lung disease; the remainder had medical complexity that was expected to remain static or decline. Parent perspectives about home ventilation generally reflected whether the child was early, or later, in their disease trajectory. Early on, parents often interpreted prognostic uncertainty as hope and saw home ventilation as a tool permitting time for improvement. For families of children later in their disease course, often already with home technology and home nursing, home ventilation held less possibility for meaningful improvement. Nearly all families experienced the decision as very emotionally distressing. Reflecting back, most families described feeling satisfied with whatever decision they made. CONCLUSIONS: The 2 principal groups of families in our cohort-those with children whose respiratory insufficiency might improve, and those with children facing chronic decline-warrant targeted counseling approaches about initiating home ventilation. The distressing nature of this decision should be anticipated and family supports reinforced.

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NEW FINDINGS: What is the central question of this study? Herein, a methodological overview of our research team's (Global REACH) latest high altitude research expedition to Peru is provided. What is the main finding and its importance? The experimental objectives, expedition organization, measurements and key cohort data are discussed. The select data presented in this manuscript demonstrate the haematological differences between lowlanders and Andeans with and without excessive erythrocytosis. The data also demonstrate that exercise capacity was similar between study groups at high altitude. The forthcoming findings from our research expedition will contribute to our understanding of lowlander and indigenous highlander high altitude adaptation. ABSTRACT: In 2016, the international research team Global Research Expedition on Altitude Related Chronic Health (Global REACH) was established and executed a high altitude research expedition to Nepal. The team consists of ∼45 students, principal investigators and physicians with the common objective of conducting experiments focused on high altitude adaptation in lowlanders and in highlanders with lifelong exposure to high altitude. In 2018, Global REACH travelled to Peru, where we performed a series of experiments in the Andean highlanders. The experimental objectives, organization and characteristics, and key cohort data from Global REACH's latest research expedition are outlined herein. Fifteen major studies are described that aimed to elucidate the physiological differences in high altitude acclimatization between lowlanders (n = 30) and Andean-born highlanders with (n = 22) and without (n = 45) excessive erythrocytosis. After baseline testing in Kelowna, BC, Canada (344 m), Global REACH travelled to Lima, Peru (∼80 m) and then ascended by automobile to Cerro de Pasco, Peru (∼4300 m), where experiments were conducted over 25 days. The core studies focused on elucidating the mechanism(s) governing cerebral and peripheral vascular function, cardiopulmonary regulation, exercise performance and autonomic control. Despite encountering serious logistical challenges, each of the proposed studies was completed at both sea level and high altitude, amounting to ∼780 study sessions and >3000 h of experimental testing. Participant demographics and data relating to acid-base balance and exercise capacity are presented. The collective findings will contribute to our understanding of how lowlanders and Andean highlanders have adapted under high altitude stress.

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In 2015, an estimated 17.7 million U.S. persons were informal caregivers who provided substantial services through in-home, unpaid assistance to their family members and friends (1). Caregiving can have many benefits, such as enhancing the bond between caregiver and recipient, but it can also place an emotional and physical strain on caregivers, leading to higher rates of depression, lower quality of life, and poorer overall health (2). As the U.S. population continues to age (3), the need for informal caregivers will likely increase. However, little nationally representative information on prevalence of caregivers is available. This study examined demographic characteristics and health status of informal caregivers from 44 states,* the District of Columbia (DC), and Puerto Rico, based on data from the Behavioral Risk Factor Surveillance System (BRFSS) collected during 2015-2017. Overall, approximately one in five adults reported that they had provided care to a family member or friend in the preceding 30 days. Fifty-eight percent of caregivers were women, and a majority were non-Hispanic white, with at least some college education, and married or living with a partner. Across all states, 19.2% of caregivers reported being in fair or poor health, although significant state-to-state variation occurred. Caregivers provide important support to family members, friends, and the health care system and might compromise their own health to provide this support (1,2). Better understanding of caregivers and the challenges they face could inform implementation of improvements in support systems that could enhance not only the health of the caregiver, but that of the care recipient as well. For example, additional data regarding demographics at the state level might aid in more effective planning and support of caregivers with evidence-based programs and assistance (https://www.cdc.gov/aging/publications/features/caring-for-yourself.html).

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BACKGROUND: Collection of biologic samples from the nasal cavity and paranasal sinuses is of critical importance to the study of infectious or inflammatory conditions that affect both upper and lower airways. Numerous techniques for the study of ex-vivo samples exist, with specific applications, strengths, and weaknesses associated with each of them. In this compendium we summarize the available methods for collection of primary human samples and incorporate expert discussion of the pros, cons, and applications associated with each technique. METHODS: An expert panel containing members of the American Rhinologic Society's Research and Grants Committee compiled this educational reference. Rationale for use and the potential advantages and disadvantages are discussed. Research protocols and key references are enumerated. RESULTS: Sampling of the nasal cavity and paranasal sinuses can be achieved through a number of methods. Nonspecific sinonasal secretions may be collected via forced exhalation, nasal lavage, and nasal spray aspiration. Targeted collection of sinonasal secretions may be achieved via endoscopic placement of absorbent matrices. Nasal cytology or collection of superficial epithelium may be completed via brushing or scraping of endonasal structures. Collection of mucosal biopsies may be completed via sinonasal explant or full-thickness biopsy. CONCLUSION: Multiple sampling techniques are available to collect biologic samples from the sinonasal cavity. These techniques differ in their ease of application, reproducibility, sample yield, and utility for different sinonasal pathologies or research goals. An appreciation of the benefits and drawbacks of each approach will allow investigators to select the techniques most appropriate for achieving research objectives.

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