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Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration–time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration–time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week. [ABSTRACT FROM AUTHOR]

Broken time-reversal symmetry in the absence of spin order indicates the presence of unusual phases such as orbital magnetism and loop currents1–4. The recently discovered kagome superconductors AV3Sb5 (where A is K, Rb or Cs)5,6 display an exotic charge-density-wave (CDW) state and have emerged as a strong candidate for materials hosting a loop current phase. The idea that the CDW breaks time-reversal symmetry7–14 is, however, being intensely debated due to conflicting experimental data15–17. Here we use laser-coupled scanning tunnelling microscopy to study RbV3Sb5. By applying linearly polarized light along high-symmetry directions, we show that the relative intensities of the CDW peaks can be reversibly switched, implying a substantial electro-striction response, indicative of strong nonlinear electron–phonon coupling. A similar CDW intensity switching is observed with perpendicular magnetic fields, which implies an unusual piezo-magnetic response that, in turn, requires time-reversal symmetry breaking. We show that the simplest CDW that satisfies these constraints is an out-of-phase combination of bond charge order and loop currents that we dub a congruent CDW flux phase. Our laser scanning tunnelling microscopy data open the door to the possibility of dynamic optical control of complex quantum phenomenon in correlated materials.The charge-density-wave state in RbV3Sb5 can be optically manipulated by applying linearly polarized light along high-symmetry directions, which demonstrates the potential of light as a control knob to manipulate complex quantum phenomena in correlated materials. [ABSTRACT FROM AUTHOR]

The most widely used attractant to capture adult female mosquitoes is CO2. However, there are also baits available on the market that emit a scent resembling human skin. These baits were specifically designed to attract highly anthropophilic species such as Aedes albopictus and Aedes aegypti. In this study, we compare the effectiveness of CDC traps baited either with CO2 or with a commercial blend simulating skin odor, BG-Sweetscent, for trapping female mosquitoes during daylight hours in an urban reserve in the City of Buenos Aires. We employed a hurdle generalized linear mixed model to analyze trap capture probability and the number of mosquitoes captured per hour, considering the effects of attractant, mosquito species, and their interaction. Traps baited with CO2 captured ten mosquito species, while those baited with BG-Sweetscent captured six in overall significantly lower abundance. The odds of capturing mosquitoes were 292% higher for the CO2-baited traps than for those baited with BG-Sweetscent. No evidence of a combined effect of attractant type and species on female mosquito captures per hour was found. Results indicated that CDC traps baited with CO2 were more effective than those baited with BG-Sweetscent in capturing more mosquito species and a higher number of mosquitoes within each species, even if the species captured with CO2 exhibited a certain level of anthropophilia. This result has practical implications for mosquito surveillance and control in urban natural reserves. [ABSTRACT FROM AUTHOR]

Archaeological evidence supports sporadic seafaring visits to the Eastern Mediterranean island of Cyprus by Epipaleolithic hunter-gatherers over 12,000 years ago, followed by permanent settlements during the early Neolithic. The geographical origins of these early seafarers have so far remained elusive. By systematically analysing all available genomes from the late Pleistocene to early Holocene Near East (c. 14,000–7000 cal BCE), we provide a comprehensive overview of the genetic landscape of the early Neolithic Fertile Crescent and Anatolia and infer the likely origins of three recently published genomes from Kissonerga-Mylouthkia (Cypriot Late Pre-Pottery Neolithic B, c. 7600–6800 cal BCE). These appear to derive roughly 80% of their ancestry from Aceramic Neolithic Central Anatolians residing in or near the Konya plain, and the remainder from a genetically basal Levantine population. Based on genome-wide weighted ancestry covariance analysis, we infer that this admixture event took place roughly between 14,000 and 10,000 BCE, coinciding with the transition from the Cypriot late Epipaleolithic to the Pre-Pottery Neolithic A (PPNA). Additionally, we identify strong genetic affinities between the examined Cypro-LPPNB individuals and later northwestern Anatolians and the earliest European Neolithic farmers. Our results inform archaeological evidence on prehistoric demographic processes in the Eastern Mediterranean, providing important insights into early seafaring, maritime connections, and insular settlement. [ABSTRACT FROM AUTHOR]

Background: Lactating mothers taking ezetimibe, an antihyperlipidemic agent, may be hesitant to breastfeed despite the known benefit of breastfeeding to both mother and infant. Currently, no data exist on the presence or concentration of ezetimibe and its main active metabolite, ezetimibe-glucuronide (EZE-glucuronide), in human breast milk. Methods: Voluntary breast milk samples containing ezetimibe and EZE-glucuronide were attained from lactating mothers taking ezetimibe as part of their treatment. An assay was developed and validated to measure ezetimibe and EZE-glucuronide concentrations in breast milk. A workflow that utilized a developed and evaluated pediatric physiologically based pharmacokinetic (PBPK) model, the measured concentrations in milk, and weight-normalized breast milk intake volumes was applied to predict infant exposures and determine the upper area under the curve ratio (UAR). Results: Fifteen breast milk samples from two maternal-infant pairs were collected. The developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay showed an analytical range of 0.039–5.0 ng/mL and 0.39–50.0 ng/mL for ezetimibe and EZE-glucuronide, respectively. The measured concentrations in the breast milk samples were 0.17–1.02 ng/mL and 0.42–2.65 ng/mL of ezetimibe and EZE-glucuronide, respectively. The evaluated pediatric PBPK model demonstrated minimal exposure overlap in adult therapeutic dose and breastfed infant simulated area under the concentration-time curve from time zero to 24 h (AUC24). Calculated UAR across infant age groups ranged from 0.0015 to 0.0026. Conclusions: PBPK model-predicted ezetimibe and EZE-glucuronide exposures and UAR suggest that breastfeeding infants would receive non-therapeutic exposures. Future work should involve a 'mother-infant pair study' to ascertain breastfed infant plasma ezetimibe and EZE-glucuronide concentrations to confirm the findings of this work. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, often presenting comorbidities like osteoporosis and requiring, in a relevant proportion of cases, treatment with bisphosphonates (BPs). This class of drugs was shown in preclinical investigations to also possess anticancer properties. We started an in vitro study of the effects of BPs on CLL B cells activated by microenvironment-mimicking stimuli and observed that, depending on drug concentration, hormetic effects were induced on the leukemic cells. Higher doses induced cytotoxicity whereas at lower concentrations, more likely occurring in vivo, the drugs generated a protective effect from spontaneous and chemotherapy-induced apoptosis, and augmented CLL B cell activation/proliferation. This CLL-activation effect promoted by the BPs was associated with markers of poor CLL prognosis and required the presence of bystander stromal cells. Functional experiments suggested that this phenomenon involves the release of soluble factors and is increased by cellular contact between stroma and CLL B cells. Since CLL patients often present comorbidities such as osteoporosis and considering the diverse outcomes in both CLL disease progression and CLL response to treatment among patients, illustrating this phenomenon holds potential significance in driving additional investigations. [ABSTRACT FROM AUTHOR]

Background: Uptake of lung cancer screening (LCS) has been slow with less than 20% of eligible people who currently or formerly smoked reported to have undergone a screening CT. Objective: To determine individual-, health system-, and neighborhood-level factors associated with LCS uptake after a provider order for screening. Design and Subjects: We conducted an observational cohort study of screening-eligible patients within the Population-based Research to Optimize the Screening Process (PROSPR)–Lung Consortium who received a radiology referral/order for a baseline low-dose screening CT (LDCT) from a healthcare provider between January 1, 2015, and June 30, 2019. Main Measures: The primary outcome is screening uptake, defined as LCS-LDCT completion within 90 days of the screening order date. Key Results: During the study period, 18,294 patients received their first order for LCS-LDCT. Orders more than doubled from the beginning to the end of the study period. Overall, 60% of patients completed screening after receiving their first LCS-LDCT order. Across health systems, uptake varied from 41 to 87%. In both univariate and multivariable analyses, older age, male sex, former smoking status, COPD, and receiving care in a centralized LCS program were positively associated with completing LCS-LDCT. Unknown insurance status, other or unknown race, and lower neighborhood socioeconomic status, as measured by the Yost Index, were negatively associated with screening uptake. Conclusions: Overall, 40% of patients referred for LCS did not complete a LDCT within 90 days, highlighting a substantial gap in the lung screening care pathway, particularly in decentralized screening programs. [ABSTRACT FROM AUTHOR]

We introduce a definition of the fractional Laplacian (- Δ) s (·) with spatially variable order s : Ω → [ 0 , 1 ] and study the solvability of the associated Poisson problem on a bounded domain Ω . The initial motivation arises from the extension results of Caffarelli and Silvestre, and Stinga and Torrea; however the analytical tools and approaches developed here are new. For instance, in some cases we allow the variable order s (·) to attain the values 0 and 1 leading to a framework on weighted Sobolev spaces with non-Muckenhoupt weights. Initially, and under minimal assumptions, the operator (- Δ) s (·) is identified as the Lagrange multiplier corresponding to an optimization problem; and its domain is determined as a quotient space of weighted Sobolev spaces. The well-posedness of the associated Poisson problem is then obtained for data in the dual of this quotient space. Subsequently, two trace regularity results are established, allowing to partially characterize functions in the aforementioned quotient space whenever a Poincaré type inequality is available. Precise examples are provided where such inequality holds, and in this case the domain of the operator (- Δ) s (·) is identified with a subset of a weighted Sobolev space with spatially variant smoothness s (·) . The latter further allows to prove the well-posedness of the Poisson problem assuming functional regularity of the data. [ABSTRACT FROM AUTHOR]

The Uncompahgre fritillary butterfly (Boloria improba acrocnema Gall LF, Sperling FAH (1980) A new high altitude species of Boloria from southwestern Colorado (Nyphalidae), with a discussion of phenetics and hierarchical decisions. J Lepidopterists' Soc 34:230–252 1980) was listed as federally endangered in 1991 and is considered a habitat indicator for alpine ecosystem health. They are found on patches of Salix nivalis in isolated habitats of the San Juan Mountains, Colorado, USA. Here, we estimated historical B. i. acrocnema abundance from annual distance sampling (2003–2020) at seven sub-colonies and sampled current (July 2021) measurements of herbaceous coverage, soil moisture content, and slope, aspect, and elevation at 700 sample sites. We used regression models to test the effects of these microhabitat characteristics on historical abundance. Our results show that increases in slope from 11° to 31°, individual coverage of five alpine plant species (S. nivalis, Geum rossii, Phacelia sericea, Noccaea fendleri, and Lewisia pygmaea), and soil moisture content between 0.09 m3/m3 and 0.38 m3/m3 positively influence butterfly abundance. However, increases in elevation, bare ground coverage, and presence of Salix planifolia, Aster alpinus, Antennaria media, and Androsace chamaejasme were correlated with lower abundance estimates. Implications for insect conservation Effects of climate change which decrease coverage of these alpine plant species, allow encroachment of lower elevation species, or reduce soil moisture will decrease B. i. acrocnema abundance. These results emphasize the extinction risk of B. i. acrocnema due to range limitations and prolonged drought conditions in the Western U.S. By defining additional resource requirements of B. i. acrocnema, we can model climate effects on survivorship and consider nearby microhabitats that may be habitable by this endangered species. [ABSTRACT FROM AUTHOR]

Background and Objective: Knowledge about exposure to cannabidiol (CBD) in breastfed infants can provide an improved understanding of potential risk. The aim was to predict CBD exposure in breastfed infants from mothers taking CBD and CBD-containing products. Methods: Cannabidiol concentrations in milk previously attained from data collected through an existing human milk research biorepository were used to simulate infant doses and identify subgroups. A developed pediatric physiologically based pharmacokinetic model produced virtual breastfed infants administered the simulated CBD doses. Predicted breastfed infant exposures and upper area under the curve ratios were compared to the lowest therapeutic dose for approved indications in children. Results: The existing human milk research biorepository contained 200 samples from 181 unique breastfeeding mothers for whom self-reported administration data and CBD concentrations had previously been measured. Samples that were above the lower limit of quantification with only one maternal administration type revealed that administration type, i.e., joint/blunt or edible versus oil or pipe, resulted in significantly different subgroups in terms of milk concentrations. Resulting simulated infant doses (ng/kg) were described by lognormal distributions with geometric means and geometric standard deviations: 0.61 ± 2.41 all concentrations, 0.10 ± 0.37 joint/blunt or edible, and 2.23 ± 8.15 oil or pipe. Doses administered to breastfed infants had exposures magnitudes lower than exposures in children aged 4–11 years administered the lowest therapeutic dose for approved indications, and low upper area under the curve ratios. Conclusions: Based on real-world use, breastfeeding infants are predicted to receive very small exposures of CBD through milk. Studies examining adverse reactions will provide further insight into potential risk. [ABSTRACT FROM AUTHOR]

Purpose: Psychedelics are being explored for their potential therapeutic benefits across a wide range of psychiatric diagnoses and may usher in a new age in psychiatric treatment. There is stigma associated with these currently illegal substances, and use varies by race and age. We hypothesized that minoritized racial and ethnic populations, relative to White respondents, would perceive psychedelic use as riskier. Methods: Using 2019 cross-sectional data from the National Survey of Drug Use and Health, we conducted a secondary analysis of 41,679 respondents. Perceived risk of heroin was used as a surrogate for overall risk of illegal substance use; heroin and lysergic acid diethylamide were the only substances queried this way in the sample. Results: A majority regarded lysergic acid diethylamide (66.7%) and heroin (87.3%) as a great risk if used once or twice. There were clear differences by race, with White respondents and those indicating more than one race having significantly lower perceived risk of lysergic acid diethylamide than respondents from other groups. Perceived risk of use also significantly increased with age. Conclusion: Perceived risk of lysergic acid diethylamide is unevenly distributed across the population. Stigma and racial disparities in drug-related crimes likely contribute to this. As research into potential therapeutic indications for psychedelics continues, perceived risk of use may change. [ABSTRACT FROM AUTHOR]

Introduced pests (insects and pathogens) have rapidly increased the numbers of at-risk native forest tree species worldwide. Some keystone species have been functionally extirpated, resulting in severe commercial and ecological losses. When efforts to exclude or mitigate pests have failed, researchers have sometimes applied biotechnology tools to incorporate pest resistance in at-risk species to enable their reintroduction. Often erroneously equated solely with genetic engineering, biotechnology also includes traditional and genome informed breeding—and may provide a holistic approach toward applying genomic-based information and interventions to increase tree species' pest resistance. Traditional tree breeding is responsible for successes to date, but new technologies offer hope to increase the efficiency of such efforts. Remarkable recent progress has been made, and for some at-risk species, novel biotechnological advances put reintroduction within reach. The high costs of reintroduction of at-risk species at necessary scale, however, will initially limit the pursuit to a few species. Successful deployment of pest resistant material may require improved species-specific knowledge and should integrate into and leverage existing reforestation systems, but these operations are sometimes rare where pest threats are greatest. While use of some biotechnologies, such as traditional tree breeding, are commonplace, others such as genetic engineering are controversial and highly regulated, yet may be the only viable means of achieving reintroduction of some at-risk species. Efforts to modify policy toward allowing the use of appropriate biotechnology, especially genetic engineering, have lagged. Provided that risk-benefits are favorable, policy is likely to follow with public opinion; in some countries, society is now increasingly open to using available biotechnologies. Continued engagement using the most recent advances in social science to build public trust, combined with a science-based collaboration among land managers and regulators, will generate the collective momentum needed to motivate policymakers to act rapidly given the speed at which forest health threats unfold and the large areas they affect. [ABSTRACT FROM AUTHOR]

Hybridization and genetic modification are potential methods for incorporation of stress tolerance being explored to support some at-risk tree species. However, many concerns, both ecological and economic, have been identified in using these biotechnologies, such as potential for invasiveness or high cost. There is limited information on perceptions towards hybrid and genetically modified (GM) trees, particularly from individuals responsible for widescale tree management. An online survey was administered to land managers in Indiana, USA to gauge perceptions to hybrid and GM trees, and current hybrid tree use. Land managers had stronger concern for ecological, rather than economic, issues, with potential for invasiveness being strongest. Agreement was highest for using the tree types for conservation and restoration of at-risk species and production purposes. However, perceptions varied by characteristics such as concern type, age, and land type managed. Ecological concern and land type managed most strongly predicted hybrid use. Overall, the majority of land managers agreed, rather than disagreed, with a variety of potential hybrid and GM tree advantages and purposes. Thus, results indicate that if these biotechnologies are deemed appropriate for supporting at-risk species, the majority of land managers in Indiana might be agreeable to such recommendations from researchers. However, it was also clear that despite this, most respondents concurrently had strong ecological concerns about suitability as a native species replacement. To address this, it is essential that these tree types be thoroughly vetted, and land managers be actively engaged in the process, as this population would ultimately be responsible for any widescale implementation of hybrid and GM trees. [ABSTRACT FROM AUTHOR]

Purpose: The coronavirus disease (COVID-19) pandemic and its economic consequences may disproportionately impact cancer survivors and their overall health-related quality of life. The objective of this study was to examine whether cancer survivors experienced higher levels of financial strain or food insecurity compared to those without a history of cancer. Methods: Kaiser Permanente Research Bank (KPRB) study participants were invited to complete a series of electronic surveys starting April 2020 to assess the impact of the COVID-19 pandemic. Participants who completed the initial survey and one follow-up survey were included. The odds of financial strain and food insecurity in those with and without a history of cancer were estimated using multinomial logistic regression. Results: Cancer survivors (n = 16,231) had lower odds of reporting "somewhat hard" (AOR = 0.77) and "very hard" (AOR = 0.67) financial strain, and food insecurity "sometimes" (AOR = 0.70) and "often" (AOR = 0.55) compared to those with no history of cancer (n = 88,409). Non-Hispanic (NH) Black and Hispanic cancer survivors had higher odds compared to NH Whites of reporting financial strain and food insecurity. Smokers and those with multiple comorbidities had higher odds of reporting financial strain and food insecurity among cancer survivors. Conclusions: While cancer survivors overall did not report greater financial strain or food insecurity than individuals without a history of cancer, subsets of cancer survivors are experiencing greater social risks during the pandemic and should be prioritized for screening for social risk factors. Implications for Cancer Survivors: Incorporating screening for social risk factors into care coordination workflows for subsets of cancer survivors should be a priority. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the relationship between soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intracellular adhesion molecule-1 (sICAM-1), and lipid levels in rheumatoid arthritis (RA) patients with and without carotid plaque (CP). Methods: Cross-sectional study nested of a RA cohort. RA patients without a previous cardiovascular event or statins' therapy, aged 40–75 years were recruited at an outpatient cardio-rheumatology clinic. Carotid ultrasound was performed in all study subjects. RA patients with CP were included and matched to RA patients without CP by age, gender, and traditional cardiovascular risk factors. Blood samples were drawn at the time of recruitment to measure sVCAM-1, sICAM-1, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and lipid levels. Correlations between cell adhesion molecules, disease activity indexes, ESR and CRP with lipid levels were assessed with Spearman's correlation coefficient (rs). Results: We included 71 RA patients, 37 with CP and 34 without CP. RA (n = 71) patients had a moderate negative correlation of sVCAM-1 with total cholesterol (TC) (rs = − 0.366, p = 0.002) and low-density lipoprotein (LDL) (rs = − 0.316, p = 0.007), and a small negative correlation with high-density lipoprotein (rs = − 0.250, p = 0.036). ESR showed a small negative correlation with LDL (rs = − 0.247, p = 0.038). Patients with CP had a moderate negative correlation between sVCAM and TC (rs = − 0.405, p = 0.013). Patients without CP showed a moderate negative correlation between sVCAM with TC (rs = − 0.364, p = 0.034) and LDL (rs = − 0.352, p = 0.041), and sICAM with VLDL (rs = − 0.343, p = 0.047). Conclusions: RA patients showed an inverse association of sVCAM-1 and lipid levels. More studies are needed to define the precise role of sVCAM-1 in the lipid paradox of RA. Key Points • In RA patients with and without atherosclerosis, higher sVCAM-1 titers were associated with lower TC, LDL and HDL, and higher levels of ESR associated with lower LDL. • Higher levels of sVCAM-1 were associated with lower TC in RA patients with atherosclerosis, and with lower TC and LDL in RA patients without atherosclerosis. • There was an inverse association of sICAM-1 with VLDL, in RA patients without atherosclerosis. • sVCAM-1 may have a role in the detection of paradoxical lipid levels in RA, but more research is needed to validate our findings. [ABSTRACT FROM AUTHOR]

Purpose of Review: We summarized recent findings on insufficient sleep and insomnia, two prominent sleep issues that impact public health. We demonstrate the socio-ecologial impact of sleep health with findings on gender and couples' relationships as exemplars. Recent Findings: Robust gender differences in sleep duration and insomnia are due to biological and socio-ecological factors. Gender differences in insufficient sleep vary by country of origin and age whereas gender differences in insomnia reflect minoritized identities (e.g., sexual, gender). Co-sleeping with a partner is associated with longer sleep and more awakenings. Gender differences and couples' sleep were affected by intersecting social and societal influences, which supports a socio-ecological approach to sleep. Summary: Recent and seminal contributions to sleep health highlight the importance of observing individual sleep outcomes in a socio-ecological context. Novel methodology, such as global measures of sleep health, can inform efforts to improve sleep and, ultimately, public health. [ABSTRACT FROM AUTHOR]

The COVID-19 course and immunity differ in children and adults. We analyzed immune response dynamics in 28 families up to 12 months after mild or asymptomatic infection. Unlike adults, the initial response is plasmablast-driven in children. Four months after infection, children show an enhanced specific antibody response and lower but detectable spike 1 protein (S1)-specific B and T cell responses than their parents. While specific antibodies decline, neutralizing antibody activity and breadth increase in both groups. The frequencies of S1-specific B and T cell responses remain stable. However, in children, one year after infection, an increase in the S1-specific IgA class switch and the expression of CD27 on S1-specific B cells and T cell maturation are observed. These results, together with the enhanced neutralizing potential and breadth of the specific antibodies, suggest a progressive maturation of the S1-specific immune response. Hence, the immune response in children persists over 12 months but dynamically changes in quality, with progressive neutralizing, breadth, and memory maturation. This implies a benefit for booster vaccination in children to consolidate memory formation. Severity of SARS-CoV-2 infection is different in adults and children which involves the immune response. Here using a parent and children cohort with 4 month and 12 month sampling times, the authors show enhanced levels and increased breadth of anti-spike antibody level over time but reduced specific T cell and B cell numbers in children. [ABSTRACT FROM AUTHOR]

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Previous research has shown that disruptive behavior can impair students' academic success (Pierce et al. in Remedial Spec Educ 25:175–188, 2004, https://doi.org/10.1177/07419325040250030501), as well as increase teacher's stress level (Westling in Remedial Spec Educ 31:48–63, 2010, https://doi.org/10.1177/0741932508327466). The Class Pass Intervention (CPI) is a Tier 2 intervention designed to decrease disruptive behavior and increase academic engagement; however, few studies have evaluated the efficacy of CPI. The purpose of this study was to assess the effects of CPI on disruptive behavior and academic engagement of young students who engage in disruptive behavior. This study used a non-concurrent multiple baseline design to assess experimental control. In the current study, CPI led to a decrease in disruptive behavior and an increase in academic engagement for all three participants and these levels persisted throughout schedule thinning. In addition, results of teacher and student social validity assessments indicated that the intervention was effective and easy to implement and that students preferred the intervention. [ABSTRACT FROM AUTHOR]

Retrieval practice effect refers to improved memory on a final test for information retrieved one or more times. Although past theoretical work identifies cognitive mechanisms to explain retrieval practice benefits, it is possible that improving self-efficacy during learning may also contribute to better memory, in line with limited past work showing a relationship between self-efficacy and memory. Across two experiments, we examine the potential relationship between retrieval practice, self-efficacy, and memory. In Experiment 1, we examined the extent change in self-efficacy accounted for improved memory on a final test after retrieval practice compared with restudy. In Experiment 2, we gave participants (false) feedback that was either negative (i.e., you performed worse than others), neutral (i.e., you performed the same as others), or positive (i.e., you performed better than others) to more directly assess the effects of self-efficacy on memory under retrieval practice conditions. Results of Experiment 1 showed a significant retrieval practice effect, with memory on the final test being better after retrieval practice compared with restudy. Self-efficacy did not significantly mediate the retrieval practice effect. Results of Experiment 2, however, showed that decreases in self-efficacy due to (false) negative feedback resulted in worse memory performance compared with neutral feedback. Such findings may suggest that change in self-efficacy after retrieval practice attempts, particularly negative feedback, affects memory at final test. Overall, these findings suggest a relationship between retrieval practice, self-efficacy, and memory, and imply that interventions that influence self-efficacy may be a plausible mechanism to modulate memory under some conditions. [ABSTRACT FROM AUTHOR]

U.S. history is fraught with examples of systemic racism—at all ecological levels and within all geopolitical contexts. Whether scholars historically punctuate these phenomena through white racial framing begun in the 1600s or the Black civil rights movement of the 1960s, research across disciplines brings into focus a twenty-generation story of injustice. These phenomena present a paradoxical struggle within healthcare systems populated by professionals who have made a "conscious commitment to equity and helping those in need." However, both healthcare systems and embedded care providers operate in relation to organizational structures that frequently reify racist policies. As natural and professional agents of change, medical family therapists are especially positioned to examine how regulatory systems at every level influence institutional racism within the medical and mental health fields. In this manuscript we examine health system policies and practices using the lens of C.J. Peek's Four Worlds: Clinical, Operational, Financial, and Training. Examples of institutional racism are discussed and recommendations for approaches to change are provided. [ABSTRACT FROM AUTHOR]

Background and Objective: While one in five children in the USA are now obese, and more than three-quarters receive at least one drug during childhood, there is limited dosing guidance for this vulnerable patient population. Physiologically based pharmacokinetic modeling can bridge the gap in the understanding of how pharmacokinetics, including drug distribution and clearance, changes with obesity by incorporating known obesity-related physiological changes in children. The objective of this study was to develop a virtual population of children with obesity to enable physiologically based pharmacokinetic modeling, then use the novel virtual population in conjunction with previously developed models of clindamycin and trimethoprim/sulfamethoxazole to better understand dosing of these drugs in children with obesity. Methods: To enable physiologically based pharmacokinetic modeling, a virtual population of children with obesity was developed using national survey, electronic health record, and clinical trial data, as well as data extracted from the literature. The virtual population accounts for key obesity-related changes in physiology relevant to pharmacokinetics, including increased body size, body composition, organ size and blood flow, plasma protein concentrations, and glomerular filtration rate. The virtual population was then used to predict the pharmacokinetics of clindamycin and trimethoprim/sulfamethoxazole in children with obesity using previously developed physiologically based pharmacokinetic models. Results: Model simulations predicted observed concentrations well, with an overall average fold error of 1.09, 1.24, and 1.53 for clindamycin, trimethoprim, and sulfamethoxazole, respectively. Relative to children without obesity, children with obesity experienced decreased clindamycin and trimethoprim/sulfamethoxazole weight-normalized clearance and volume of distribution, and higher absolute doses under recommended pediatric weight-based dosing regimens. Conclusions: Model simulations support current recommended weight-based dosing in children with obesity for clindamycin and trimethoprim/sulfamethoxazole, as they met target exposure despite these changes in clearance and volume of distribution. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties. Methods: We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities. Results: Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white. Conclusions: Rectal cancer survivors' participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors. [ABSTRACT FROM AUTHOR]

Purpose: We have hypothesized that a high concentration of circulating monocytes and macrophages may contribute to the fast weight-based clearance of monoclonal antibodies (mAbs) in young children. Exploring this hypothesis, this work uses modeling to clarify the role of monocytes and macrophages in the elimination of mAbs. Methods: Leveraging pre-clinical data from mice, a minimal physiologically-based pharmacokinetic model was developed to characterize mAb uptake and FcRn-mediated recycling in circulating monocytes, macrophages, and endothelial cells. The model characterized IgG disposition in complex scenarios of site-specific FcRn deletion and variable endogenous IgG levels. Evaluation was performed for predicting IgG disposition with co-administration of high dose IVIG. A one-at-a-time sensitivity analysis quantified the role of relevant cellular parameters on IgG elimination in various scenarios. Results: The plasma AUC of mAbs was highly sensitive to endothelial cell parameters, but had near-nil sensitivity to monocyte and macrophage parameters, even in scenarios with 90% loss of FcRn expression/activity. In mice with normal FcRn expression, simulations suggest that less than 2% of an IV dose is eliminated in macrophages, while endothelial cells are predicted to dominate mAb elimination. Conclusions: The model suggests that the role of monocytes and macrophages in IgG homeostasis includes extensive uptake and highly efficient FcRn-mediated protection, but not appreciable degradation when FcRn is present. Therefore, it is very unlikely that a high concentration of circulating monocytes can contribute to explaining the fast weight-based clearance of mAbs in very young children, even if FcRn expression/activity was 90% lower in children than in adults. [ABSTRACT FROM AUTHOR]

Capillary endothelial cells of the human blood–brain barrier (BBB) express high levels of P-glycoprotein (P-gp, encoded by ABCB1) and ABCG2 (encoded by ABCG2). However, little information is available regarding ATP-binding cassette transporters expressed at the zebrafish BBB, which has emerged as a potential model system. We report the characterization and tissue localization of two genes that are similar to ABCB1, zebrafish abcb4 and abcb5. When stably expressed in HEK293 cells, both Abcb4 and Abcb5 conferred resistance to P-gp substrates; however, Abcb5 poorly transported doxorubicin and mitoxantrone compared to zebrafish Abcb4. Additionally, Abcb5 did not transport the fluorescent P-gp probes BODIPY-ethylenediamine or LDS 751, while they were transported by Abcb4. High-throughput screening of 90 human P-gp substrates confirmed that Abcb4 has an overlapping substrate specificity profile with P-gp. In the brain vasculature, RNAscope probes for abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. The abcb4 probe also colocalized with claudin-5 in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, potentially indicating different functions. The data suggest that zebrafish Abcb4 functionally phenocopies P-gp and that the zebrafish may serve as a model to study the role of P-gp at the BBB. [ABSTRACT FROM AUTHOR]

Background: Meropenem is a broad-spectrum carbapenem antibiotic approved by the US Food and Drug Administration for use in pediatric patients, including treating complicated intra-abdominal infections in infants < 3 months of age. The impact of maturation in glomerular filtration rate and tubular secretion by renal transporters on meropenem pharmacokinetics, and the effect on meropenem dosing, remains unknown. We applied physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of meropenem in preterm and term infants. Methods: An adult meropenem PBPK model was developed in PK-Sim® (Version 8) and scaled to infants accounting for renal transporter ontogeny and glomerular filtration rate maturation. The PBPK model was evaluated using 645 plasma concentrations from 181 infants (gestational age 23–40 weeks; postnatal age 1–95 days). The PBPK model-based simulations were performed to evaluate meropenem dosing in the product label for infants < 3 months of age treated for complicated intra-abdominal infections. Results: Our model predicted plasma concentrations in infants in agreement with the observed data (average fold error of 0.90). The PBPK model-predicted clearance in a virtual infant population was successfully able to capture the post hoc estimated clearance of meropenem in this population, estimated by a previously published model. For 90% of virtual infants, a 4-mg/L target plasma concentration was achieved for > 50% of the dosing interval following product label-recommended dosing. Conclusions: Our PBPK model supports the meropenem dosing regimens recommended in the product label for infants <3 months of age. [ABSTRACT FROM AUTHOR]

To compare overall number of downstream tests and total costs between negative exercise stress echocardiograms (ESE) or cardiac computed tomography angiography scans (CCTA) in symptomatic Tricare beneficiaries suspected of having coronary artery disease (CAD). This is a retrospective cohort study examining 651 propensity-matched patients who underwent ESE or CCTA with normal results between 2008 and 2014 at the United States' largest Department of Defense hospital. The total number of additional downstream tests over the next five years was determined. The total costs associated with each arm, inclusive of the initial test and all subsequent tests, were calculated using the 2018 Medicare Physician Fee Schedule. 18.5 percent of patients with a normal ESE result underwent some additional form of cardiac testing over the five years after initial testing compared to 12.8 percent of patients with a normal CCTA. The absolute difference in total number of downstream tests between both study groups was 5.7 percent (p = 0.03). When factoring the costs of the initial test as well as the downstream tests, the ESE group was associated with overall lower costs compared to the CCTA group, 351 United States Dollars (USD) versus 496 USD (p < 0.0001). This study demonstrates that, when compared to CCTA, ESE is associated with a higher total number of downstream tests, but overall lower total costs when chosen as initial testing strategy for suspected CAD. [ABSTRACT FROM AUTHOR]

This paper examines the reliability and validity of parent target problems (PTPs) in a multi-site randomized controlled trial of parent training (PT) versus psychoeducation (PEP) in children (150 boys, 19 girls; mean age 4.7 ± 1.2 years) with autism spectrum disorder (ASD) and disruptive behavior. At baseline, treatment blind, independent evaluators asked parents to nominate the child's top two problems. Each problem was documented in a brief narrative. Narratives were reviewed and revised at follow-up visits during the six-month trial. When the trial was completed, five judges, blind to treatment condition, independently rated change from baseline on a 9-point scale (1 = normal; 2 = markedly improved; 3 = definitely improved; 4 = equivocally improved; 5 = no change; 6 = possibly worse; 7 = definitely worse; 8 = markedly worse; 9 = disastrously worse) at Weeks 8, 12, 16, and 24 (inter-rater intraclass correlation = 0.78). PTP scores for the two target problems were averaged across the five raters, yielding a mean score for each child at each time point. Mean PTP scores showed improvement in both treatment groups over the 24-week study. Compared to PEP, PTP ratings showed a steeper decline in PT based on significant interaction of group and time (t(df) = 2.14(155.9), p = 0.034; Week 24 effect size = 0.75). In categorical analysis, we compared cutoffs mean PTP scores of 3.0 (definitely improved), 3.25, and 3.5 with the positive response rate on the Clinical Global Impressions-Improvement scale from the original study. Sensitivities ranged from 52–78%. PTP narratives offer a systematic, reliable, and valid way to track child-specific outcomes in clinical trials and clinical practice. [ABSTRACT FROM AUTHOR]

Additive manufacturing (AM) allows agile, rapid manufacturing of geometrically complex components that would otherwise be impossible through traditional manufacturing methods. With this maturing manufacturing technology comes the need to adopt testing methods that are commensurate with the speed of additive manufacturing and take advantage of its geometric flexibility. High-throughput tensile testing (HTT) is a technique that allows a large number of tensile bars to be tested in a short amount of time. In the present study, HTT is used to evaluate AM AlSi10Mg produced using powder bed fusion with a Renishaw AM250 machine. Three parameters were varied in this study: (1) powder reuse history, (2) location on the build plate, and (3) size of the tensile specimen. For all parameter combinations, at least 22 specimens were tested; in several cases, over 40 were tested. This large dataset, consisting of over 500 tensile tests, permits Weibull statistical analysis and provides sufficient fidelity to isolate subtle trends that would have likely been missed in smaller, traditional datasets. The observed trends are rationalized in terms of the role of porosity and surface crust on mechanical response. [ABSTRACT FROM AUTHOR]

Background: There are no published data on Mild Cognitive Impairment (MCI) incidence in people over 65 years of age in Greece, relevant literature is scarce for Southern Europe, and reported rates worldwide show great variability. Aims: To investigate the incidence and risk factors of MCI and its subtypes in the elderly population in Greece. Methods: The incidence cohort of the HELIAD study (Hellenic Epidemiological Longitudinal Investigation of Aging and Diet) comprised 955 individuals who received full neurological and neuropsychological evaluation on two separate occasions about three years apart. Results: The MCI incidence rate in our cohort is 54.07 new cases per 1000 person-years, standardized by age and sex to 59.99. Each additional year of age over 65 raises the probability of novel MCI by 6.2%, while lower educational attainment more than doubles the risk for incident MCI. Apolipoprotein E-ε4 (APOE-ε4) carriage results in increased risk for MCI by more than 1.7 times. Incidence rates for amnestic MCI are slightly higher than for the non-amnestic subtype, and AD is the most common potential underlying etiology. Discussion: The MCI incidence rate in the Greek population over 65 years of age is 54/1000 person-years. Advanced age and APOE-ε4 carriage are predisposing factors, while higher educational attainment was found to exert a protective effect. Conclusions: MCI incidence in people over 65 years-old in Greece is consistent with reported rates around the world. Larger studies encompassing neuroimaging and cerebrospinal fluid biomarkers will hopefully shed more light on MCI epidemiology in Greece in the future. [ABSTRACT FROM AUTHOR]

Background: Breast cancer-related lymphedema (BCRL) is a source of postoperative morbidity for breast cancer survivors. Lymphatic microsurgical preventive healing approach (LYMPHA) is a technique used to prevent BCRL at the time of axillary lymph node dissection (ALND). We report the 5-year experience of a breast surgeon trained in LYMPHA and investigate the outcomes of patients who underwent LYMPHA following ALND for treatment of cT1–4N1–3M0 breast cancer. Methods: A retrospective review of patients with cT1–4N1–3M0 breast cancer was performed in patients who underwent ALND with and without LYMPHA. Diagnosis of BCRL was made by certified lymphedema therapists. Descriptive statistics and lymphedema surveillance data were analyzed using results of Fisher's exact or Wilcoxon rank-sum tests. Logistic regression and propensity matching were performed to assess the reduction of BCRL occurrence following LYMPHA. Results: In a 5-year period, 132 patients met inclusion criteria with 76 patients undergoing LYMPHA at the time of ALND and 56 patients undergoing ALND alone. Patients who underwent LYMPHA at the time of ALND were significantly less likely to develop BCRL than those who underwent ALND alone (p = 0.045). Risk factors associated with BCRL development were increased patient age (p = 0.007), body mass index (BMI) (p = 0.003), and, in patients undergoing LYMPHA, number of positive nodes (p = 0.026). Conclusions: LYMPHA may be successfully employed by breast surgeons trained in lymphatic–venous anastomosis at the time of ALND. While research efforts should continue to focus on prevention and surveillance of BCRL, LYMPHA remains an option to reduce BCRL and improve patient quality of life. [ABSTRACT FROM AUTHOR]

Bycatch continues to be a challenge to sustainable fisheries management (The term "bycatch" in this paper covers discards and does not include retained incidental catch). Bycatch estimates can inform stock status determinations by improving understanding of fishing mortality, and help managers monitor the effectiveness of regulations. Assessments of the quality of bycatch estimation programs and procedures are necessary to evaluate the precision and limitations of their results over time. NOAA Fisheries experts used a "Tier Classification System" (TCS) to compare the quality of fish bycatch data and estimation methods for U.S. commercial fisheries in 2005 and 2015. The TCS included criteria related to data adequacy and analytical approaches. A comparison of U.S. fishery tier scores demonstrated that most fisheries were classified into higher tiers in 2015 compared to 2005 due to factors including improved sampling design. In addition, this comparison identified region-specific trends (e.g., mostly improvements occurred for Alaska fisheries with more mixed results for Greater Atlantic fisheries). The improvements in bycatch data quality and estimation methods in the United States are a result of financial investments in observer programs by NOAA Fisheries and industry partners, as well as effective conservation measures implemented by regional fishery management councils and NOAA Fisheries. The TCS was also used to assess bycatch data and estimation methods in all of Australia's fishery jurisdictions for the decade 2010–19, illustrating the international applicability of the method. Overall, Australian state fisheries scored lower than federally managed fisheries in both the United States and Australia, reflecting the fact that the latter fisheries tend to be larger (and more valuable) than those in state jurisdictions, with a larger investment in observer programs. A comparison of tier scores and estimates of discards by fishery may provide a useful input for decision-making processes regarding allocation of resources to improve bycatch monitoring. [ABSTRACT FROM AUTHOR]

As ecosystems that support human health, societies, and civilization change in the era of the Anthropocene, individuals with disproportionate balance of salivary hormones may be at greatest risk of morbidity and mortality. Vulnerable communities, in particular, are overburdened by inequities in features of built environments linked to health disparities. This study examined the cross-sectional association of greenness in the built environment with the ratio of cortisol to dehydroepiandrosterone (DHEA) in an urban-dwelling high-risk community sample of African American women (n = 84, age 18-44 years). Saliva samples, collected across 2 consecutive days, were assayed for cortisol and DHEA. Controlling for sexual violence, perceived stress, education, and income, as well as crime, traffic density, and vacant properties, we observed a significant positive cross-sectional association between greenness and the cortisol to DHEA ratio, (β = 7·5, 95% CI: 0.89, 14.19). The findings highlight environmental influence on stress response at waking when there is the greatest individual variation. Implications for advancing our understanding of the waking ratio of cortisol to DHEA as a potential marker of physiological resilience are discussed. [ABSTRACT FROM AUTHOR]

Some research suggests that GI symptoms seen in children with ASD may relate to behavior problems. The objective of this pilot study was to assess the effect of the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet on GI and behavioral problems in children with ASD. At follow-up, the low FODMAP diet group had significant relief in some GI problems compared with both baseline in the group and control group. At baseline and at follow-up, there were no significant differences in behavioral problems between the low FODMAP diet group and the control group. Randomized controlled studies including larger sample sizes are needed to confirm the effects of low FODMAP diets in children with autism who have gastrointestinal problems. [ABSTRACT FROM AUTHOR]