Search

AbstractThis review, part of a special issue on drug-drug interactions (DDIs) spearheaded by the International Society for the Study of Xenobiotics (ISSX) New Investigators, explores the critical role of drug transporters in absorption, disposition, and clearance in the context of DDIs. Over the past two decades, significant advances have been made in understanding the clinical relevance of these transporters. Current knowledge on key uptake and efflux transporters that affect drug disposition and development is summarized. Regulatory guidelines from the FDA, EMA, and PMDA that inform the evaluation of potential transporter-mediated DDIs are discussed in detail. Methodologies for preclinical and clinical testing to assess potential DDIs are reviewed, with an emphasis on the utility of physiologically based pharmacokinetic (PBPK) modeling. This includes the application of relative abundance and expression factors to predict human pharmacokinetics (PK) using preclinical data, integrating the latest regulatory guidelines. Considerations for assessing transporter-mediated DDIs in special populations, including pediatric, hepatic, and renal impairment groups, are provided. Additionally, the impact of transporters at the blood-brain barrier (BBB) on the disposition of CNS-related drugs is explored. Enhancing the understanding of drug transporters and their role in drug disposition and toxicity can improve efficacy and reduce adverse effects. Continued research is essential to bridge remaining gaps in knowledge, particularly in comparison with cytochrome P450 (CYP) enzymes. [ABSTRACT FROM AUTHOR]

Although the public portrays individuals with paedophilia as adult men, research indicates that the onset of paedophilia develops earlier (around the teenage years). The purpose of this qualitative study was to analyse public attitudes toward teenagers with paedophilia and gauge the support for preventative programs and psychological treatment. We conducted a content analysis of online posts describing community attitudes toward teenagers with paedophilia and identified four categories: rejection, distortions, pity, and responsiveness (comprised of three subcategories – acknowledgement, therapy and professional help, and public awareness). We identified that the public not only rejects adults but also youth with paedophilia. However, the responsiveness category showed that part of the public believes that (1) the attraction is unwanted for many teenagers with paedophilia, (2) these youth should have the opportunity to receive psychological treatment to control their urges, and (3) preventative programs should be established. Clinical and social implications are examined. This study offers insight into public reactions toward teenagers with paedophilia which can influence public policy and availability of services (i.e. psychological treatment). It also discusses clinical factors and considerations for practices serving this population. [ABSTRACT FROM AUTHOR]

Background: The Adult Changes in Thought (ACT) study is a cohort of Kaiser Permanente Washington members ages 65+ that began in 1994. Objective: We wanted to know how well ACT participants represented all older adults in the region, and how well ACT findings on eye disease and its relationship with Alzheimer's disease generalized to all older adults in the Seattle Metropolitan Region. Methods: We used participation weights derived from pooling ACT and Behavioral Risk Factor Surveillance System (BRFSS) data to estimate prevalences of common eye diseases and their associations with Alzheimer's disease incidence. Cox proportional hazards models accounted for age, education, smoking, sex, and APOE genotype. Confidence intervals for weighted analyses were bootstrapped to account for error in estimating the weights. Results: ACT participants were fairly similar to older adults in the region. The largest differences were more self-reported current cholesterol medication use in BRFSS and higher proportions with low education in ACT. Incorporating the weights had little impact on prevalence estimates for age-related macular degeneration or glaucoma. Weighted estimates were slightly higher for diabetic retinopathy (weighted 5.7% (95% Confidence Interval 4.3, 7.1); unweighted 4.1% (3.6, 4.6)) and cataract history (weighted 51.8% (49.6, 54.3); unweighted 48.6% (47.3, 49.9)). The weighted hazard ratio for recent diabetic retinopathy diagnosis and Alzheimer's disease was 1.84 (0.34, 4.29), versus 1.32 (0.87, 2.00) in unweighted ACT. Conclusions: Most, but not all, associations were similar after participation weighting. Even in community-based cohorts, extending inferences to broader populations may benefit from evaluation with participation weights. [ABSTRACT FROM AUTHOR]

Feedback and evaluation from peers is fundamental to trainees' professional development but may be uncomfortable to provide non-anonymously. We aimed to understand resident perception of anonymous and open written evaluation systems and to analyze evaluations in each of these systems. We compared two years of intern peer evaluations at a large United States-based pediatric residency program – the 2018-2019 and 2019-2020 years during which intern peer evaluations were anonymous and open, respectively. We electronically surveyed interns about their perceptions of peer evaluations and analyzed four aspects of the evaluations themselves: (1) orientation, (2) caliber, (3) Likert-scale, and (4) word count. 40 (78%) and 38 (75%) interns participated in the survey in the anonymous and open years, respectively. Respondents reported being more likely to avoid writing constructive comments in the open year. There were more high caliber comments in the open year. Likert-scale ratings of peers were lower in the open year. Word count was longer in the open year. While interns expressed more discomfort evaluating peers in an open evaluation system, they wrote longer and more high caliber comments in an open system than in an anonymous system. Residency programs should consider professional development in writing peer evaluation. [ABSTRACT FROM AUTHOR]

Objective: To compare preterm birth rates and reasons before and during the COVID‐19‐pandemic using a monocentric, retrospective study. Methods: Univariate analysis identified differences in rates and reasons for preterm birth and neonatal outcomes between the pre‐pandemic period (January 1, 2018 to December 31, 2019) and during the pandemic (January 1, 2020 to December 31, 2021) among all births at our tertiary obstetrical center, the University Hospital of Essen. Results: The cohort consisted of 6086 deliveries with 593 liveborn preterm singletons. During the pandemic, the incidence of preterm birth decreased (10.7% vs. 8.6%; odds ratio [OR] 0.79; 95% confidence interval [CI] 0.66–0.93). Spontaneous preterm birth (43.2% vs. 52.3%; OR 1.47; 95% CI 1.05–2.03), and placenta accreta spectrum disorder (3.7% vs. 8.2%; OR 2.36; 95% CI 1.15–4.84) were more common reasons for preterm birth. Placental dysfunction was a less common reason (34.1% vs. 24.3%; OR 0.62; 95% CI 0.43–0.90). Incidences of preterm premature rupture of membranes (28.13% vs. 40.25%; OR 1.72; 95% CI 1.12–2.43) and oligo−/anhydramnios (3.98% vs. 7.88%; OR 2.06; 95% CI 1.02–4.21) increased. Iatrogenic preterm birth decreased (54.5% vs. 49.5%; OR 0.81; 95% CI 0.58–1.13). Stillbirth rates did not change significantly. Among term births, there were fewer spontaneous deliveries (71.0% vs. 65.8%; OR 0.78; 95% CI 0.69–0.88), and more elective (12.3% vs. 15.1%; OR 1.26; 95% CI 1.07–1.50) and unplanned (9.3% vs. 10.9%; OR 1.19; 95% CI 0.98–1.45) cesarean sections. During the pandemic, more term newborns were admitted to neonatal intensive care (1.4% vs. 2.5%; OR 1.86; 95% CI 1.20–2.88). Conclusion: Our results, in line with data from other high‐income countries, suggest that the likely reason for the decreased preterm birth rates is the underdiagnosis of pregnancy complications. Synopsis: The decrease in preterm births in high‐income countries during the COVID‐19 pandemic resulted most likely from underdiagnosed pregnancy complications. [ABSTRACT FROM AUTHOR]

Background: Adolescent Idiopathic Scoliosis (AIS) affects 2%–4% of the general pediatric population. While surgical correction remains one of the most common orthopedic procedures performed in pediatrics, limited consensus exists on the perioperative anesthetic management. Aims: To examine the current state of anesthetic management of typical AIS spine fusions at institutions which have a dedicated pediatric orthopedic spine surgeon. Methods: A web‐based survey was sent to all members of the North American Pediatric Spine Anesthesiologists (NAPSA) Collaborative. This group included 34 anesthesiologists at 19 different institutions, each of whom has a Harms Study Group surgeon performing spine fusions at their hospital. Results: Thirty‐one of 34 (91.2%) anesthesiologists completed the survey, with a missing response rate from 0% to 16.1% depending on the question. Most anesthesia practices (77.4%; 95% confidence interval [CI], 67.7–93.4) do not have patients come for a preoperative visit prior to the day of surgery. Intravenous induction was the preferred method (74.2%; 95% CI 61.3–89.9), with the majority utilizing two peripheral IVs (93.5%; 95% CI 90.3–100) and an arterial line (100%; 95% CI 88.8–100). Paralytic administration for intubation and/or exposure was divided (51.6% rocuronium/vecuronium, 45.2% no paralytic, and 3.2% succinylcholine) amongst respondents. While tranexamic acid was consistently utilized for reducing blood loss, dosing regimens varied. When faced with neuromonitoring signal issues, 67.7% employ a formal protocol. Most anesthesiologists (93.5%; 95% CI 78.6–99.2) extubate immediately postoperatively with patients admitted to an inpatient floor bed (77.4%; 95% CI 67.7–93.3). Conclusion: Most anesthesiologists (87.1%; 95% CI 80.6–99.9) report the use of some form of an anesthesia‐based protocol for AIS fusions, but our survey results show there is considerable variation in all aspects of perioperative care. Areas of agreement on management comprise the typical vascular access required, utilization of tranexamic acid, immediate extubation, and disposition to a floor bed. By recognizing the diversity of anesthetic care, we can develop areas of research and improve the perioperative management of AIS. [ABSTRACT FROM AUTHOR]

Young people with special educational needs (SEN), such as intellectual disability and/or autism, are particularly vulnerable to child sexual exploitation and abuse (CSEA). This mixed-methods systematic literature review consolidates findings in respect to how young people with SEN are currently being taught about CSEA in the UK, incorporating empirical and practice-based findings to counteract publication bias. Key databases were searched, and relevant organizations were contacted regarding studies published between 2015 and 2022 (inclusive). Thirteen articles met the inclusion criteria. Of these, 10 adopted a qualitative methodology, and three a mixed-methods approach. The thematic synthesis of the qualitative studies identified the following themes: (a) beliefs and stereotypes about CSEA, vulnerability. and risk have led to young people with SEN being misinformed and misunderstood, and (b) anxiety about the topic of sex and abuse creates polarized views regarding CSEA education in adult guardians of young people with SEN. Themes are discussed in the context of societal biases in respect to vulnerability and risk, and these biases are considered to have a negative effect on how young people with SEN are supported. The findings of this review encourage providers of CSEA awareness education to be mindful of not endorsing harmful stereotypes, and to involve parent–carers as much as possible. This review additionally encourages services and organizations to increase focus on practitioner reflexivity and regular training to counteract potential biases in respect to gender, vulnerability, and risk. [ABSTRACT FROM AUTHOR]

Background: The prevalence of metabolic syndrome (MetS) in American adults increased from 37.6% in the 2011–12 period to 41.8% in 2017–2018. Environmental exposure, particularly to common compounds such as glyphosate, has drawn increasing attention as a potential risk factor. Methods: We employed three cycles of data (2013–2018) from the National Health and Nutrition Examination Survey (NHANES) in a cross-sectional study to examine potential associations between urine glyphosate measurements and MetS incidence. We first created a MetS score using exploratory factor analysis (EFA) of the International Diabetes Federation (IDF) criteria for MetS, with data drawn from the 2013–2018 NHANES cycles, and validated this score independently on an additional associated metric, the albumin-to-creatinine (ACR) ratio. The score was validated via a machine learning approach in predicting the ACR score via binary classification and then used in multivariable regression to test the association between quartile-categorized glyphosate exposure and the MetS score. Results: In adjusted multivariable regressions, regressions between quartile-categorized glyphosate exposure and MetS score showed a significant inverted U-shaped or saturating dose‒response profile, often with the largest effect for exposures in quartile 3. Exploration of potential effect modification by sex, race, and age category revealed significant differences by race and age, with older people (aged > 65 years) and non-Hispanic African American participants showing larger effect sizes for all exposure quartiles. Conclusions: We found that urinary glyphosate concentration is significantly associated with a statistical score designed to predict MetS status and that dose–response coefficient is nonlinear, with advanced age and non-Hispanic African American, Mexican American and other Hispanic participants exhibiting greater effect sizes. [ABSTRACT FROM AUTHOR]

Mule deer (Odocoileus hemionus) are important economically, culturally, and recreationally to the Pueblo of Santa Ana in central New Mexico, USA. Studies of habitat selection improve our understanding of mule deer ecology in central New Mexico and provide the Tribe with valuable information for management of mule deer. We used global positioning system telemetry‐collar data collected on mule deer around the Pueblo of Santa Ana to create resource selection functions from proximity‐based habitat predictors using a generalized linear mixed model. We created separate resource selection functions for females and males during summer and winter at different times of the day. Season generally had a greater effect on mule deer habitat use than the time of day. Female and male mule deer selected for similar habitats but were sexually segregated in their summer distributions. These findings are consistent with results from other locations where mule deer partitioned habitat similarly between seasons and sexes. Supported models reaffirm accepted patterns of habitat selection for mule deer to the Pueblo of Santa Ana where local results were lacking. Our results can help managers identify locations in and around the Pueblo of Santa Ana where future development such as highway expansion are likely to conflict with mule deer activity and locations where habitat enhancement projects such as adding water sources can have the greatest effect for the deer population. [ABSTRACT FROM AUTHOR]

Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in 3 independent mouse models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments—a nonperceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1)-mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment and define a nondevelopmental source of such deficits in ASD. Autism has diverse genetic origins which converge on a similar set of behaviors. This study shows that 3 genetic models of autism have similar impairments in visual threat responses, and that these are driven by potassium channel misregulation in Setd5 haploinsufficient mice. [ABSTRACT FROM AUTHOR]

Simple Summary: In the southeastern United States of America, shifts in the environment such as climate change and host availability are pushing tick populations to spread into new areas. It is hypothesized that, as they migrate, tick populations have developed a behavior known as incomplete feeding. With this, ticks feed on more than one host at each life stage, increasing the chance of pathogen transmission. In South Carolina, we found evidence of ticks displaying this behavior. We collected engorged female ticks from stray dogs at animal shelters across the state in 2022. Testing showed that about a third of these ticks had fed on humans. The patterns varied depending on the tick species, where they were found, and the time of collection. This pilot study reflects the growing trend of tick-borne diseases in the southeastern USA. It is crucial to dig deeper into how factors like the season, location, and species are linked to incomplete feeding behavior in South Carolina's tick populations. Dynamic environmental conditions, such as climate change and host availability, have greatly influenced the expansion of medically relevant tick vectors into new regions throughout the southeastern United States of America. As tick populations migrate into new areas, it has been suggested they can exhibit a phenomenon known as incomplete feeding. With this phenomenon, tick vectors feed on more than one host at each life stage, thus increasing the likelihood of pathogen transmission. Although this behavior is not well understood, it presents an important threat to human health. Here we present evidence of incomplete feeding behaviors in multiple tick species in South Carolina. Engorged, blood-fed female ticks were collected from feral dogs at animal shelters across South Carolina in 2022. All ticks were tested for human blood meals using rapid stain identification blood tests. Approximately one third (33.78%) of all ticks tested positive for a human blood meal, with various patterns seen across species, geographic location, and collection month. The results of this pilot study follow the current national trend of increasing rates of tick-borne disease incidence in the southeastern United States of America and warrant further investigation into the relationship between seasonality, geographic distribution, species, and incomplete feeding among tick populations in South Carolina. [ABSTRACT FROM AUTHOR]

Background Insulin is a mainstay of treatment in diabetic ketoacidosis (DKA) however controversy remains over the optimal dose and administration. An initial bolus dose of insulin prior to a continuous infusion is utilized despite a lack of data showing clinical benefit and potential for complications. Objective This study was designed to evaluate the safety and efficacy of an initial insulin bolus in the treatment of DKA. Methods A retrospective chart review of patients with DKA was conducted. Fifty-nine patients met inclusion for the bolus group and 108 in the no-bolus group. The primary outcome was a composite of interruption of insulin infusion, hypoglycemia (BG <70 mg/dL), or hypokalemia (K+ <3.4 mEq/L) occurring within eight hours of starting insulin. Secondary outcomes included time to discontinuation of insulin infusion, as well as time to discharge from the ICU and the hospital. Results Baseline characteristics were similar between groups. The majority of patients were classified as having mild DKA. The primary outcome occurred significantly more frequently in the bolus group (45.8% vs 25%, P =.003) which was primarily driven by incidence of hypokalemia. Time to anion gap closure (6:39 vs 9:00, P =.063) was shorter with a bolus, although not significantly so. This finding carried forward to non-significant differences in time to stopping insulin infusion as well as ICU and hospital discharge. Conclusion An insulin bolus prior to initiation of an insulin infusion was associated with significantly more adverse effects early in therapy without a corresponding benefit in time to resolution of DKA. [ABSTRACT FROM AUTHOR]

In the face of growing critiques, charter management organizations (CMOs) increasingly contend with criticism as they maintain their presence in districts, particularly with school board members who often serve as gatekeepers for charter authorization. Yet, little is known about how CMOs navigate these politically muddy waters in local settings. The localized political maneuvers of CMOs are the central focus of this case study, which demonstrates how CMOs in one city deployed strategic discourse to buffer anticipated critiques and assuage concerns though questions as to the equitable and democratic character of their actions and rhetoric remain. [ABSTRACT FROM AUTHOR]

Background Older men frequently develop lower urinary tract symptoms attributed to benign prostatic hyperplasia (LUTS/BPH). Risk factors for LUTS/BPH include sedentary lifestyle, anxiety/depression, obesity, and frailty, which all increase with age. Although physical exercise may reduce the progression and/or severity of LUTS/BPH, the age-related mechanisms responsible remain unknown. Methods Voiding symptoms, body mass, and frailty were assessed after 4-weeks of voluntary wheel running in 2-month (n  = 10) and 24-month (n  = 8) old C57Bl/6J male mice. In addition, various social and individual behaviors were examined in these cohorts. Finally, cellular and molecular markers of inflammation and mitochondrial protein expression were assessed in prostate tissue and systemically. Results Despite running less (aged vs young X ¯ = 12.3 vs 30.6 km/week; p  = .04), aged mice had reduced voiding symptoms (⁠ X ¯ = 67.3 vs 23.7; p  < .0001) after 1 week of exercise, which was sustained through week 4 (⁠ X ¯ = 67.3 vs 21.5; p  < .0001). Exercise did not affect voiding symptoms in young mice. Exercise also increased mobility and decreased anxiety in both young and aged mice (p  < .05). Exercise decreased expression of a key mitochondrial protein (PINK1; p  < .05) and inflammation within the prostate (CD68; p  < .05 and plasminogen activator inhibitor-1; p  < .05) and in the serum (p  < .05). However, a frailty index (⁠ X ¯ = 0.17 vs 0.15; p  = .46) and grip strength (⁠ X ¯ = 1.10 vs 1.19; p  = .24) were unchanged after 4 weeks of exercise in aged mice. Conclusions Voluntary aerobic exercise improves voiding behavior and mobility, and decreases prostatic mitochondrial protein expression and inflammation in aged mice. This promising model could be used to evaluate molecular mechanisms of aerobic exercise as a novel lifestyle intervention for older men with LUTS/BPH. [ABSTRACT FROM AUTHOR]

Introduction: High‐quality health systems rely on care that centers on patient preferences. Realization of patient preferences can improve the birth experience. However, in the dynamic setting of birth, birth preferences can diverge from what is medically indicated. Through studying women and birthing peoples' experiences of unplanned labor procedures, we aimed to identify ways in which practitioners can support women and birthing people through unexpected or unwanted aspects of their delivery. Specifically, we focused on labor induction. Methods: In one large US academic center, women and birthing people participated in prenatal and postpartum surveys regarding their desires, expectations, and experiences of labor induction. From April to November 2021, participants were eligible if they showed discordance between having labor induction and whether it was initially wanted or expected. Interviews focused on attitudes toward birth preferences and outcomes, with attention to discordances. We analyzed interviews through a modified grounded theory approach. Results: Of 22 participants, our sample was predominantly white (91%). Participants in this sample reported discordance between wanting and experiencing (73%) and/or expecting and experiencing (54%) an induction. We identified two themes: "Discordance without mitigation is perceived as a negative experience" and "Practitioner interaction can buffer against negative experience" which includes three ways in which participants prefer support in instances of discordance: preparation, communication, and care and comfort. These methods of support foster patient autonomy and can lead to positive patient experiences. Conclusions: While medical systems should work to support patient preferences, our results suggest that patients can still have positive birth experiences, even when preferences are not fulfilled. Early practitioner preparation, positive communication, and responsive care and comfort may help to improve patient birth experience when challenges arise. [ABSTRACT FROM AUTHOR]

Health represents the dynamic balance of physical, mental, social, and existential well‐being in adapting to conditions of life and the environment. Health is essential for the quality of life (QoL) of all individuals, including those with intellectual disability (ID). People with ID experience health inequities and barriers to quality health care that must be addressed to foster the QoL of this population. This paper illustrates how poor health negatively impacts each of the eight domains of the QoL model proposed by Shalock and Verdugo (2002) (e.g., health conditions limit work performance, decreasing opportunities for personal development and self‐determination). Suggestions for healthcare practices and behaviors that would improve the quality of healthcare provided to people with ID, and thus their health and QoL, are offered (e.g., engaging people with ID in the medical conversation, talking to them in plain language and without jargon enhances the personal development, self‐determination, interpersonal relationships, and social inclusion domains of QoL). Finally, we suggest actions that people with ID and their families might implement to maximize their health and wellness (e.g., maintaining a healthy lifestyle, and using the health promotion resources provided by disability organizations). [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) is the leading cause of preventable death in hospitalized patients. Artificial intelligence (AI) and machine learning (ML) can support guidelines recommending an individualized approach to risk assessment and prophylaxis. We conducted electronic surveys asking clinician and healthcare informaticians about their perspectives on AI/ML for VTE prevention and management. Of 101 respondents to the informatician survey, most were 40 years or older, male, clinicians and data scientists, and had performed research on AI/ML. Of the 607 US-based respondents to the clinician survey, most were 40 years or younger, female, physicians, and had never used AI to inform clinical practice. Most informaticians agreed that AI/ML can be used to manage VTE (56.0%). Over one-third were concerned that clinicians would not use the technology (38.9%), but the majority of clinicians believed that AI/ML probably or definitely can help with VTE prevention (70.1%). The most common concern in both groups was a perceived lack of transparency (informaticians 54.4%; clinicians 25.4%). These two surveys revealed that key stakeholders are interested in AI/ML for VTE prevention and management, and identified potential barriers to address prior to implementation. [ABSTRACT FROM AUTHOR]

The problem of gender discrimination and sexual harassment in medicine is long-standing and widespread. This project aims to document and understand how gendered experiences encountered by final-year medical students in Switzerland are experienced by these individuals and how they influence their career choice. It also aims to identify representations and stereotypes linked to the different specialties. The project will take place at all Swiss universities offering a master's degree in human medicine, for a total of 9 programs. Around 36 participants will be recruited. Semi-structured qualitative individual interviews will be conducted. Analysis will be based on Grounded Theory principles. [ABSTRACT FROM AUTHOR]

Brain metastatic breast cancer is particularly lethal largely due to therapeutic resistance. Almost half of the patients with metastatic HER2-positive breast cancer develop brain metastases, representing a major clinical challenge. We previously described that cancer-associated fibroblasts are an important source of resistance in primary tumors. Here, we report that breast cancer brain metastasis stromal cell interactions in 3D cocultures induce therapeutic resistance to HER2-targeting agents, particularly to the small molecule inhibitor of HER2/EGFR neratinib. We investigated the underlying mechanisms using a synthetic Notch reporter system enabling the sorting of cancer cells that directly interact with stromal cells. We identified mucins and bulky glycoprotein synthesis as top-up-regulated genes and pathways by comparing the gene expression and chromatin profiles of stroma-contact and no-contact cancer cells before and after neratinib treatment. Glycoprotein gene signatures were also enriched in human brain metastases compared to primary tumors. We confirmed increased glycocalyx surrounding cocultures by immunofluorescence and showed that mucinase treatment increased sensitivity to neratinib by enabling a more efficient inhibition of EGFR/HER2 signaling in cancer cells. Overexpression of truncated MUC1 lacking the intracellular domain as a model of increased glycocalyx-induced resistance to neratinib both in cell culture and in experimental brain metastases in immunodeficient mice. Our results highlight the importance of glycoproteins as a resistance mechanism to HER2-targeting therapies in breast cancer brain metastases. [ABSTRACT FROM AUTHOR]

Flowering plants contain tightly controlled pollen–pistil interactions required for promoting intraspecific fertilization and preventing interspecific hybridizations. In Arabidopsis (Arabidopsis thaliana), several receptor kinases (RKs) are known to regulate the later stages of intraspecific pollen tube growth and ovular reception in the pistil, but less is known about RK regulation of the earlier stages. The Arabidopsis RECEPTOR-LIKE KINASE IN FLOWERS1 (RKF1)/RKF1-LIKE (RKFL) 1-3 cluster of 4 leucine-rich repeat malectin (LRR-MAL) RKs was previously found to function in the stigma to promote intraspecific pollen hydration. In this study, we tested additional combinations of up to 7 Arabidopsis LRR-MAL RK knockout mutants, including RKF1, RKFL1-3, LysM RLK1-INTERACTING KINASE1, REMORIN-INTERACTING RECEPTOR1, and NEMATODE-INDUCED LRR-RLK2. These LRR-MAL RKs were discovered to function in the female stigma to support intraspecific Arabidopsis pollen tube growth and to establish a prezygotic interspecific barrier against Capsella rubella pollen. Thus, this study uncovered additional biological functions for this poorly understood group of RKs in regulating the early stages of Arabidopsis sexual reproduction. Arabidopsis leucine-rich repeat malectin receptor–like kinases function in the stigma to promote self-pollen and block interspecies pollen. [ABSTRACT FROM AUTHOR]

Context: Reliable seed production is a key requirement for successful year-on-year regeneration of annual pasture legumes. Aims: The study aims were to investigate the developmental patterns of flowers and pods and the effect on seed number among cultivars of French (Ornithopus sativus Brot.) and yellow serradella (O. compressus L.); and to assess the effects of early flower loss. Methods: Four cultivars of each species were grown in a glasshouse under non-limiting growth conditions. Date of flowering and numbers of flowers, pods and seeds were assessed for up to 20 reproductive nodes on two stem axes per plant (n = 5 plants). A flower removal treatment was imposed to assess whether early flower loss affected flower and/or pod production. Key results: Flowering in the serradellas was indeterminate, but for all cultivars there was a peak period of flower and pod production, with the timing and duration of the peak period differing among cultivars. Peak flowering occurred primarily because the proportion of plants flowering began to decline, but the number of flowers per reproductive node and the number of pods formed per node also declined with time. Compensation for early flower loss was observed for most cultivars because of a longer duration of pod formation and/or greater numbers of pods developed on higher reproductive nodes. Conclusions: This study demonstrated that there is diversity in the patterns of flowering and podding and number of seeds initiated among serradellas. Implications: Diversity in flowering and podding patterns combined with a capacity to compensate for early flower loss may be used to develop serradellas better able to cope with environmental stressors (frost, drought, heat) experienced during the flowering window. To ensure the continued existence of annual legume species in temperate regions, it is essential to understand the factors contributing to successful seed production; for instance, certain cultivars of French and yellow serradella occasionally flower at suboptimal times, potentially leading to reduced seed production. This study uncovered differences in how these cultivars produce flowers, pods and seeds. Some showed the ability to adapt to early flower loss, suggesting that selective breeding could improve seed yield resilience. [ABSTRACT FROM AUTHOR]

Winchcombe is a CM chondrite that fell in England on February 28, 2021. Its rapid retrieval was well characterized. Within two polished sections of Winchcombe, terrestrial phases were observed. Calcite and calcium sulfates were found in a sample recovered from a field on March 6, 2021, and halite was observed on a sample months after its recovery from a driveway on March 2, 2021. These terrestrial phases were characterized by scanning electron microscopy, Raman spectroscopy, and transmission electron microscopy. Calcite veins crosscut the fusion crust and therefore postdate it. The calcite likely precipitated in the damp environment (sheep field) where the meteorite lay for six days prior to its retrieval. The sulfates occur on the edges of the sample and were identified as three minerals: gypsum, bassanite, and anhydrite. Given that the sulfates occur only on the sample's edges, including on top of the fusion crust, they formed after Winchcombe fell. Sulfate precipitation is attributed to the damp fall environment, likely resulted from sulfide‐derived H2S reacting with calcite within the meteorite. Halite occurs as euhedral crystals only on the surface of a polished section and exclusively in areas relatively enriched in sodium. It was likely produced by the interaction of the polished rock slice with the humid laboratory air over a period of months. The sulfates, fusion crust calcite, and halite all post‐date Winchcombe's entry into the Earth's atmosphere and showcase how rapidly meteorite falls can be terrestrially altered. [ABSTRACT FROM AUTHOR]

Family homeless shelters are critical contexts in which many young children develop; however, little is known about the developmental appropriateness of these settings, including their resources and the capacity of their staff to effectively meet the needs of the children and families they serve. The current study involves both quantitative and qualitative components to assess aspects of developmental appropriateness of US shelter spaces for children ages birth to 5 years, with an emphasis on staff knowledge, parenting programmes, and play spaces. Participants were 64 staff working in different family homeless shelters representing all 10 Housing and Urban Development regions. Data were collected via semistructured phone interviews. Results indicated that most shelters offered some type of parenting programme (65.5%) and had some developmentally appropriate space for families with young children (87.5%); however, the nature of these spaces and programmes varied considerably, with very few respondents describing use of evidence‐based practices. Findings on knowledge of early child development among shelter staff indicated substantial need for trainings on a range of topics, including typical child development, parent–child relationships, and impacts of trauma on families with young children. Furthermore, we identified a need for better measurement tools to assess knowledge of child development. [ABSTRACT FROM AUTHOR]

Successful treatment of ulcerative colitis (UC) is highly dependent on several parameters, including dosing regimen and the ability to deliver drugs to the disease site. In this study two strategies for delivering mesalazine (5-aminosalicylic acid, 5-ASA) to the colon were compared in an advanced in vitro model of the human gastrointestinal (GI) tract, the SHIME® system. Herein, a prodrug strategy employing bacteria-mediated drug release (sulfasalazine, Azulfidine®) was evaluated alongside a formulation strategy that utilised pH and bacteria-mediated release (5-ASA, Octasa® 1600 mg). SHIME® experiments were performed simulating both the GI physiology and colonic microbiota under healthy and inflammatory bowel disease (IBD) conditions, to study the impact of the disease state and ileal pH variability on colonic 5-ASA delivery. In addition, the effects of the products on the colonic microbiome were investigated by monitoring bacterial growth and metabolites. Results demonstrated that both the prodrug and formulation approaches resulted in a similar percentage of 5-ASA recovery under healthy conditions. On the contrary, during experiments simulating the GI physiology and microbiome of IBD patients (the target population) the formulation strategy resulted in a higher proportion of 5-ASA delivery to the colonic region as compared to the prodrug approach (P < 0.0001). Interestingly, the two products had distinct effects on the synthesis of key bacterial metabolites, such as lactate and short chain fatty acids, which varied according to disease state and ileal pH variability. Further, both 5-ASA and sulfasalazine significantly reduced the growth of the faecal microbiota sourced from six healthy humans. The findings support that the approach selected for colonic drug delivery could significantly influence the effectiveness of UC treatment, and highlight that drugs licensed for UC may differentially impact the growth and functioning of the colonic microbiota. [Display omitted] • The semi-dynamic SHIME® system modelled the GI tract in the healthy and IBD states. • Prodrug and formulation strategies for colonic 5-ASA delivery were compared. • The formulation strategy delivered a higher proportion of 5-ASA to the IBD colon. • The two IBD medications had distinct effects on gut microbiome metabolism. • 5-ASA and sulfasalazine reduced the growth of healthy gut microbiota. [ABSTRACT FROM AUTHOR]

The production of short chain fatty acids (SCFAs) by the colonic microbiome has numerous benefits for human health, including maintenance of epithelial barrier function, suppression of colitis, and protection against carcinogenesis. Despite the therapeutic potential, there is currently no optimal approach for elevating the colonic microbiome's synthesis of SCFAs. In this study, poly(D, l -lactide- co -glycolide) (PLGA) was investigated for this application, as it was hypothesised that the colonic microbiota would metabolise PLGA to its lactate monomers, which would promote the resident microbiota's synthesis of SCFAs. Two grades of spray dried PLGA, alongside a lactate bolus control, were screened in an advanced model of the human colon, known as the M-SHIME® system. Whilst the high molecular weight (Mw) grade of PLGA was stable in the presence of the microbiota sourced from three healthy humans, the low Mw PLGA (PLGA 2) was found to be metabolised. This microbial degradation led to sustained release of lactate over 48 h and increased concentrations of the SCFAs propionate and butyrate. Further, microbial synthesis of harmful ammonium was significantly reduced compared to untreated controls. Interestingly, both types of PLGA were found to influence the composition of the luminal and mucosal microbiota in a donor-specific manner. An in vitro model of an inflamed colonic epithelium also showed the polymer to affect the expression of pro- and anti-inflammatory markers, such as interleukins 8 and 10. The findings of this study reveal PLGA's sensitivity to enzymatic metabolism in the gut, which could be harnessed for therapeutic elevation of colonic SCFAs. [Display omitted] • PLGA is susceptible to metabolism by the human gut microbiome. • Digestion of PLGA with Mw 2000–2500 g/mol led to sustained lactate release. • Lactate from PLGA was converted to propionate and butyrate in a colonic model. • PLGA affected the abundance and composition of luminal and mucosal microbiota. • PLGA exerted donor-specific effects on intestinal epithelial cells. [ABSTRACT FROM AUTHOR]

Summary: This study deals with the results of the 2023 fieldwork at the extramural cemetery of the Late Bronze Age harbour city of Hala Sultan Tekke. One of the three excavated tombs in 2023 was the undisturbed Chamber Tomb XX, which is dated around 1300 BC. It contained a riveted bronze mirror, a rare type in Cyprus at that time, which is part of a mortuary context of four individuals out of a total of 17 individuals and 264 complete objects, many of them imported from a vast area, which includes the Mycenaean, Minoan, Egyptian and Levantine cultures. The current paper presents this mirror and associated contexts. As regards the provenance of the mirror, the Aegean is suggested as the area of manufacture, and more precisely Crete, suggesting potential evidence of direct contact between individuals from Crete and Hala Sultan Tekke. [ABSTRACT FROM AUTHOR]

The actin cytoskeleton performs multiple cellular functions, and as such, actin polymerization must be tightly regulated. We previously demonstrated that reversible, non-degradative ubiquitylation regulates the function of the actin polymerase VASP in developing neurons. However, the underlying mechanism of how ubiquitylation impacts VASP activity was unknown. Here, we show that mimicking multi-monoubiquitylation of VASP at K240 and K286 negatively regulates VASP interactions with actin. Using in vitro biochemical assays, we demonstrate the reduced ability of multimonoubiquitylated VASP to bind, bundle, and elongate actin filaments. However, multi-monoubiquitylated VASP maintained the ability to bind and protect barbed ends from capping protein. Finally, we demonstrate the electroporation of recombinant multimonoubiquitylated VASP protein altered cell spreading morphology. Collectively, these results suggest a mechanism in which ubiquitylation controls VASP-mediated actin dynamics. [ABSTRACT FROM AUTHOR]

Many mainstream organizations celebrate their historical successes. In their history, however, they often marginalized racial minorities, women, and other underrepresented groups. We suggest that when organizations celebrate their histories, even without mentioning historical marginalization, they can undermine belonging and intentions to join the organization among historically marginalized groups. Four experiments demonstrate that Black participants who were exposed to an organization that celebrated their history versus the present showed reduced belonging and intentions to participate in the organization. These effects were mediated by expectations of biased treatment in the organization. Further, when organizations had a history of Black people in power, celebrating history was no longer threatening, highlighting that the negative effects of celebrating history are most likely when organizations are or are assumed to be majority-White and have treated Black Americans poorly. Taken together, these findings suggest that emphasizing organizational history can be a source of social identity threat among Black Americans. [ABSTRACT FROM AUTHOR]

Host-directed therapies (HDTs) represent an emerging approach for bacterial clearance during tuberculosis (TB) infection. While most HDTs are designed and implemented for immuno-modulation, other host targets-such as nonimmune stromal components found in pulmonary granulomas-may prove equally viable. Building on our previous work characterizing and normalizing the aberrant granuloma-associated vasculature, here we demonstrate that FDA-approved therapies (bevacizumab and losartan, respectively) can be repurposed as HDTs to normalize blood vessels and extracellular matrix (ECM), improve drug delivery, and reduce bacterial loads in TB granulomas. Granulomas feature an overabundance of ECM and compressed blood vessels, both of which are effectively reduced by losartan treatment in the rabbit model of TB. Combining both HDTs promotes secretion of proinflammatory cytokines and improves anti-TB drug delivery. Finally, alone and in combination with second-line antitubercular agents (moxifloxacin or bedaquiline), these HDTs significantly reduce bacterial burden. RNA sequencing analysis of HDT-treated lung and granuloma tissues implicates up-regulated antimicrobial peptide and proinflammatory gene expression by ciliated epithelial airway cells as a putative mechanism of the observed antitubercular benefits in the absence of chemotherapy. These findings demonstrate that bevacizumab and losartan are well-tolerated stroma-targeting HDTs, normalize the granuloma microenvironment, and improve TB outcomes, providing the rationale to clinically test this combination in TB patients. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a life‐threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. This harsh treatment process causes adherence issues for patients because of the long treatment times and a myriad of adverse effects. Therefore, the World Health Organization has focused goals of shortening standard treatment regimens for TB in their End TB Strategy efforts, which aim to reduce TB‐related deaths by 95% by 2035. For this purpose, many novel and promising combination antibiotics are being explored that have recently been discovered, such as the bedaquiline, pretomanid, and linezolid (BPaL) regimen. As a result, testing the number of possible combinations with all possible novel regimens is beyond the limit of experimental resources. In this study, we present a unique framework that uses a primate granuloma modeling approach to screen many combination regimens that are currently under clinical and experimental exploration and assesses their efficacies to inform future studies. We tested well‐studied regimens such as HRZE and BPaL to evaluate the validity and accuracy of our framework. We also simulated additional promising combination regimens that have not been sufficiently studied clinically or experimentally, and we provide a pipeline for regimen ranking based on their efficacies in granulomas. Furthermore, we showed a correlation between simulation rankings and new marmoset data rankings, providing evidence for the credibility of our framework. This framework can be adapted to any TB regimen and can rank any number of single or combination regimens. [ABSTRACT FROM AUTHOR]

Background: This study investigated the relationship between sleep disturbance and somatic symptoms among adolescents residing on a psychiatric inpatient unit. Given the evidence that sleep disturbance may precede the onset of depression and anxiety and the clear associations between mood and somatic symptoms, depression and anxiety were considered as potential mediators of this relationship. Gender was tested as a potential moderator of the relationship between sleep disturbance and depression and anxiety, respectively. Method: A convenience sample of 83 adolescents completed a packet of self-report measures after admission to the unit. Measures assessed depression, sleep disturbance, anxiety, and somatic symptoms. Mediation and moderation analyses were conducted using SPSS PROCESS macro. Results: With anxiety included as a covariate, the overall indirect effect of sleep disturbance on somatic symptoms through depression was significant. No significant moderation effects were found, although females reported significantly higher levels of sleep disturbance, depression, anxiety, and somatic symptoms than males. Conclusions: Results indicated that depression mediated the relationship between sleep disturbance and somatic symptoms above and beyond the effects of anxiety. These findings suggest that interventions aimed at reducing the negative effects of sleep disturbance should also target mood in this population. Individual differences including gender should be considered when developing interventions. [ABSTRACT FROM AUTHOR]

Objective The purpose of this scoping review was to evaluate and characterize the scope of care for low back pain that falls under the specific label of manual therapy. Methods PubMed database, Ovid MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), and SPORTDiscus were searched from journal inception through May 2022 for randomized controlled trials that investigated the treatment of low back pain using manual therapy. Terminology used to define manual therapy was extracted and categorized by using only the words included in the description of the intervention. An expert consultation phase was undertaken to gather feedback. Results One hundred seventy-six trials met final inclusion criteria, and 169 unique terms labeled as manual therapy for the treatment of low back pain were found. The most frequent terms were mobilization (29.0%), manipulation (16.0%), and thrust (6.4%). Eight percent of trials did not define or specify what type of manual therapy was used in the study. After removing duplicates, 169 unique terms emerged within 18 categories. Conclusions Manual therapy intervention labels used in low back pain trials are highly variable. With such variation, the heterogeneity of the intervention in trials is likely large, and the likelihood that different trials are comparing the same interventions is low. Researchers should consider being more judicious with the use of the term manual therapy and provide greater detail in titles, methods, and supplementary appendices in order to improve clarity, clinical applicability, and usefulness of future research. Impact The ability to interpret and apply findings from manual therapy–related research for low back pain is challenging due to the heterogeneity of interventions under this umbrella term. A clear use of terminology and description of interventions by researchers will allow for improved understanding for the role of manual therapy in managing back pain. [ABSTRACT FROM AUTHOR]

Irritability, defined as proneness to anger that may impair an individual's functioning, is common in youths. There has been a recent upsurge in relevant research. The authors combine systematic and narrative review approaches to integrate the latest clinical and translational findings and provide suggestions for addressing research gaps. Clinicians and researchers should assess irritability routinely, and specific assessment tools are now available. Informant effects are prominent, are stable, and vary by age and gender. The prevalence of irritability is particularly high among individuals with attention deficit hyperactivity disorder, autism spectrum disorder, and mood and anxiety disorders. Irritability is associated with impairment and suicidality risk independent of co-occurring diagnoses. Developmental trajectories of irritability (which may begin early in life) have been identified and are differentially associated with clinical outcomes. Youth irritability is associated with increased risk of anxiety, depression, behavioral problems, and suicidality later in life. Irritability is moderately heritable, and genetic associations differ based on age and comorbid illnesses. Parent management training is effective for treating psychological problems related to irritability, but its efficacy in treating irritability should be tested rigorously, as should novel mechanism-informed interventions (e.g., those targeting exposure to frustration). Associations between irritability and suicidality and the impact of cultural context are important, underresearched topics. Analyses of large, diverse longitudinal samples that extend into adulthood are needed. Data from both animal and human research indicate that aberrant responses to frustration and threat are central to the pathophysiology of irritability, revealing important translational opportunities. [ABSTRACT FROM AUTHOR]

Weight discrimination has adverse effects on health that include increasing the risk factors for developing type 2 diabetes. Preliminary evidence suggests a positive association between weight discrimination and diagnosed diabetes; however, it is unknown whether psychosocial resources may buffer this association. In logistic regressions stratified by gender, we examined links between weight discrimination and diabetes among a nationally representative sample of U.S. adults (the National Social Life, Health, and Aging Project; N = 2,794 adults age 50 and older in 2015-16). We also tested the extent to which trait-resilience and social support from a spouse/partner, family, and friends buffered any observed association. We adjusted for known predictors of diabetes (age, race/ethnicity, Body Mass Index) and conducted sensitivity analyses restricted to men and women with obesity. Net of covariates, in the overall sample, weight discrimination was associated with significantly greater odds of having ever had diabetes among women (OR = 2.00, 95% CI [1.15, 3.47]), but not men. Among women with obesity, weight discrimination was only significantly associated with greater odds of diabetes for those with low resilience (OR = 1.84, 95% CI [1.01, 3.35]). Among men overall, weight discrimination was associated with lower odds of diabetes for those with high family support (OR = 0.03, 95% CI [0.003, 0.25]) as well as those with high friend support (OR = 0.34, 95% CI [0.13, 0.91]); similar effects were observed in men with obesity. These novel findings evince a role for psychosocial resources in buffering associations between weight discrimination and diabetes. [ABSTRACT FROM AUTHOR]

Stratospheric ozone, which has been depleted in recent decades by the release of anthropogenic gases, is critical for shielding the biosphere against ultraviolet‐B (UV‐B) radiation. Although the ozone layer is expected to recover before the end of the 21st century, a hole over Antarctica continues to appear each year. Ozone depletion usually peaks between September and October, when fortunately, most Antarctic terrestrial vegetation and soil biota is frozen, dormant and protected under snow cover. Similarly, much marine life is protected by sea ice cover. The ozone hole used to close before the onset of Antarctic summer, meaning that most biota were not exposed to severe springtime UV‐B fluxes. However, in recent years, ozone depletion has persisted into December, which marks the beginning of austral summer. Early summertime ozone depletion is concerning: high incident UV‐B radiation coincident with snowmelt and emergence of vegetation will mean biota is more exposed. The start of summer is also peak breeding season for many animals, thus extreme UV‐B exposure (UV index up to 14) may come at a vulnerable time in their life cycle. Climate change, including changing wind patterns and strength, and particularly declining sea ice, are likely to compound UV‐B exposure of Antarctic organisms, through earlier ice and snowmelt, heatwaves and droughts. Antarctic field research conducted decades ago tended to study UV impacts in isolation and more research that considers multiple climate impacts, and the true magnitude and timing of current UV increases is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Tamoxifen is prescribed to premenopausal patients with estrogen-receptor-positive breast cancers for a period of 5–10 years after cancer diagnosis. This prolonged treatment regimen, though effective at preventing cancer recurrence, is often associated with unwanted cognitive and affective symptoms. To understand the clinical side effects of tamoxifen, animal studies investigating the effect of tamoxifen on the brain must model the chronic nature of tamoxifen therapy. This study describes a novel method of tamoxifen administration in female rats conducive to long-term administration of tamoxifen. Blood samples from treated rats showed levels of tamoxifen similar to levels in humans. Brain samples revealed tamoxifen-induced changes of a neurotrophic factor in the hippocampus, a structure critical to cognitive and affective processing. This study, therefore, suggests a potential mechanism that may underlie the cognitive side effects reported in patients. Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography–tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients. [ABSTRACT FROM AUTHOR]

Nicotine and tobacco product (NTP) and cannabis use are common in adolescence/young adulthood and increase risk for negative psychosocial outcomes. This study investigated associations among adolescent/young adults' initial experiences with NTPs, lifetime frequency of substance use, substance-related problems, and mental health symptoms. Adolescents and young adults enrolled in a study on NTP and cannabis use were asked at what age they initiated the use of NTPs and were assigned to groups based on which product or substance(s) they reported using at the earliest age. Participants who reported use of NTPs (in isolation, without cannabis) first (N = 78, "NTP-only"), simultaneous use of NTPs and cannabis first (e.g., blunt or bowl; N = 25, "Simult-only"), use of both NTPs in isolation and simultaneous use at the same age (N = 48, "NTP + Simult"), and no NTP use (N = 53, "NTP-naïve") were compared on substance use, substance-related problems, and mental health symptoms. Groups differed on lifetime frequency of NTP, simultaneous, and cannabis use, with NTP users reporting more substance use episodes and substance-related problems than the NTP-naïve group. The lifetime frequency of cannabis use did not differ across NTP use groups. NTP use was associated with increased anxiety and depression, with no significant differences between groups. Adolescents and young adults who use nicotine may be at increased risk for greater nicotine use and mental health consequences, but initiating NTP use simultaneously with cannabis may not increase the risk of negative outcomes above and beyond nicotine initiation. Prospective longitudinal research is needed to establish temporal associations between first-used NTP/cannabis products and relevant outcomes. [ABSTRACT FROM AUTHOR]

AbstractIn this paper, the authors consider the intersections of philosophy and education. Extending the concept of a minor pedagogy first presented by Mazzei and Smithers (2020), the authors reorient thinking toward more equitable and just pedagogy as a cultivation of difference. This paper has three major sections. In the first two, the authors review Deleuze and Guattari’s (1986, 1987) concept of the minor, and then connect this to the concept of a minor pedagogy. The final section explores the work of a minor pedagogy as continuous variation with the potential to engender difference. Given that racialized neoliberal efficiency and accountability movements have perpetuated injustice across generations, the work of educational practice that contests this must be practice that slips from these major grips to produce new, more just, worlds. Minor pedagogy produces educational justice through everyday shifts in the conditions of our collective possibility, shifts that manifest difference in ways that reject re-form in the pursuit of the not yet. [ABSTRACT FROM AUTHOR]

Background A unique enzootic focus of Mycobacterium bovis in free-ranging deer was identified in northern lower Michigan in 1994, with subsequent evidence of transmission to local cattle herds. Between 2002 and 2017, 3 Michigan deer hunters with M. bovis disease were previously reported. We present 4 additional human cases linked to the zoonotic focus in deer, utilizing genomic epidemiology to confirm close molecular associations among human, deer and cattle M. bovis isolates. Methods Identification of human tuberculosis (TB) cases with cultures of M. bovis was provided from the Michigan Department of Health and Human Services (MDHHS) tuberculosis database. Clinical review and interviews focused on risk factors for contact with wildlife and cattle. Whole genome sequences of human isolates were compared with a veterinary library of M. bovis strains to identify those linked to the enzootic focus. Results Three confirmed and 1 probable human case with M. bovis disease were identified between 2019 and 2022, including cutaneous disease, 2 severe pulmonary disease cases, and human-to-human transmission. The 3 human isolates had 0–3 single-nucleotide polymorphisms (SNPs) with M. bovis strains circulating in wild deer and domestic cattle in Michigan. Conclusions Spillover of enzootic M. bovis from deer to humans and cattle continues to occur in Michigan. Future studies should examine the routes of transmission and degree of risk to humans through expanded epidemiological surveys. A One Health approach linking human, veterinary and environmental health should address screening for TB infection, public education, and mitigation of transmission. [ABSTRACT FROM AUTHOR]

Myeloid sarcoma (MS) is an extramedullary manifestation of acute myeloid leukemia (AML) and commonly occurs in sites such as the lymph nodes, skin, soft tissues, and bone. It more rarely manifests in the pancreas, with less than 20 cases reported in the literature since 1987. Despite its rarity, MS should be considered in the differential diagnosis of a soft tissue mass causing obstructive jaundice, especially if the patient has a known hematologic disease. Isolated cases of pancreatic MS have been known to progress to AML; therefore, it is crucial to differentiate MS from more common diagnoses, such as pancreatic cancer or pancreatitis. This is a case of a 70-year-old male with symptomatic obstructive jaundice secondary to pancreatic MS, ultimately requiring endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) for diagnosis and management. Also included is a comprehensive review of previous case reports with similar clinical presentations, management, and treatment of pancreatic MS. [ABSTRACT FROM AUTHOR]

Within the first billion years of Earth's history, the planet transformed from a hot, barren, and inhospitable landscape to an environment conducive to the emergence and persistence of life. This chapter will review the state of knowledge concerning early Earth's (Hadean/Eoarchean) geochemical environment, including the origin and composition of the planet's moon, crust, oceans, atmosphere, and organic content. It will also discuss abiotic geochemical cycling of the CHONPS elements and how these species could have been converted to biologically relevant building blocks, polymers, and chemical networks. Proposed environments for abiogenesis events are also described and evaluated. An understanding of the geochemical processes under which life may have emerged can better inform our assessment of the habitability of other worlds, the potential complexity that abiotic chemistry can achieve (which has implications for putative biosignatures), and the possibility for biochemistries that are vastly different from those on Earth. [ABSTRACT FROM AUTHOR]

The article focuses on the contentious issue of judicial review availability in administrative law, particularly examining recent debates in Medicare, immigration, and patent contexts. It provides insights into how Congress has expressly precluded review, revealing that at least 190 statutory provisions bar judicial review, with most targeting internal management decisions, while also discussing alternative oversight tools to balance efficient program implementation with democratic values.

This article describes how rights, the United Nations Sustainable Development Goals (SDGs), and the quality of life (QOL) framework are closely interrelated. Although legislation can be used as a tool for the practical application of QOL principles, QOL assessment information is required to further develop legislation and monitor the fulfillment of laws, policies, and the SDGs. A validated QOL model, which provides a set of concepts that can be one useful way for understanding and assessing QOL, can also function to assess many of the rights and goals promulgated in the Convention on the Rights of Persons with Disabilities (CRPD) and in the SDGs. This article illustrates the overlap between the CRPD, SDGs and QOL using the #Rights4MeToo Scale, a new measurement instrument for people with intellectual and developmental disabilities (IDD). The instrument's value lies in its potential to: (a) raise awareness about the rights enshrined in the CRPD; (b) design, implement, and evaluate the effectiveness of interventions aimed at facilitating the exercise of those rights and the achievement of the SDGs; and (c) ultimately improve the QOL of people with IDD. [ABSTRACT FROM AUTHOR]

Particulates emitted from the ocean's surface such as sea salt and byproducts of marine biogenic activity form atmospheric aerosols. Aerosols are important for climate change because they have offset some of the historical warming caused by greenhouse gases. Aerosols are also significant for human health: they are small enough to be inhaled and contribute to respiratory problems and other illnesses. Marine aerosol is the primary source of natural aerosol present in urban areas of Aotearoa New Zealand and, as part of the natural aerosol background, cannot be managed. Here, we review the production and presence of marine aerosols in New Zealand's air, and the implications for human health and climate change. Because marine aerosol is sensitive to physical changes in climate such as sea surface temperature and winds, production is likely to be affected by climate change. Overall, marine aerosol is unlikely to become a smaller contributor to urban atmospheric aerosol loading in New Zealand towns and cities under future climate change scenarios. Continued assessment of anthropogenic aerosols will be necessary to ensure that air quality targets are met. [ABSTRACT FROM AUTHOR]

Knee function is rarely measured objectively during functional tasks following total knee arthroplasty. Inertial measurement units (IMU) can measure knee kinematics and range of motion (ROM) during dynamic activities and offer an easy-to-use system for knee function assessment post total knee arthroplasty. However, IMU must be validated against gold standard three-dimensional optical motion capture systems (OMC) across a range of tasks if they are to see widespread uptake. We computed knee rotations and ROM from commercial IMU sensor measurements during walking, squatting, sit-to-stand, stair ascent, and stair descent in 21 patients one-year post total knee arthroplasty using two methods: direct computation using segment orientations (r_IMU), and an IMU-driven iCloud-based interactive lower limb model (m_IMU). This cross-sectional study compared computed knee angles and ROM to a gold-standard OMC and inverse kinematics method using Pearson's correlation coefficient (R) and root-mean-square-differences (RMSD). The r_IMU and m_IMU methods estimated sagittal plane knee angles with excellent correlation (>0.95) compared to OMC for walking, squatting, sit-to-stand, and stair-ascent, and very good correlation (>0.90) for stair descent. For squatting, sit-to-stand, and walking, the mean RMSD for r_IMU and m_IMU compared to OMC were <4 degrees, < 5 degrees, and <6 degrees, respectively but higher for stair ascent and descent (~12 degrees). Frontal and transverse plane knee kinematics estimated using r_IMU and m_IMU showed poor to moderate correlation compared to OMC. There were no differences in ROM measurements during squatting, sit-to-stand, and walking across the two methods. Thus, IMUs can measure sagittal plane knee angles and ROM with high accuracy for a variety of tasks and may be a useful in-clinic tool for objective assessment of knee function following total knee arthroplasty. [ABSTRACT FROM AUTHOR]

Observers experience visual biases in the area around handheld tools. These biases may occur when active use leads an observer to incorporate a tool into the body schema. However, the visual salience of a handheld tool may instead create an attentional prioritization that is not reliant on body-based representations. We investigated these competing explanations of near-tool visual biases in two experiments during which participants performed a target detection task. Targets could appear near or far from a tool positioned next to a display. In Experiment 1, participants showed facilitation in detecting targets that appeared near a simple handheld rake tool regardless of whether they first used the rake to retrieve objects, but participants who only viewed the tool without holding it were no faster to detect targets appearing near the rake than targets that appeared on the opposite side of the display. In a second experiment, participants who held a novel magnetic tool again showed a near-tool bias even when they refrained from using the tool. Taken together, these results suggest active use is unnecessary, but visual salience is not sufficient, to introduce visual biases in peri-tool space. [ABSTRACT FROM AUTHOR]

Background: In March 2020, when public health stay home orders began in order to halt the spread of COVID-19, child care as an industry was drastically and abruptly impacted. This public health emergency highlighted the weaknesses in the child care system in the United States. Objective: This study investigated the changes in operations cost, child enrollment and attendance, and state and federal support that occurred during the first year of the COVID-19 pandemic among both center-based and home-based child care programs. Methods: A total of 196 licensed centers and 283 home-based programs across Iowa participated in an online survey as a part of the 2020 Iowa Narrow Costs Analysis. This mixed method study utilizes qualitative analysis of response as well as descriptive statistics and pre- post comparison testing. Results: Analysis of qualitative and quantitative data revealed that the COVID-19 pandemic had a marked impact on child care enrollment, the operational cost of child care, the availability of child care, and a variety of other areas including staff workload and mental health. In many instances, participants shared that state and federal COVID-19 relief funds were critical. Conclusion: Although state and federal COVID-19 relief funds were critical for child care providers in Iowa during the pandemic, results suggest similar financial support will be necessary beyond the pandemic to sustain the workforce. Policy suggestions are made for how to continue to support the child care workforce in the future. [ABSTRACT FROM AUTHOR]

Premise: Understanding the factors that limit reproductive success is a key component of plant biology. Carnivorous plants rely on insects as both nutrient sources and pollinators, providing a unique system for studying the effects of both resource and pollen limitation on plant reproduction. Methods: We conducted a field experiment using wild‐growing Dionaea muscipula J. Ellis (Droseraceae) in which we manipulated prey and pollen in a factorial design and measured flower production, number of fruits, and number of seeds. Because understanding reproduction requires knowledge of a plant species' reproductive and pollination biology, we also examined the pollination system, per‐visit pollinator effectiveness, and pollen‐ovule (P/O) ratio of D. muscipula. Results: Plants that received supplemental prey produced more flowers than control plants. They also had a higher overall fitness estimate (number of flowers × fruit set (total fruits/total flowers) × seeds per fruit), although this benefit was significant only when prey supplementation occurred in the previous growing season. Neither pollen supplementation nor the interaction between pollen and prey supplementation significantly affected overall plant fitness. Conclusions: This study reinforces the reliance of D. muscipula on adequate prey capture for flower, fruit, and seed production and a mobile pollen vector for reproduction, indicating the importance of considering insects as part of an effective conservation management plan for this species. [ABSTRACT FROM AUTHOR]

Bobcats (Lynx rufus) are terrestrial mammals that also inhabit tree islands (i.e., topographically elevated patches of forested land) embedded in the subtropical Everglades wetlands, which serve as a dry refuge habitat during the wet season in this region of Florida, USA. The Comprehensive Everglades Restoration Plan seeks to restore Everglades water flow to pre‐drainage conditions, but little is known about how water levels or other landscape‐level factors may influence mammalian occurrence, such as bobcats, on the tree islands in this ecosystem. We used game camera records and occupancy modeling to test for effects of static habitat variables and dynamic hydrologic variables. We hypothesized that deep water levels would limit the accessibility of tree islands to bobcats; therefore, we predicted that bobcat occupancy would decline with higher water levels. We also tested for the effect of an expanding invasive snake (i.e., Burmese python [Python molarus bivittatus]) using output from a model constructed to predict density and spread of Burmese pythons across southern Florida. We hypothesized that increases in Burmese pythons on the landscape would influence the food resources of bobcats, resulting in reduced bobcat occupancy at higher predicted densities of pythons. We built detection histories using 1,855 bobcat images from game cameras set on 87 tree islands in an Everglades conservation area from 2005–2019. Bobcat occupancy was significantly diminished when predicted Burmese python densities exceeded approximately 3 Burmese pythons/km2. Bobcat occupancy probability also increased with tree‐island density around the focal tree island. Although water depth and hydroperiod surrounding tree islands appeared in our top 3 candidate models, the hydrologic variables had weak effects on bobcat occupancy. Our results suggest that while hydrologic dynamics may play a role, the invasive Burmese python has stronger influences on bobcat occupancy of tree islands in this Everglades conservation area. [ABSTRACT FROM AUTHOR]

The mosquito microbiome is critical for host development and plays a major role in many aspects of mosquito biology. While the microbiome is commonly dominated by a small number of genera, there is considerable variation in composition among mosquito species, life stages, and geography. How the host controls and is affected by this variation is unclear. Using microbiome transplant experiments, we asked whether there were differences in transcriptional responses when mosquitoes of different species were used as microbiome donors. We used microbiomes from four different donor species spanning the phylogenetic breadth of the Culicidae, collected either from the laboratory or the field. We found that when recipients received a microbiome from a donor reared in the laboratory, the response was remarkably similar regardless of donor species. However, when the donor had been collected from the field, many more genes were differentially expressed. We also found that while the transplant procedure did have some effect on the host transcriptome, this is likely to have had a limited effect on mosquito fitness. Overall, our results highlight the possibility that variation in mosquito microbiome communities is associated with variability in host–microbiome interactions and further demonstrate the utility of the microbiome transplantation technique for investigating host–microbe interactions in mosquitoes. [ABSTRACT FROM AUTHOR]