Pharmacokinetics of immunosuppressive agents during hemoperfusion in a sheep model.

Introduction: Hemoadsorption shows promising signals in organ preservation and post lung transplantation. However, its potential impact on the pharmacokinetics of immunosuppressant drugs (ID) is still unknown. Methods: In this interventional study, CytoSorb® hemoperfusion was tested in healthy sheep (n = 5) against a sham extracorporeal circuit (n = 3). Seven different ID (tacrolimus (TAC), cyclosporin A (CYA), mycophenolate mofetil (MMF), everolimus (EVER), basiliximab (BAS), methylprednisolone (MP) and prednisolone (PRED)) were administered in clinically relevant doses and combinations. Their levels were measured repeatedly in blood samples from the extracorporeal circulation over 6 h following administration. Population pharmacokinetic modeling analysis (NONMEM® 7.5) was performed. Results: Negligible clearance was observed for PRED and BAS. For all other substances, a saturable adsorption sub-model with linear decrease of the adsorption effect over the adsorbed amount best described the measured concentrations. The maximum absolute adsorbed amounts (95% CI) for TAC, CYA, MMF, EVER, and MP were 0.040 (0.028-0.053), 1.15 (0.39-1.91), 4.17 (2.00-6.35), 0.0163 (0.007-0.026), and 53.4 mg (20.9-85.9), respectively, indicating an adsorption of less than 5% of the daily administered dosages for all investigated substances. Discussion: In this large animal model, CytoSorb® hemoperfusion appears to have a limited effect on the clearance of tested ID.

Unilateral Lung Agenesis: A Case Series and Review of Literature.

Unilateral lung agenesis is a rare congenital abnormality that typically presents with respiratory distress after birth. Prognostic factors include the side of the lung affected along with the presence or absence of other congenital abnormalities. Prenatal imaging can make the diagnosis that can assist the healthcare team in preparing to care for the neonate, as well as set expectations for the family. In this case series, we describe three cases of unilateral lung agenesis, two infants with right lung agenesis, and one with the left. We describe their presentation, provide a brief clinical course, and discuss outcomes.

Transcutaneous Bilirubin Monitoring in Preterm Infants of 23 to 34 Weeks' Gestation.

OBJECTIVE: The study aimed to evaluate the validity of transcutaneous bilirubin (TcB) measurements at three sites in premature infants born at 230/7 to 346/7 weeks' gestational age (GA) compared with total serum bilirubin (TSB) measurements. STUDY DESIGN: A prospective study was conducted at Banner - University Medical Center Phoenix, where informed consent was obtained from the infant's parent or legally authorized representative. Cohort A was comprised of infants 230/7 to 286/7 weeks' GA and Cohort B contained subjects 290/7 to 346/7 weeks' GA. Baseline TSB measurements were collected at approximately 24 hours of life, as the standard of care and the TcB measurements were obtained from the sternum, interscapular, and buttock areas at approximately ± 30 minutes from collection of the TSB. Statistical analysis of measurements including sensitivity, specificity, positive, and negative predictive values, and the area under the receiver operator characteristic curve (AUROC) were performed. RESULTS: A total of 166 infants were included in the study population. Cohort A consisted of 41 subjects and Cohort B contained 125 subjects. The results showed that baseline TcB measurements from the interscapular area were the most sensitive and specific with TSB levels >5.0 mg/dL in Cohort A. Baseline TcB measurements from the sternum demonstrated greatest sensitivity and specificity when the TSB level was >8.0 mg/dL in Cohort B. In general, each of the three sites in both cohorts demonstrated excellent AUROCs and negative predictive values. CONCLUSION: The use of a TcB meter in preterm infants can be a reliable noninvasive screening tool for hyperbilirubinemia, and it may be beneficial in decreasing painful stimuli and iatrogenic blood loss when used as an adjunct to TSB monitoring. KEY POINTS: · Interscapular TcB is sensitive/specific in 23 to 29 weeks' GA.. · Sternal TcB is sensitive/specific in 29 to 35 weeks' GA.. · TcB readings are reliable in preterm infants.. · TcB is reliable when serum bilirubin is >5.0 mg/dL..

Breeding system and geospatial variation shape the population genetics of Triodanis perfoliata.

Both intrinsic and extrinsic forces work together to shape connectivity and genetic variation in populations across the landscape. Here we explored how geography, breeding system traits, and environmental factors influence the population genetic patterns of Triodanis perfoliata, a widespread mix-mating annual plant in the contiguous US. By integrating population genomic data with spatial analyses and modeling the relationship between a breeding system and genetic diversity, we illustrate the complex ways in which these forces shape genetic variation. Specifically, we used 4705 single nucleotide polymorphisms to assess genetic diversity, structure, and evolutionary history among 18 populations. Populations with more obligately selfing flowers harbored less genetic diversity (π: R 2 = .63, p = .01, n = 9 populations), and we found significant population structuring (F ST = 0.48). Both geographic isolation and environmental factors played significant roles in predicting the observed genetic diversity: we found that corridors of suitable environments appear to facilitate gene flow between populations, and that environmental resistance is correlated with increased genetic distance between populations. Last, we integrated our genetic results with species distribution modeling to assess likely patterns of connectivity among our study populations. Our landscape and evolutionary genetic results suggest that T. perfoliata experienced a complex demographic and evolutionary history, particularly in the center of its distribution. As such, there is no singular mechanism driving this species' evolution. Together, our analyses support the hypothesis that the breeding system, geography, and environmental variables shape the patterns of diversity and connectivity of T. perfoliata in the US.

Relaxin and Erythropoietin Significantly Reduce Uterine Tissue Damage during Experimental Ischemia-Reperfusion Injury.

Successful uterus transplantation, a potential treatment method for women suffering from absolute uterine infertility, is negatively affected by ischemia-reperfusion injury (IRI). The aim of this study is to investigate the protective effect of relaxin (RLX) or/and erythropoietin (EPO) on experimental uterus IRI. Eighty rats, randomly assigned into eight groups (n = 10/group), were pretreated with either saline, 5 µg/kg human relaxin-2, 4000 IU/kg recombinant human erythropoietin or their combination. Ischemia was achieved by clamping the aorta and ovarian arteries for 60 min, following 120 min of reperfusion and tissue sampling. For sham animals, clamping was omitted during surgery. There were no differences in tissue histological score, malondialdehyde (MDA) and superoxide dismutase (SOD) levels, myeloperoxidase (MPO) and TUNEL-positive cell count between all sham-operated rats. Pretreatment with RLX preserved normal tissue morphology, reduced MDA levels, MPO and TUNEL-positive cell count, preserved SOD activity and upregulated NICD and HES1 gene expression when compared to the control group. Pretreatment with EPO reduced MDA levels. In conclusion, pretreatment with RLX, EPO or a combination of both EPO and RLX significantly alleviates uterine tissue damage caused by IRI.

Correction to: A Large-Scale Naturalistic Evaluation of the AIM Curriculum in a Public-School Setting.

[This corrects the article DOI: 10.1007/s40617-021-00569-5.].

A Large-Scale Naturalistic Evaluation of the AIM Curriculum in a Public-School Setting.

This study evaluated the effectiveness of the AIM curriculum when implemented in a public-school setting by schoolteachers and direct care staff. Three hundred eighteen students took part in this quasiexperimental design where all received the AIM curriculum every day for an entire school year. The participants completed a series of self-assessments (the Avoidance and Fusion Questionnaire for Youth, the Child and Adolescent Mindfulness Measure, and the Strength and Difficulties Questionnaire) at the onset of the study and at the end of the school year to assess psychological flexibility, mindfulness, and emotional behavioral skills. Results suggest that at the end of the school year, participants increased psychological flexibility and mindfulness. State standardized testing scores also showed increases school-wide as compared to the previous 2 years. These results suggest that the AIM curriculum may be effective in large school settings, appeared easy to implement by school staff to address the needs of both the individual student and the entire student body, and likely participated in improving school-wide academic success.

Custodiol® Supplemented with Synthetic Human Relaxin Decreases Ischemia-Reperfusion Injury after Porcine Kidney Transplantation.

Objective. Ischemia-reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing outcomes. Relaxin-2 (RLX) is a promising insulin-related peptide hormone that protects against renal IRI in rodents, although large animal models are needed before RLX can be tested in a human setting. Methods. In this blinded, randomized, and placebo-controlled experimental study kidneys from 19 donor pigs were retrieved after perfusion with Custodiol® ± RLX (5 or 20 nmol/L) and underwent static cold storage (SCS) for 24 and 48 h, respectively. Subsequently, KT was performed after unilateral right nephrectomy. Study outcomes included markers for kidney function, oxidative stress, lipid peroxidation, and endothelial cell damage. PCR analysis for oxidative stress and apoptosis-related gene panels as well as immunohistochemistry were performed. Results. RLX upregulated SOD2 and NFKB expression to 135% (p = 0.042) and 125% (p = 0.019), respectively, while RIPK1 expression was downregulated to 82% (p = 0.016) of corresponding controls. Further RLX significantly downregulated RIPK1 and MLKL expression and decreased the number of Caspase 3- and MPO-positive cells in grafts after SCS. Conclusions. RLX supplemented Custodiol® significantly decreased IRI via both antioxidant and anti-apoptotic mechanisms. Clinical trials are warranted to implement synthetic human RLX as a novel additive to preservation solutions against IRI.

Oklahoma Family Child Care Home Provider Perceptions of the Child and Adult Care Food Program and Menu Contents.

AIMS: In 2017, the Child and Adult Care Food Program (CACFP), which reimburses qualifying food expenses for Family Child Care Home (FCCH) providers, was substantially enhanced. This study's purpose was to explore the perceptions of Oklahoma FCCH providers of these enhancements and to determine current meal practices as an opportunity to foster collaborations between educators, service providers, and health and nutrition professionals. METHODS: This mixed-methods study included a cross-sectional survey (n=30) and semi-structured interviews (n=30) and menu analysis (n=25) of FCCH providers participating in the CACFP. RESULTS: There were 30 survey and interview respondents. Five main themes emerged from the qualitative interviews with providers: 1) they are satisfied, but... ; 2) base meals on what is creditable; 3) choose foods that children will eat; 4) serve what they perceive as healthy; and 5) have limited food preparation time. Quantitative menu analysis indicates most menus met minimum requirements of the CACFP. However, only 4% served a vegetable/fruit for snack; 27% served family-style meals; and 20% limited pre-fried foods. The providers expressed frustrations with CACFP implementation, and they demonstrated limited knowledge of child nutrition. CONCLUSIONS: Providers want to do what is best for children while saving money and time. Collaborative practice between allied health, nutrition, and CACFP service providers and child educators would likely assist FCCH providers in meeting nutrition best practices.

Impact of a Parent Video Viewing Program in the Neonatal Intensive Care Unit.

Purpose: Video visits, or televisits, have become increasingly popular across various medical subspecialties. Within the University of California, Davis, Neonatal Intensive Care Unit, a video visitation program known as FamilyLink allows families to remotely view their babies when they are otherwise unable to visit. This study aimed to explore parents' perceived effects of video camera use as well as the relationship of video visit use with rates of breast milk feedings at hospital discharge. Materials and Methods: Families enrolled in this study completed a series of two identical surveys that gathered self-reported data on their experiences during their infant's hospitalization. Comparisons were made considering whether the FamilyLink program was utilized during the admission as well as changes in self-reported experiences over the time course of the hospital admission. The type of enteral feeding at discharge was recorded and reviewed for each baby. Results: Of 100 families enrolled in the study, 30 were found to have used FamilyLink to visit with their baby. The use of FamilyLink was associated with survey findings of sustained intention to breastfeed or provide breast milk to the baby, as well as increased perceived parental involvement in the baby's care. Improved rates of breast milk feedings at the time of discharge were also found among babies whose families conducted televisits using FamilyLink. Conclusions: Video viewing in the NICU has effected a positive impact on breast milk feedings and parents' feelings of involvement during the admission, with the potential to further improve on families' experiences with a hospitalized baby.

Lymphopenia in primary Sjögren's syndrome is associated with premature aging of naïve CD4+ T cells.

OBJECTIVE: To investigate peripheral lymphopenia, a frequent finding in primary Sjögren's syndrome (pSS) associated with higher disease activity and increased mortality. METHODS: Prospective, cross-sectional study of consecutive patients with pSS (n = 66) and healthy controls (n = 181). Lymphocyte subsets were analysed by flow cytometry, naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells were purified by MACS technology. In vitro proliferation and senescence-associated ß-galactosidase (SABG) were assessed by flow cytometry. Telomere length and TCR excision circles (TREC) were measured by real-time PCR. Telomerase activity was analysed according to the telomeric repeat amplification protocols (TRAP). RESULTS: In pSS, lymphopenia mainly affected naïve CD4+ T cells. We noted a lower frequency of proliferating naïve CD4+ T cells ex vivo and decreased homeostatic proliferation in response to IL-7 stimulation in vitro. Furthermore, naïve CD4+ T cells exhibited signs of immune cell aging including shortened telomeres, a reduction in IL-7R expression and accumulation of SABG. The senescent phenotype could be explained by telomerase insufficiency and drastically reduced levels of T-cell receptor excision circles (TRECs), indicating a history of extensive post-thymic cell division. TRECs correlated with the number of naïve CD4+ T cells linking the extend of earlier proliferation to the inability to sustain normal cell numbers. CONCLUSION: In pSS, evidence for increased proliferation of naïve CD4+ T cells earlier in life is associated with a senescent phenotype unable to sustain homeostasis. The lack of naïve CD4+ T cells forms the basis of lymphopenia frequently observed in pSS.

An examination of climate-driven flowering-time shifts at large spatial scales over 153 years in a common weedy annual.

PREMISE: Understanding species' responses to climate change is a critical challenge facing biologists today. Though many species are widespread, few studies of climate-driven shifts in flowering time have examined large continuous spatial scales for individual species. And even fewer studies have examined these shifts at time scales greater than a few decades. METHODS: We used digitized herbarium specimens and PRISM climate data to produce the spatially and temporally broadest-scale study of flowering time in a single species to date, spanning the contiguous United States and 153 years (1863-2016) for a widespread weedy annual, Triodanis perfoliata (Campanulaceae). We examined factors driving phenological shifts as well as the roles of geographic and temporal scale in understanding these trends. RESULTS: Year was a significant factor in both geospatial and climatic analyses, revealing that flowering time has advanced by ~9 days over the past ~150 years. We found that temperature as well as vapor pressure deficit, an understudied climatic parameter associated with evapotranspiration and water stress, were strongly associated with peak flowering. We also examined how sampling at different spatiotemporal scales influences the power to detect flowering-time shifts, finding that relatively large spatial and temporal scales are ideal for detecting flowering-time shifts in this widespread species. CONCLUSIONS: Our results emphasize the importance of understanding the interplay of geospatial factors at different scales to examine how species respond to climate change.

Interventions to promote healthy environments in family child care homes in Oklahoma-Happy Healthy Homes: study protocol for a randomized controlled trial.

BACKGROUND: Early childhood is a critical period of development. Caregivers, including providers of early care and education (ECE), have a substantial influence on the health of young children. Family child care homes (FCCHs), which are small, licensed ECE businesses operated out of the residences of providers, are important settings for promoting child health. However, to date, few interventions to promote the health of children have been developed for FCCHs. The purpose of this article is to describe the protocol for Happy Healthy Homes, a pilot interdisciplinary, community-based study to improve FCCH environments and the health of children in Oklahoma. We describe the development and evaluation of two interventions to be tested in a matched attention randomized controlled trial: 1) a nutrition intervention aimed at enhancing the nutritional quality of meals served to young children, incorporating the Child and Adult Care Food Program best practices, and improving nutritional self-efficacy of providers; and 2) an environmental intervention aimed at increasing providers' environmental health literacy, self-efficacy for integrated pest management (IPM), and awareness of less toxic cleaning practices and FCCH provider cleaning behaviors. METHODS: Both interventions are informed by common theoretical principles and are matched in attention (i.e., 6 h), format (i.e., two individual 90-min educational home visits and a 3-h small group class) and materials (i.e., tool kit of educational materials and supplies tailored to the allocated intervention). A randomized trial of both interventions is currently underway with 52 FCCH providers in the Oklahoma City metropolitan area who participate in the Child and Adult Care Food Program. Observed and self-reported measures will be collected at baseline, and 3 months and 12 months after baseline measurements. Randomization to one of the two interventions will occur after baseline data collection. DISCUSSION: This study aims to support FCCH providers in creating healthier FCCH environments for nutrition and environmental health. Successful completion will provide critical information about the nutritional quality and the environmental health of children in FCCHs, as well as much needed evidence about the efficacy of two community-based interventions to improve the nutrition and environmental health of children in home-based ECE settings. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03560050 . Retrospectively registered on 23 May 2018.

Riverscape genetic variation, migration patterns, and morphological variation of the threatened Round Rocksnail, Leptoxis ampla.

Within riverine systems, headwater populations are hypothesized to harbour higher amounts of genetic distinctiveness than populations in the main stem of a river and display increased genetic diversity in large, downstream habitats. However, these hypotheses were mostly developed with insects and fish, and they have not been tested on many invertebrate lineages. Pleuroceridae gastropods are of particular ecological importance to rivers of eastern North America, sometimes comprising over 90% of macroinvertebrate biomass. Yet, virtually nothing is known of pleurocerid landscape genetics, including whether genetic diversity follows predictions made by hypotheses developed on more mobile species. Moreover, the commonly repeated hypothesis that intraspecific morphological variation in gastropods results from ecophenotypic plasticity has not been well tested on pleurocerids. Using 2bRAD-seq to discover single nucleotide polymorphisms, we show that the threatened, Cahaba River endemic pleurocerid, Leptoxis ampla, has limited gene flow among populations and that migration is downstream-biased, conflicting with previous hypotheses. Both tributary and main stem populations harbour unique genomic profiles, and genetic diversity was highest in downstream populations. Furthermore, L. ampla shell morphology was more correlated with genetic differences among individuals and populations than habitat characteristics. We anticipate similar genetic and demographic patterns to be seen in other pleurocerids, and hypotheses about gene flow and population demographics that were based on more mobile taxa often, but not always, apply to freshwater gastropods. From a conservation standpoint, genetic structure of L. ampla populations suggests distinctive genetic diversity is lost with localized extirpation, a phenomenon common across the range of Pleuroceridae.

The influence of environmental factors on breeding system allocation at large spatial scales.

Plant breeding systems can vary widely among populations, yet few studies have investigated abiotic factors contributing to variation across a broad geographic range. Here we investigate variation in reproductive traits of Triodanis perfoliata (Campanulaceae), a species that exhibits dimorphic cleistogamy, a condition in which individual plants have both closed (selfing: cleistogamous: CL) and open (selfing or outcrossing: chasmogamous: CH) flowers. Chasmogamous production is theorized to be more costly because CH flowers have a larger exposed surface area and thus are more likely to lose more water than CL flowers. We examine relationships between abiotic conditions (temperature, precipitation and soil characteristics) and variation in breeding systems across 14 widespread populations using ordinary least squares models. We found that a large proportion of breeding system variation was described by climate and soil variables (R 2 = 0.65-0.92). These results support the hypothesis that variation in the environment drives variation in breeding system allocation. Our broad geographic analyses provide a framework for mechanistic studies of cleistogamy, and employ a novel approach for examining reproductive traits and environmental variation at large scales. Given that two major components of our models were temperature and precipitation, our study further emphasizes the potential for ongoing climate change to alter plant breeding systems.

The best of both worlds? A review of delayed selfing in flowering plants.

PREMISE OF STUDY: In a seminal body of theory, Lloyd showed that the fitness consequences of selfing will depend on its timing in anthesis. Selfing that occurs after opportunities for outcrossing or pollen dispersal can provide reproductive assurance when pollinators are limited and is expected to incur little cost, even when inbreeding depression is high. As a result, delayed selfing is often interpreted as a "best-of-both-worlds" mating system that combines the advantages of selfing and outcrossing. METHODS: We surveyed 65 empirical studies of delayed selfing, recording floral mechanisms and examining information on inbreeding depression, autofertility, and other parameters to test the support for delayed selfing as a best-of-both-worlds strategy. KEY RESULTS: Phylogenetic distribution of the diverse floral mechanisms suggests that some basic floral structures may predispose plant taxa to evolve delayed selfing. Delayed selfing appears to serve as a best-of-both-worlds strategy in some but not all species. While the capacity for autonomous selfing is often high, it is lower, in some cases, than in related species with earlier modes of selfing. In other delayed-selfers, low inbreeding depression and reduced investment in corollas and pollen suggest limited benefits from outcrossing. CONCLUSIONS: Despite a growing literature on the subject, experimental evidence for delayed selfing is limited and major gaps in knowledge remain, particularly with respect to the stability of delayed selfing and the conditions that may favor transitions between delayed and earlier selfing. Finally, we suggest a potential role of delayed selfing in facilitating transitions from self-incompatibility to selfing.

Educational intervention for physicians to address the risk of opioid abuse.

OBJECTIVE: To evaluate the impact of a pilot intervention for physicians to support their treatment of patients at risk for opioid abuse. SETTING, DESIGN AND PATIENTS, PARTICIPANTS: Patients at risk for opioid abuse enrolled in Medicare plans were identified from July 1, 2012 to April 30, 2014 (N = 2,391), based on a published predictive model, and linked to 4,353 opioid-prescribing physicians. Patient-physician clusters were randomly assigned to one of four interventions using factorial design. INTERVENTIONS: Physicians received one of the following: Arm 1, patient information; Arm 2, links to educational materials for diagnosis and management of pain; Arm 3, both patient information and links to educational materials; or Arm 4, no communication. MAIN OUTCOME MEASURES: Difference-in-difference analyses compared opioid and pain prescriptions, chronic high-dose opioid use, uncoordinated opioid use, and opioid-related emergency department (ED) visits. Logistic regression compared diagnosis of opioid abuse between cases and controls postindex. RESULTS: Mailings had no significant impact on numbers of opioid or pain medications filled, chronic high-dose opioid use, uncoordinated opioid use, ED visits, or rate of diagnosed opioid abuse. Relative to Arm 4, odds ratios (95% CI) for diagnosed opioid abuse were Arm 1, 0.95(0.63-1.42); Arm 2, 0.83(0.55-1.27); Arm 3, 0.72(0.46-1.13). While 84.7 percent had ≥1 psychiatric diagnoses during preindex (p = 0.89 between arms), only 9.5 percent had ≥1 visit with mental health specialists (p = 0.53 between arms). CONCLUSIONS: Although this intervention did not affect pain-related outcomes, future interventions involving care coordination across primary care and mental health may impact opioid abuse and improve quality of life of patients with pain.

Development and Validation of the Amphetamine-Type Stimulants Motive Questionnaire in a Clinical Population.

Approximately 35.7 million people world-wide use amphetamine-type stimulants (ATS) leading to a high demand for effective treatment. Understanding the motives behind ATS use is a necessary basis for preventive and therapeutic treatment. The objective of this study is to develop the Amphetamine-Type stimulants Motive Questionnaire (AMQ) and to confirm its construct and concurrent validity in respect to the first and the latest month of ATS use based on answers of 233 patients with ATS disorders (74.2% male; mean age: 31.1 years). Confirmatory factor analyses were employed to test for the construct validity of the AMQ. Nested models of confirmatory factor analyses with increasing constraints for gender and age were estimated to test the equivalence of the factor structure in different subgroups. Independent sample t-tests were conducted to test for mean differences in the motive dimensions. A structural equation model was estimated to confirm the concurrent validity using the latent four motive factors (i.e., enhancement, coping, social, and conformity motives) as independent variables and frequency of ATS use in the first and the latest month of use as a dependent variable. The results confirmed the AMQ's four-dimensional factor structure in general, and across gender and age groups for both periods of time. Men (first month: M = 4.21, SD = 0.75; latest month: M = 3.86, SD = 0.93) use ATS more frequently due to enhancement motives than women (first month: M = 3.85, SD = 1.12; latest month: M = 3.46, SD = 1.29) at both periods of time [first month: t(77) = -2.33, p = 0.022; latest month: t(80) = -2.19, p = 0.031]. Structural equation modeling confirmed an association between coping motives and use frequency, for both periods of time (first and latest month: ß = 0.32, p < 0.001), as well as between social motives and frequency of use for the latest month of use (ß = 0.30, p < 0.01). To conclude, the AMQ is a valid and reliable instrument for assessing motives of ATS use in a clinical population. It can provide important insights into the motivational structure of the first and latest months of ATS use which are useful for preventive and therapeutic treatments as well as the development of abstinence skills.