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Abstract Positive word of mouth in the form of recommendations and referrals is the most effective way to recruit new students. The purpose of this study was to determine how service quality, parental satisfaction, and brand trust affect the likelihood of parents recommending their child’s international school to family and friends and to test the mediating effect of parent satisfaction. The study developed a contextually relevant and reliable survey to measure the perception of 458 Generation X parents at The International School of Macao. Scale items from the literature were contextualized for education. Confirmatory factor analysis was used to confirm convergent and discriminant validity. Structural equation modeling was used to determine the relationships. It was found that parent satisfaction had the biggest influence on the likelihood of parents recommending their child’s international school by word of mouth. While the service quality that parents experience and the trust that they have in the school brand had an impact on satisfaction, it was found that parent satisfaction fully mediates the relationship between service quality and word of mouth as well as the relationship between brand trust and word of mouth. Schools must ensure that current parents are satisfied to cultivate positive word of mouth through recommendations and referrals to prospective parents. Previous studies have demonstrated the mediating role of satisfaction, but no significant studies have empirically tested the same in K-12 international contexts. The study contributes to the existing field of knowledge by providing support to the contention that satisfaction mediates the relationships between service quality, brand trust, and word of mouth.

Using a self-determination theory (SDT) framework, the aims of our study were to examine the perfectionism-exercise dependence relationships, and whether basic psychological needs and introjected regulation explained these relationships. Distance runners (n = 260, M age: = 42.41 years; SD: = 11.95 years, n = 144 female) completed measures of multidimensional perfectionism (self-oriented perfectionism (SOP); socially prescribed perfectionism (SPP)), basic psychological need satisfaction and thwarting, introjected regulation, and exercise dependence. Bivariate correlations revealed significant positive SOP-exercise dependence and SPP-exercise dependence relationships. Structural equation modelling suggested that, in combination, perfectionism, basic psychological need satisfaction/thwarting and introjected regulation accounted for large amounts of variance in exercise dependence. Tests of indirect effects showed that the SPP-exercise dependence relationship was mediated by basic psychological need thwarting and introjected regulation. Our findings suggest that while the SOP-exercise dependence relationship is more direct, need thwarting and introjected regulation represent a motivational signature of SPP and exercise dependence. [ABSTRACT FROM AUTHOR]

In set theory without the Axiom of Choice we prove that the assertion "For every metric space (X, d) with a Borel measure μ such that the measure of every open ball is positive and finite, (X, d) is separable.' is implied by the axiom of choice for countable collections of sets and implies the axiom of choice for countable collections of finite sets. We also show that neither implication is reversible in Zermelo–Fraenkel set theory weakend to permit the existence of atoms and that the second implication is not reversible in Zermelo–Fraenkel set theory. This gives an answer to a question of Dybowski and Górka (Arch Math Logic 62:735–749, 2023. https://doi.org/10.1007/s00153-023-00868-4). [ABSTRACT FROM AUTHOR]

Recent advances in Rosai-Dorfman-Destombes disease (RDD), notably molecular testing, targeted therapy, and PET-CT imaging, hold promise for better recognition and improved outcomes. This study presents patients diagnosed and treated in a "real world" setting, where navigating limited resources must be considered. This retrospective single-center review includes 15 adult patients diagnosed with RDD at Vancouver General Hospital between November 2015 and October 2023. The cohort comprised five males and ten females with a median age 53 years (range 19–80 years). All 15 patients had extra-nodal disease; 11 patients exclusively had extra-nodal disease, and four patients also had lymph node involvement. Seven patients had tissue next-generation sequencing, identifying MAP2K1 mutations in four cases and a KRAS p.K117N mutation in one case that was treated with targeted therapy using trametinib. PET-CT was used for disease staging in four cases. Six patients with refractory disease tolerated lenalidomide and dexamethasone without significant toxicity; three patients achieved complete response, and three had partial response. This study highlights RDD's diverse extra-nodal manifestations. Lenalidomide combined with dexamethasone is an effective and well-tolerated treatment option for select patients, especially those with refractory disease. Broad utilization of NGS and PET-CT can positively influence management decisions. [ABSTRACT FROM AUTHOR]

Microtubules are dynamic filaments that assemble spindles for eukaryotic cell division. As the concentration profiles of soluble tubulin and regulatory proteins are non-uniform during spindle assembly, we asked if diffusiophoresis - motion of particles under solute gradients - can act as a motorless transport mechanism for microtubules. We identify the migration of stable microtubules along cytoplasmic and higher concentration gradients of soluble tubulin, MgCl2, Mg-ATP, Mg-GTP, and RanGTP at speeds O(100) nm/s, validating the diffusiophoresis hypothesis. Using two buffers (BRB80 and CSF-XB), microtubule behavior under MgCl2 gradients is compared with negatively charged particles and analyzed with a multi-ion diffusiophoresis and diffusioosmosis model. Microtubule diffusiophoresis under gradients of tubulin and RanGTP is also compared with the charged particles and analyzed with a non-electrolyte diffusiophoresis model. Further, we find that tubulin and RanGTP display concentration dependent cross-diffusion that influences microtubule diffusiophoresis. Finally, using Xenopus laevis egg extract, we show that diffusiophoretic transport occurs in an active cytoplasmic environment. The authors show microtubule motion along concentration gradients of proteins and salts similar to those found in the cytoplasm. Based on their observations they propose diffusiophoresis as a potential motorless transport mechanism for cytoplasmic particles along intracellular solute gradients. [ABSTRACT FROM AUTHOR]

Germline genomic sequencing is increasingly integrated into pediatric cancer care, with pathogenic cancer-predisposing variants identified among 5–18% of affected children and variants of uncertain significance (VUS) in up to 70%. Given the potential medical implications for children and their families, parents' psychosocial responses to learning results are important to understand. Parents of children with cancer who learned their children's germline pathogenic or VUS results following paired tumor and germline genomic sequencing described their cognitive and affective responses to results in an open-ended write-in question after disclosure (M = 10 months post-disclosure; range = 1–28). Responses were coded and categorized using content analysis, then compared across results using chi-square and Fisher's exact test. Parents of children with pathogenic (n = 9), VUS (n = 52), and pathogenic plus VUS results (n = 9) described negative emotions, positive reactions, mixed emotions (i.e., positive and negative emotions), and neutral reactions. Negative emotions were described significantly more frequently with pathogenic results than VUS only (χ2 = 5.19; p =.02), with peace of mind and empowerment only described for those with VUS. Parents also described approach(es) to coping (e.g., faith, plan of action) and reactions specific to the uncertainty of VUS (e.g., disappointment at no explanation for cancer etiology). A subset with VUS described decreasing worry/distress with increased understanding of results, whereas others displayed misconceptions regarding VUS. Screening for emotional adjustment is warranted for parents of children with cancer receiving pathogenic germline results, and screening for understanding is warranted with VUS. Findings highlight the importance of pre-and posttest genetic counseling. [ABSTRACT FROM AUTHOR]

Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumour efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2–11.8) months (vs. 6 months in historical control, p = 0.018). The median overall survival was 16.5 (90% CI 9.8–17.5) months. Sixty-seven per cent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhoea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard-of-care therapy is warranted. Clinical trial registration: ClinicalTrials.gov NCT04109924. [ABSTRACT FROM AUTHOR]

People with HIV face challenges securing housing and employment. Patient navigation is an effective intervention that can improve the receipt of these services, which have been linked to better health outcomes. The purpose of this study was to assess implementation of patient navigation in diverse delivery settings. We also evaluated the relationship between these services and health outcomes among participants. Twelve sites in the United States (N = 1,082) implemented navigation using single or multiple navigator interventions to improve housing, employment, viral suppression, and retention in care. Sites included health departments, health centers, and AIDS service organizations (ASO). Client-level data were used to model relationships of interest. Across the 12 sites, regardless of model, housing (odds ratio (OR) = 1.18, p <.001), employment (OR = 1.09, p <.001) and retention in care (OR 1.11, p =.007) improved significantly over time; however, viral suppression did not (OR = 1.04, p =.120). Regardless of model of care, patient navigation improved housing, employment, and retention in care. This study demonstrated that while navigation supports people with HIV in securing housing and employment, models using a more intensive format worked best in specific settings. While most studies focus on unimodal strategies, this study builds on the evidence by examining how navigation models can be delivered to reduce barriers to care. [ABSTRACT FROM AUTHOR]

Background: Conventional advice to reduce the risk of breast cancer-related lymphedema (BCLE) suggests avoidance of daily-living risks, and limited research has investigated these risks. Objective: This study aimed to examine the occurrence, patterns, and effects of daily-living risks on BCLE. Methods: A cross-sectional design was used to collect data from 567 patients at a metropolitan cancer center in the United States. The Lymphedema Risk-Reduction Behavior Checklist was used to assess the occurrence of 11 daily-living risks. Descriptive, regression, and factor analyses were performed. Results: Significant odds of BCLE were associated with infection (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.95–3.42), cuts/scratches (OR 2.65, 95% CI 1.97–3.56), sunburn (OR 1.89, 95% CI 1.39–3.56), oil splash or steam burns (OR 2.08, 95% CI 1.53–3.83), and insect bites (OR 1.59, 95% CI 1.18–2.13). The daily-living risks were clustered into factors related to skin trauma and carrying objects. Skin trauma risk was significantly associated with BCLE (B = 0.539, z = 3.926, OR 1.714, 95% CI 1.312–2.250; p < 0.001). Having three, four, or five skin trauma risks significantly increased the odds of BCLE to 4.31, 5.14, and 6.94 times, respectively. The risk of carrying objects had no significant or incremental effects on BCLE. Conclusion: Complete avoidance of daily-living risks is challenging given 52.73% of patients incurred more than five daily-living risks. Our study findings underscore the importance of 'what to do' strategies to minimize infection and skin trauma. [ABSTRACT FROM AUTHOR]

This study was designed to increase our understanding about characteristics and the impact of sensory symptoms (SS) and signs of hyperarousal (HA) in individuals with fragile X syndrome (FXS) from childhood through early adulthood and by gender. Data derived from the Fragile X Online Registry With Accessible Research Database (FORWARD), a natural history study of FXS, were analyzed using descriptive statistics and multivariate linear and logistic regression models to examine SS and signs of HA, their impact on behavioral regulation and limitations on the subject/family. The sample (N = 933) consisted of 720 males and 213 females. More males were affected with SS (87% vs. 68%) and signs of HA (92% vs. 79%). Subjects who were endorsed as having a strong sensory response had more comorbidities, including behavioral problems. The predominant SS was difficulty with eye gaze that increased with age in both genders. As individuals age, there was less use of non-medication therapies, such as occupational therapy (OT)/physical therapy (PT), but there was more use of psychopharmacological medications and investigational drugs for behaviors. Multiple regression models suggested that endorsing SS and signs of HA was associated with statistically significantly increased ABC-C-I subscale scores and limited participation in everyday activities. This study improves our understanding of SS and signs of HA as well as their impact in FXS. It supports the need for more research regarding these clinical symptoms, especially to understand how they contribute to well-known behavioral concerns. [ABSTRACT FROM AUTHOR]

Tidal freshwater marshes (TFMs), found in the upper tidal reaches of river estuaries, are characterized by high diversity and productivity. These ecosystems are threatened by climate change, but unlike other coastal wetlands, there is a lack of information about the impact and their response to this threat. To understand the resilience of Jug Bay TFMs to sea level rise (SLR), surface elevation change was measured in low and mid-high marsh areas along primary and secondary channels. Elevation change exhibited significant temporal and spatial variability. A marked seasonality showed higher elevation during the growing season, and episodic storms altered elevation trajectories. Spatially, elevation change was significantly affected by channel category and marsh zone. Low marsh along primary channels lost elevation (−11.57 mm year−1), while the mid-high marsh gained elevation (+2.65 mm year−1). In secondary channels, both low (+11.29 mm year−1) and mid-high marshes (+5.43 mm year−1) gained elevation. A shoreline change analysis for the Patuxent and Western Branch rivers (2007–2018) showed change rates between −0.35 and −0.90 m year−1. A 2019 upland migration study indicated that most TFMs studied are not able to migrate due to steep slopes. Overall, marsh in more protected areas, along secondary channels, are more resilient, while low marsh in primary channels the most vulnerable to SLR. With low upland migration potential, studied marshes have to rely mainly on vertical elevation gain to keep up with SLR. If restoration is considered in this system, it should focus on the vulnerable low marsh zones along primary channels. [ABSTRACT FROM AUTHOR]

Coastal wetlands adapt to rising seas via feedbacks that build soil elevation, which lead to wetland stability. However, accelerated rates of sea-level rise can exceed soil elevation gain, leading to wetland instability and loss. Thus, there is a pressing need to better understand regional and landscape variability in rates of wetland soil elevation change. Here, we conducted a regional synthesis of surface elevation change data from mangrove forests and coastal marshes in the iconic Greater Everglades region of south Florida (USA). We integrated data from 51 sites in which a total of 122 surface elevation table-marker horizon (SET-MH) stations were installed. Several of these sites have been periodically monitored since the 1990s and are among the oldest SET-MH datasets in the world. Rates of surface elevation change ranged from −9.8 to 15.2 mm year−1, indicating some wetlands are keeping pace with sea-level rise while others are at risk of submergence and conversion to open water. Vertical accretion rates ranged from 0.6 to 12.9 mm year−1, and subsurface change rates ranged from −13.5 to 8.6 mm year−1. Rates of surface elevation change were positively related to subsurface change but not vertical accretion. There were no significant relationships between rates of surface elevation change and elevation (NAVD 88) or rates of sea-level rise. Site-specific examples indicate that hurricanes, plant productivity, hydrologic exchange, and proximity to sediment and nutrient inputs are critical but confounding drivers of surface elevation change dynamics in the Greater Everglades region. Collectively, our results reinforce the value of long-term SET-MH data that incorporate spatial variability for advancing understanding of surface elevation change dynamics in coastal wetlands. [ABSTRACT FROM AUTHOR]

The current exploratory study investigates self-reported perceptions of successful ageing, and preferences for information access and support, amongst sexually and gender diverse people living with HIV in Australia. Cross-sectional data, derived from a larger survey, were extracted for 12 participants who self-reported as living with HIV and completed questions pertaining to successful ageing and information/support preferences. Qualitative responses regarding successful ageing were explored through thematic analysis while descriptive statistics were used to analyse information/support preferences. Themes of (1) social factors, agency, and autonomy; (2) physical and mental wellbeing; and (3) considerations of care needs and information were generated from qualitative data about successful ageing. General practitioners (83.3%) and HIV support services (75.0%) were the most preferred sources of information about ageing and care supports. Findings from this exploratory study identify opportunities for policy improvements, provision of funding, and coordinated community support to enable sexually and gender diverse people living with HIV to experience successful ageing in Australia. [ABSTRACT FROM AUTHOR]

Social situations can present challenges for those looking to reduce or avoid eating meat. In an experimental vignette study with a large representative sample of 1,117 UK-based meat eaters, we explore affective responses to requests for vegetarian meals and perceptions of those making the request across four social situations: a BBQ, a pub, a restaurant dinner, and a dinner party. We examine moderators of these perceptions including whether the requester presents themselves as vegetarian or a meat restrictor and whether they cite health, environmental or no motives for their request. Overall, we find that these moderators have a greater impact on meat eaters' perceptions of the requester than on their affective responses to the request. We also find that these outcomes are more impacted by the mention of motives than they are diet type. Standout findings include evidence that people citing environmental motives for their vegetarian meal request are perceived more negatively, while those with health motives are perceived more positively. We also identify substantial heterogeneity across the respondents' levels of meat attachment: those who are more attached to meat have more negative perceptions of vegetarian meal requesters and experience higher negative affect and lower positive affect in response to the request. [ABSTRACT FROM AUTHOR]

Human mitochondrial tRNAs (mt-tRNAs), critical for mitochondrial biogenesis, are frequently associated with pathogenic mutations. These mt-tRNAs have unusual sequence motifs and require post-transcriptional modifications to stabilize their fragile structures. However, whether a modification that stabilizes a wild-type (WT) mt-tRNA would also stabilize its pathogenic variants is unknown. Here we show that the N1-methylation of guanosine at position 9 (m1G9) of mt-Leu(UAA), while stabilizing the WT tRNA, has a destabilizing effect on variants associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). This differential effect is further demonstrated, as removal of the m1G9 methylation, while damaging to the WT tRNA, is beneficial to the major pathogenic variant, improving the structure and activity of the variant. These results have therapeutic implications, suggesting that the N1-methylation of mt-tRNAs at position 9 is a determinant of pathogenicity and that controlling the methylation level is an important modulator of mt-tRNA-associated diseases. Here the authors show that the m1G9 post-transcriptional methylation differentially regulates the stability of the native and the MELAS variants of human mt-Leu(UAA) tRNA, contributing to mitochondrial pathology. [ABSTRACT FROM AUTHOR]

α7 nicotinic acetylcholine receptors (nAChRs) are homopentameric ligand-gated ion channels with critical roles in the nervous system. Recent studies have resolved and functionally annotated closed, open, and desensitized states of these receptors, providing insight into ion permeation and lipid binding. However, the process by which α7 nAChRs transition between states remains unclear. To understand gating and lipid modulation, we generated two ensembles of molecular dynamics simulations of apo α7 nAChRs, with or without cholesterol. Using symmetry-adapted Markov state modeling, we developed a five-state gating model. Free energies recapitulated functional behavior, with the closed state dominating in absence of agonist. Open-to-nonconducting transition rates corresponded to experimental open durations. Cholesterol relatively stabilized the desensitized state, and reduced open-desensitized barriers. These results establish plausible asymmetric transition pathways between states, define lipid modulation effects on the α7 nAChR conformational cycle, and provide an ensemble of structural models applicable to rational design of lipidic pharmaceuticals. The α7 nicotinic acetylcholine receptor plays important roles in the human nervous system. Here, authors use molecular simulations to develop a gating model and reveal cholesterol effects, offering insights applicable to drug design. [ABSTRACT FROM AUTHOR]

Continuous exposure to environmental hypoxia (11% O2) has been shown to markedly slow the progressive degeneration of retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy with RGC-specific deletion of the key mitochondrial complex I accessory subunit ndufs4. As a first step toward identifying the therapeutic mechanism of hypoxia in this model, we conducted a series of experiments to investigate the role of the hypoxia-inducible factor (HIF) regulatory pathway in RGC neuroprotection. Vglut2-Cre; ndufs4loxP/loxP mice were crossed with strains bearing floxed alleles of the negative HIF regulatory vhl or of the two major HIF α-subunit isoforms, Hif1α and Hif2α. Deletion of vhl within ndufs4-deficient RGCs failed to prevent RGC degeneration under normoxia, indicating that HIF activation is not sufficient to achieve RGC rescue. Furthermore, the rescue of ndufs4-deficient RGCs by hypoxia remained robust despite genetic inactivation of Hif1α and Hif2α. Our findings demonstrate that the HIF pathway is entirely dispensable to the rescue of RGCs by hypoxia. Future efforts to uncover key HIF-independent molecular pathways induced by hypoxia in this mouse model may be of therapeutic relevance to mitochondrial optic neuropathies such as Leber hereditary optic neuropathy. [ABSTRACT FROM AUTHOR]

Background: Internal mammary lymphadenopathy (IML) plays a role in breast cancer stage and prognosis. We aimed to evaluate method of IML detection, how IML impacts response to neoadjuvant chemotherapy (NAC), and oncologic outcomes. Methods: We evaluated patients enrolled in the I-SPY-2 clinical trial from 2010 to 2022. We captured the radiographic method of IML detection (magnetic resonance imaging [MRI], positron emission tomography/computed tomography [PET/CT], or both) and compared patients with IML with those without. Rates of locoregional recurrence (LRR), distant recurrence (DR) and event-free survival (EFS) were compared by bivariate analysis. Results: Of 2095 patients, 198 (9.5%) had IML reported on pretreatment imaging. The method of IML detection was 154 (77.8%) MRI only, 11 (5.6%) PET/CT only, and 33 (16.7%) both. Factors associated with IML were younger age (p = 0.001), larger tumors (p < 0.001), and higher tumor grade (p = 0.027). Pathologic complete response (pCR) was slightly higher in the IML group (41.4% vs. 34.0%; p = 0.03). There was no difference in breast or axillary surgery (p = 0.41 and p = 0.16), however IML patients were more likely to undergo radiation (68.2% vs. 54.1%; p < 0.001). With a median follow up of 3.72 years (range 0.4–10.2), there was no difference between IM+ versus IM− in LRR (5.6% vs. 3.8%; p = 0.25), DR (9.1% vs. 7.9%; p = 0.58), or EFS (61.6% vs. 57.2%; p = 0.48). This was true for patients with and without pCR. Conclusions: In this large cohort of patients treated with NAC, outcomes were not negatively impacted by IML. We demonstrated that IML influences treatment selection but is not a poor prognostic indicator when treated with modern NAC and multidisciplinary disease management. [ABSTRACT FROM AUTHOR]

Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal delivery of surface and extracellular targets while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer. Targeted protein degradation (TPD) can be employed to eliminate disease-causing proteins. Here, the authors present CYpHER, a TPD tool that uses molecules engineered for intracellular target release with drug recycling via transferrin receptor. CYpHER induces depletion of extracellular targets in vitro and in xenograft tumours. [ABSTRACT FROM AUTHOR]

DNA double-strand break (DSB) repair by homologous recombination is initiated by DNA end resection, a process involving the controlled degradation of the 5′-terminated strands at DSB sites1,2. The breast cancer suppressor BRCA1–BARD1 not only promotes resection and homologous recombination, but it also protects DNA upon replication stress1,3–9. BRCA1–BARD1 counteracts the anti-resection and pro-non-homologous end-joining factor 53BP1, but whether it functions in resection directly has been unclear10–16. Using purified recombinant proteins, we show here that BRCA1–BARD1 directly promotes long-range DNA end resection pathways catalysed by the EXO1 or DNA2 nucleases. In the DNA2-dependent pathway, BRCA1–BARD1 stimulates DNA unwinding by the Werner or Bloom helicase. Together with MRE11–RAD50–NBS1 and phosphorylated CtIP, BRCA1–BARD1 forms the BRCA1–C complex17,18, which stimulates resection synergistically to an even greater extent. A mutation in phosphorylated CtIP (S327A), which disrupts its binding to the BRCT repeats of BRCA1 and hence the integrity of the BRCA1–C complex19–21, inhibits resection, showing that BRCA1–C is a functionally integrated ensemble. Whereas BRCA1–BARD1 stimulates resection in DSB repair, it paradoxically also protects replication forks from unscheduled degradation upon stress, which involves a homologous recombination-independent function of the recombinase RAD51 (refs. 4–6,8). We show that in the presence of RAD51, BRCA1–BARD1 instead inhibits DNA degradation. On the basis of our data, the presence and local concentration of RAD51 might determine the balance between the pronuclease and the DNA protection functions of BRCA1–BARD1 in various physiological contexts.BRCA1–BARD1 directly promotes double-strand break repair by stimulating long-range DNA end resection pathways. [ABSTRACT FROM AUTHOR]

Chemical modifications to mRNA respond dynamically to environmental cues and are important modulators of gene expression. Nanopore direct RNA sequencing has been applied for assessing the presence of pseudouridine (ψ) modifications through basecalling errors and signal analysis. These approaches strongly depend on the sequence context around the modification, and the occupancies derived from these measurements are not quantitative. In this work, we combine direct RNA sequencing of synthetic RNAs bearing site-specific modifications and supervised machine learning models (ModQuant) to achieve near-analytical, site-specific ψ quantification. Our models demonstrate that the ionic current signal features important for accurate ψ classification are sequence dependent and encompass information extending beyond n + 2 and n − 2 nucleotides from the ψ site. This is contradictory to current models, which assume that accurate ψ classification can be achieved with signal information confined to the 5-nucleotide k-mer window (n + 2 and n − 2 nucleotides from the ψ site). We applied our models to quantitatively profile ψ occupancy in five mRNA sites in datasets from seven human cell lines, demonstrating conserved and variable sites. Our study motivates a wider pipeline that uses ground-truth RNA control sets with site-specific modifications for quantitative profiling of RNA modifications. The ModQuant pipeline and guide are freely available at https://github.com/wanunulab/ModQuant. [ABSTRACT FROM AUTHOR]

Institutions of higher education (IHEs) often disseminate risk reduction strategies intended to reduce sexual assault victimization and/or perpetration. This research examined the content and context of publicly available risk reduction strategies offered by a nationally representative sample of 4-year IHEs in the United States (N = 242; public and private not-for-profit institutions, Historically Black Colleges and Universities, and Tribal institutions). We identified strategies for 102 (42%) IHEs. Using a sociocognitive approach to critical discourse analysis, we examined the specific messages conveyed via IHE risk reduction strategies, how larger sociocultural discourses and power structures were reproduced or reinforced, and the potential implications for readers (i.e., university students). Nearly all IHEs directed their strategies toward potential victims. These strategies were broad in scope, imploring behavioral modification and restriction (e.g., never be alone), and requiring specific responses to sexual assault (e.g., physical resistance). Fewer IHEs directed their strategies toward potential perpetrators; these strategies were narrower in scope, focusing on sexual consent. Overall, strategies reproduced rape myths (e.g., stranger-perpetrated assault is common) and positioned potential victims as uniquely responsible for preventing sexual assault—messaging that may be particularly harmful when disseminated by powerful institutions responsible for sexual assault prevention and response. IHEs should assess the utility of risk reduction strategies and, if retained, revise their strategies to counter harmful sexual assault messaging. [ABSTRACT FROM AUTHOR]

Objective: The present study investigated regretted actions and inactions of military Veterans. The aims of this study were to: (a) explore whether acts of omission may be an important predictor of psychological problems; and (b) investigate Service Members' endorsement of cognitions (i.e., regret) associated with their wartime actions and inactions. Method: 505 Iraq/Afghanistan military veterans (19% female) completed questionnaires measuring their (in)actions and the level of regret associated with their (in)action(s). They also completed questionnaires measuring PTSD, dysphoria, alcohol and substance use, and combat/postcombat experience. Results: Roughly half (49.3%) of the sample reported at least one type of action and/or inaction. When shared variance with common variables (e.g., age, combat experience) was removed, acts of omission were most strongly associated with psychological problems. The association between regret and psychological problems differed significantly depending on the type of action or inaction endorsed by participants. Conclusion: Our findings suggest that both acts of commission and acts of omission, and how they are interpreted, are important for understanding psychological problems. [ABSTRACT FROM AUTHOR]

This research explores the perspectives of academic physicists from three national contexts concerning their roles and responsibilities within the realm of science. Using a dataset comprised of 211 interviews with scientists working in China, the United States, and the United Kingdom, the study seeks to explain whether and in what manner physicists conceptualize scientific ethics within a global or national framework. The empirical findings bring to light disparities across nations in the physicists’ perceptions of what constitutes responsible mentorship and engagement in public service. These cross-national variations underscore the moral agency of physicists as they navigate the ethical standards embraced by the global scientific community vis-à-vis those that are specific to their respective national contexts. The study’s empirical insights may carry significant implications for both policymakers and ethicists, underscoring the imperative of soliciting and acknowledging the perspectives of academic scientists working and living in disparate national contexts when formulating comprehensive science ethics frameworks. Such inclusive and context-aware approaches to shaping ethics in science can contribute to the cultivation of a more robust and universally relevant ethical foundation for the scientific community. [ABSTRACT FROM AUTHOR]

Actinic keratosis (AK) is a common precancerous skin condition predominantly affecting older males with fair skin and significant UV exposure. The clinical significance of AK is related to its potential for malignant transformation and progression to squamous cell carcinoma (SCC). Accurate diagnosis of AK is essential for adequate treatment, evaluation of therapeutic efficacy, and mitigating the risk of developing SCC. However, clinician variability due to the subjective nature of current diagnostic tools presents significant challenges to achieving consistent and reliable AK diagnoses. Thus, there is no universally accepted standard for measuring AK. This review evaluates current methods for evaluating and diagnosing AK, focusing on clinician variability through inter- and intraobserver agreement. Eight peer-reviewed studies investigating the reliability of various approaches for AK evaluation show substantial variability in interobserver or intraobserver agreement, with most methods demonstrating only slight to moderate reliability. Some suggest that consensus discussions and simplified rating scales can modestly improve diagnostic reliability. However, remaining variability and the lack of a universally accepted standard for measuring AK underscore the need for more robust and standardized diagnostic and evaluation methods. The review emphasizes the need for improved diagnostic tools and standardized methods to enhance the accuracy and reliability of AK assessments. It also proposes applying a novel examination approach using 1,3-dihydroxyacetone (DHA) staining which may improve the visualization and identification of AK lesions. Advancements in these areas have significant potential, promising better clinical practices and patient outcomes in AK management. [ABSTRACT FROM AUTHOR]

Data from 318 diverse high school students from three different types of high schools in the United States were collected. School types varied by location (e.g., suburban, urban), size, and student demographics (e.g., race, ethnicity, socioeconomic status). Exploratory Factor Analysis (EFA) was conducted to examine the factor structure of the STRESS-Y. Mean comparisons were performed to assess variations in Racial Stress Appraisal across different school types. The EFA of the STRESS-Y confirmed its factor structure, supporting its validity as a measure of RSA in youth and we were able to extract two robust factors—Racial Threat Appraisal and Racial Support Appraisal. Mean comparisons revealed that Racial Threat Appraisal and Racial Support Appraisal varied across different school types, highlighting the influence of school context on students' experiences of racial stress. This study provides evidence for the validity of the STRESS-Y as a measure of Racial Stress Appraisal in youth. The findings demonstrate the importance of considering school type as a factor influencing students' experiences of racial stress as well as how support, racial coping, and stress management skills may help mitigate ongoing interpersonal harm that youth are experiencing. The validated measure and the understanding of the factors contributing to Racial Stress Appraisal can inform interventions aimed at supporting students in managing and coping with racial stressors in their respective school environments. [ABSTRACT FROM AUTHOR]

Purpose: The study aims to establish the diagnostic accuracy of community spine x-rays for brace candidates. Methods: A review of adolescent idiopathic scoliosis patients seen for initial visit at a tertiary care pediatric hospital was conducted (n = 170). The index test was the pre-referral community spine x-ray interpreted by a community radiologist. Measures of diagnostic accuracy for the index test were determined against the reference standard if images were obtained within 90 days (n = 111). The reference standard was the 3-foot standing EOS spine x-ray evaluated by spine specialists. Diagnostic criterion for a brace candidate was dichotomized by Cobb angle range (25–40°) according to Scoliosis Research Society criteria. Risser stage was not included given significant missing data in index reports. To mitigate the uncertainty around true progression, sensitivity analyses were conducted on a sub-sample of data when index test was within 60 days of the reference standard (n = 67). Results: Accuracy of the community spine x-ray to detect a brace candidate was 65.8% (95% CI 56.2–74.5). Sensitivity of the index test was 65.4% with a false negative rate of 34.6%. Specificity was 66.1% with a false positive rate of 33.9%. Positive and negative predictive values were 63.0% and 68.4%, respectively. Of the total number of brace candidates (n = 52), 32.7% were missed because of underestimation in Cobb angle (95% CI 21.5–46.2). The proportion of missed brace candidates because of underestimation was unchanged with 60-day data (p = 0.37). Conclusions: Inaccuracies in community spine radiology may lead to missed opportunities for non-operative treatment. [ABSTRACT FROM AUTHOR]

Clinical studies on the treatment of type 1 diabetes with device-encapsulated pancreatic precursor cells derived from human embryonic stem cells found that insulin output was insufficient for clinical benefit. We are conducting a phase 1/2, open-label, multicenter trial aimed at optimizing cell engraftment (ClinicalTrials.gov identifier: NCT03163511). Here we report interim, 1-year outcomes in one study group that received 2–3-fold higher cell doses in devices with an optimized membrane perforation pattern. β cell function was measured by meal-stimulated plasma C-peptide levels at 3-month intervals, and the effect on glucose control was assessed by continuous glucose monitoring (CGM) and insulin dosing. Of 10 patients with undetectable baseline C-peptide, three achieved levels ≥0.1 nmol l−1 from month 6 onwards that correlated with improved CGM measures and reduced insulin dosing, indicating a glucose-controlling effect. The patient with the highest C-peptide (0.23 nmol l−1) increased CGM time-in-range from 55% to 85% at month 12; β cell mass in sentinel devices in this patient at month 6 was 4% of the initial cell mass, indicating directions for improving efficacy. β cells derived from stem cells improve blood glucose control in patients with diabetes. [ABSTRACT FROM AUTHOR]

Objective, quantitative measures of caregiver-child interaction during play are needed to complement caregiver or examiner ratings for clinical assessment and tracking intervention responses. In this exploratory study, we examined the feasibility of using automated video tracking, Noldus EthoVision XT, to measure 159 2-to-7-year-old autistic children's patterns of movement during play-based, caregiver-child interactions and examined their associations with standard clinical measures and human observational coding of caregiver-child joint engagement. Results revealed that autistic children who exhibited higher durations and velocity of movement were, on average, younger, had lower cognitive abilities, greater autism-related features, spent less time attending to the caregiver, and showed lower levels of joint engagement. After adjusting for age and nonverbal cognitive abilities, we found that children who remained in close proximity to their caregiver were more likely to engage in joint engagement that required support from the caregiver. These findings suggest that video tracking offers promise as a scalable, quantitative, and relevant measure of autism-related behaviors. [ABSTRACT FROM AUTHOR]

Purpose: Although there is growing interest in telehealth to deliver parent-mediated intervention for autistic children, empirical evaluations are limited, and little is known regarding the relative benefits of self-directed and therapist-assisted telehealth interventions. This study examined the effect of self-directed and therapist-assisted ImPACT Online on parent learning and well-being, moderators of treatment, and predictors of program engagement. Method: Sixty-four young autistic children and their primary caregiver participated. Children were matched on age and developmental quotient and randomly assigned to a therapist-assisted, self-directed, or resource support control group. Participants were assessed at intake, after 6 months (post), and at a 3-month follow-up. Results: There was a significant treatment effect for parent learning for the therapist-assisted but not self-directed program; when analysis was limited to parents who completed the program, treatment effects were observed for both groups. There were no treatment effects for parent self-efficacy or parenting stress; however, there was an effect on parents' perception of their child's positive impact. Parenting stress did not moderate the effect of group on parent outcomes. Parent age, program satisfaction, and therapist assistance were all significant predictors of parent program engagement. Conclusion: This study supports the efficacy of therapist-assisted telehealth parent-mediated intervention for teaching parents intervention strategies to support their child's social communication and improving their perceptions of their child's positive impact, and suggests that self-directed programs may be beneficial for parents who fully engage with the program. [ABSTRACT FROM AUTHOR]

Purpose: To compare the prevalence of emotional and physical intimate partner violence (IPV) across pregnancy and the first year postpartum in those with and without clinical depression and assess the association between maternal childhood trauma, current stressful life events and depression and IPV over the perinatal period. Methods: Data were obtained from 505 pregnant women from the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS), a cohort study with data collected across pregnancy until 12 months postpartum. Maternal antenatal depression was measured using the Structured Clinical Interview for DSM-IV (SCID-IV) with repeat measurement of perinatal depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS). Trauma was measured using the Childhood Trauma Questionnaire, and experiences of physical and emotional intimate partner violence using items in the Stressful Life Events Scale. Results: Women experiencing IPV across the perinatal period were significantly more likely to score over 13 on the EPDS (p <.001) at each timepoint in pregnancy and the postpartum and physical IPV was associated with clinical depression. Further, a history of childhood trauma and current additional stressful life events were significantly associated with reporting current IPV in the perinatal period. Conclusions: This study confirmed the risk factors of childhood trauma and current stressful life events for reporting experiences of IPV in the perinatal period. Furthermore, women experiencing IPV reported higher depressive symptoms, providing evidence supporting the value of assessing those women who screen higher on the EPDS for IPV. Together these findings also support trauma informed care across pregnancy and the postpartum. [ABSTRACT FROM AUTHOR]

Non-destructive electrical fault isolation (FI) techniques such as emission- and laser-based techniques have been utilized widely for chip-level failure analysis (FA). However, these techniques by themselves can sometimes be inadequate for certain failure modes. In this paper, we present six FA case studies using Time-domain Reflectometry (Electro-optical terahertz pulse reflectometry, EOTPR) in combination with the traditional FI techniques. We also present continuing development in making EOTPR accessible to the semiconductor process and packaging communities. [ABSTRACT FROM AUTHOR]

Background: Severe hypoglycemia is a serious adverse drug event associated with hypoglycemia-prone medications; older patients with diabetes are particularly at high risk. Economic food insecurity (food insecurity due to financial limitations) is a known risk factor for hypoglycemia; however, less is known about physical food insecurity (due to difficulty cooking or shopping for food), which may increase with age, and its association with hypoglycemia. Objective: Study associations between food insecurity and severe hypoglycemia. Design: Survey based cross-sectional study. Participants: Survey responses were collected in 2019 from 1,164 older (≥ 65 years) patients with type 2 diabetes treated with insulin or sulfonylureas. Main Measures: Risk ratios (RR) for economic and physical food insecurity associated with self-reported severe hypoglycemia (low blood glucose requiring assistance) adjusted for age, financial strain, HbA1c, Charlson comorbidity score and frailty. Self-reported reasons for hypoglycemia endorsed by respondents. Key Results: Food insecurity was reported by 12.3% of the respondents; of whom 38.4% reported economic food insecurity only, 21.1% physical food insecurity only and 40.5% both. Economic food insecurity and physical food insecurity were strongly associated with severe hypoglycemia (RR = 4.3; p = 0.02 and RR = 4.4; p = 0.002, respectively). Missed meals ("skipped meals, not eating enough or waiting too long to eat") was the dominant reason (77.5%) given for hypoglycemia. Conclusions: Hypoglycemia prevention efforts among older patients with diabetes using hypoglycemia-prone medications should address food insecurity. Standard food insecurity questions, which are used to identify economic food insecurity, will fail to identify patients who have physical food insecurity only. [ABSTRACT FROM AUTHOR]

Introduction: Vortioxetine is an antidepressant with a multimodal mechanism of action. It is used as a treatment option for patients with major depressive episodes. There have only been two previously reported non-fatal overdoses of vortioxetine; neither of these were analytically confirmed There has also been one case of serotonin syndrome potentially related to vortioxetine and two deaths where vortioxetine was detected. We report here a non-fatal analytically confirmed case of vortioxetine overdose. Case report: A 32-year-old male presented to the emergency department (ED) 12–13 h after oral ingestion of 1,260 mg of vortioxetine and 350 mg of diazepam. A family member reported that he had been drowsy after the overdose, but his level of consciousness and observations (heart rate, blood pressure and temperature) were normal on review by the pre-hospital emergency services and on arrival to the ED. During a period of observation, he did not develop any features of serotonin syndrome or any other significant toxicity. Toxicological analysis of a blood sample taken in the ED detected vortioxetine (plasma concentration 457 ng/mL 10 h after ingestion) and sub-therapeutic concentrations of diazepam and pregabalin. Discussion: Despite having a plasma vortioxetine concentration nearly 15-times therapeutic vortioxetine concentrations, this patient did not develop any significant toxicity. In particular he did not develop any clinical or biochemical features of serotonin toxicity that would be expected with this class of antidepressant. Additional reporting of analytically confirmed vortioxetine overdoses will allow clinicians and licensing authorities to further understand the safety of this medication in overdose. [ABSTRACT FROM AUTHOR]

Introduction: Thallium is a highly toxic metal, with most publications demonstrating poisoning from thallium salts. We report on a patient with elevated serum and urine thallium concentrations from an intentional ingestion of elemental thallium purchased from the internet for self-harm. Case Report: The regional poison center was contacted about an 18-year-old man who ingested a fragment from a 100-gram bar reported to be elemental thallium. Serial serum and urine thallium concentrations were obtained. Prussian blue was started on hospital day (HD) 2. A metal fragment was seen on abdominal x-ray and removed via colonoscopy on HD3. The ingested fragment was analyzed via inductively coupled plasma mass spectrometry (ICP-MS) and found to be 87.0% elemental thallium. The initial serum thallium concentration obtained on HD1 was 423.5 mcg/L (reference range < 5.1 mcg/L), which subsequently decreased to 4.5 mcg/L, 29 days after the ingestion. An initial random urine thallium concentration obtained on HD 3 was 1850.5 mcg/g creatinine (reference range < 0.4 mcg/g creatinine). The patient remained hospitalized for 23 days and, when seen in follow-up, had not developed any signs or symptoms of thallium toxicity. Discussion: Elemental thallium ingestion is a rare toxicologic exposure, with limited published clinical and analytical experience to guide management. This case report describes a patient with ingestion of elemental thallium who developed elevated serum and urine thallium concentrations and was treated with Prussian blue. Despite having elevated serum and urine thallium concentrations consistent with previous fatal exposures, more evidence is needed to understand the differences between elemental thallium and thallium salts. [ABSTRACT FROM AUTHOR]

Introduction: Transdiagnostic self-help cognitive behavioral therapy (CBT) approaches may help ease the burden of untreated symptoms of internalizing distress, especially in geographic areas with relatively small numbers of mental health providers. Methods: Over the course of 12 months, we conducted a six-week randomized controlled trial (N = 275) across Indiana, a state with high unmet need for mental health care. All participants were given immediate access to a single-session intervention (SSI) followed by randomization to either guided or unguided CBT-based bibliotherapy. We used mixed models to model change over time in distress, well-being, and emotion regulation as a piecewise function of study week. Results: The sample was in their early 30s (M = 34.10, SD = 11.68), mostly female (75.64%, n = 208) and, consistent with the demographics of the state, mostly Non-Hispanic White (80.36%, n = 221). Less than half of participants accessed the SSI (39.27%, n = 108). There was no evidence that completing the SSI was associated with improved outcomes, though it improved study engagement. Participants randomized to the guided (vs. unguided) condition experienced greater overall improvements in internalizing distress (SMD=-0.44, 95% CI: -0.74, -0.13) and cognitive reappraisal (SMD = 0.32, 95% CI: 0.06, 0.58). The differences between groups in improvements in well-being (SMD = 0.25, 95% CI: -0.13, 0.63) and expressive suppression (SMD=-0.24, 95% CI: -0.55, 0.07) were smaller and not statistically significant. Virtually all participants expressed some interest in more therapy via telehealth (89.74%, n = 140). Findings were sensitive to multiple imputation using random forests as well as propensity score matching. Discussion: Self-help approaches are scalable interventions for individuals in under-served states. As in previous work, guided self-help was more effective than unguided self-help. More work should focus on adding additional treatment steps past self-help. [ABSTRACT FROM AUTHOR]

The cultivated apple (Malus domestica Borkh.) is an economically important fruit crop in countries worldwide, including Bosnia and Herzegovina (BIH).The gene bank activities in BIH were initiated in the 1930s and continued until the war in the 1990s, when much of the documentation was lost. Since then, uncoordinated efforts were made to establish apple collections in different regions, but a comprehensive analysis of genetic resources was lacking. This prompted the current study where we present the first thorough overview of the national genetic resources of BIH apples. Thus, we analyzed 165 accessions in the apple gene bank at the Institute for Genetic Resources (IGR) established at Banja Luka using the 20 K apple Infinium® single nucleotide polymorphism (SNP) array. We combined the results with previously published data on the germplasm collections at Srebrenik and Goražde, genotyped using the Axiom® Apple 480 K SNP array. In total, 234 accessions were included in the study of which 220 were presumed to be local cultivars and 14 were known international reference cultivars. We identified numerous genotypic duplicates within and between collections and suggested preferred names to be used in the future. We found the BIH germplasm to have relatively few parent-offspring relationships, particularly among local cultivars, which might reflect the country's history and patterns of apple cultivar introduction. A number of cultivars unique to BIH and a weakly defined genetic group were identified via STRUCTURE analysis, representing interesting targets for future research and preservation efforts. [ABSTRACT FROM AUTHOR]

Laser directed energy deposition (LDED), a class of additive manufacturing (AM) processes, has immense potential to be used for various engineering applications to build components with medium to high complexity. However, dimensional deviations from intended values and inadequate surface quality of the built parts limit its wide deployment. The present work reports the development of an adaptive tool path trajectory platform to correct the dimensional inaccuracies in-situ to build high-quality components using LDED. The study deploys a laser line scanner to scan the part after the deposition of the definite number of layers followed by the detection of concave, convex, and flat surfaces using deep learning. Further, a novel adaptive trajectory planning algorithm is deployed by using three different strategies to control material deposition on concave, convex, and flat surfaces. The material deposition is controlled by using adaptive scanning speed control (ASSC), and a combination of laser on–off and scanning speed control (ASSLC). Subsequently, the built geometries are subjected to geometric, microstructure, and mechanical characterizations. It is observed that the deviation of the part was reduced by 30%, and 27.5% using ASSC and ASSLC, respectively. The structures built using the three strategies show some micropores at isolated locations. The microstructure is mainly cellular under all conditions with a similar average microhardness of ~ 210 HV. The study provides an integrated and comprehensive approach for building high-quality large-scale components using LDED with minimal dimensional deviation from the original CAD model. [ABSTRACT FROM AUTHOR]

Purpose: Neuroimaging is often used in the emergency department (ED) to evaluate for posterior circulation strokes in patients with dizziness, commonly with CT/CTA due to speed and availability. Although MRI offers more sensitive evaluation, it is less commonly used, in part due to slower turnaround times. We assess the potential for abbreviated MRI to improve reporting times and impact on length of stay (LOS) compared to conventional MRI (as well as CT/CTA) in the evaluation of acute dizziness. Materials and methods: We performed a retrospective analysis of length of stay via LASSO regression for patients presenting to the ED with dizziness and discharged directly from the ED over 4 years (1/1/2018-12/31/2021), controlling for numerous patient-level and logistical factors. We additionally assessed turnaround time between order and final report for various imaging modalities. Results: 14,204 patients were included in our analysis. Turnaround time for abbreviated MRI was significantly lower than for conventional MRI (4.40 h vs. 6.14 h, p < 0.001) with decreased impact on LOS (0.58 h vs. 2.02 h). Abbreviated MRI studies had longer turnaround time (4.40 h vs. 1.41 h, p < 0.001) and was associated with greater impact on ED LOS than non-contrast CT head (0.58 h vs. 0.00 h), however there was no significant difference in turnaround time compared to CTA head and neck (4.40 h vs. 3.86 h, p = 0.06) with similar effect on LOS (0.58 h vs. 0.53 h). Ordering both CTA and conventional MRI was associated with a greater-than-linear increase in LOS (additional 0.37 h); the same trend was not seen combining CTA and abbreviated MRI (additional 0.00 h). Conclusions: In the acute settings where MRI is available, abbreviated MRI protocols may improve turnaround times and LOS compared to conventional MRI protocols. Since recent guidelines recommend MRI over CT in the evaluation of dizziness, implementation of abbreviated MRI protocols has the potential to facilitate rapid access to preferred imaging, while minimizing impact on ED workflows. [ABSTRACT FROM AUTHOR]

Purpose: Unmet social needs pose barriers to cancer care, contributing to adverse outcomes and health inequities. A better understanding of how social needs change after cancer diagnosis can inform more effective, equity-focused interventions. Methods: In this study, we examined self-reported social needs at 0, 3, and 6 months after a breast cancer diagnosis in a racially diverse, multilingual sample (n = 222) enrolled in patient navigation intervention at an urban safety-net hospital. At each timepoint, respondents completed surveys about social needs related to employment, disability benefits, housing and utilities, and personal and family stability. Results: Over three-quarters (78%, n = 175) reported ≥ 1 social need, and 46% (n = 102) reported ≥ 3 social needs. The most frequently reported need was housing and utilities (64%, n = 142), followed by employment (40%, n = 90). Individuals from minoritized groups more frequently reported an increased number of social needs over time, compared with their White counterparts (p = 0.02). Conclusion: Our findings suggest that despite navigation, many cancer patients from historically underrepresented populations continue to experience social concerns over the first 6 months of treatment. Further research, conducted with historically underrepresented populations in research, is needed to better understand the social needs of breast cancer patients to inform effective and equitable interventions. [ABSTRACT FROM AUTHOR]

Metabolic imbalance leading to inflammatory hypoxia and stabilization of hypoxia-inducible transcription factors (HIFs) is a hallmark of inflammatory bowel diseases. We hypothesize that HIF could be stabilized in CD4+ T cells during intestinal inflammation and alter the functional responses of T cells via regulation of microRNAs. Our assays reveal markedly increased T cell-intrinsic hypoxia and stabilization of HIF protein during experimental colitis. microRNA screen in primary CD4+ T cells points us towards miR-29a and our subsequent studies identify a selective role for HIF-2α in CD4-cell-intrinsic induction of miR-29a during hypoxia. Mice with T cell-intrinsic HIF-2α deletion display elevated T-bet (target of miR-29a) levels and exacerbated intestinal inflammation. Mice with miR-29a deficiency in T cells show enhanced intestinal inflammation. T cell-intrinsic overexpression of HIF-2α or delivery of miR-29a mimetic dampen TH1-driven colitis. In this work, we show a previously unrecognized function for hypoxia-dependent induction of miR-29a in attenuating TH1-mediated inflammation. Inflammatory intestinal lesions are often hypoxic, which results in the stabilization and activation of hypoxia-inducible-factors (HIF). Here authors show that in a mouse model of colitis, HIF-2α is specifically stabilized in CD4+ type 1T helper (TH1) cells, leading to the upregulation of miR-29a expression and suppression of TH1 cell function, which pathway is potentially targetable for therapeutic purposes. [ABSTRACT FROM AUTHOR]

ρ-type γ-aminobutyric acid-A (GABAA) receptors are widely distributed in the retina and brain, and are potential drug targets for the treatment of visual, sleep and cognitive disorders. Endogenous neuroactive steroids including β-estradiol and pregnenolone sulfate negatively modulate the function of ρ1 GABAA receptors, but their inhibitory mechanisms are not clear. By combining five cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of β-estradiol and pregnenolone sulfate at the human ρ1 GABAA receptor. β-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the ρ subfamily, and disturbs allosteric conformational transitions linking GABA binding to pore opening. In contrast, pregnenolone sulfate binds inside the pore to block ion permeation, with a preference for activated structures. These results illuminate contrasting mechanisms of ρ1 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design. Neurological processes from vision to cognition rely on precise control of ion channels, particularly GABAA receptors. Here, the authors report structures of a ρ1 GABAA receptor with naturally occurring steroids, revealing their specific interactions and suggesting approaches to understand and develop drugs. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between periodontitis and cardiometabolic and haemostatic parameters. Materials and methods: Between 2014 and 2019, 54 individuals needing full mouth extraction, and 50 control individuals, were recruited for a combined cross-sectional (individuals versus controls) and longitudinal (individuals before and after extraction) study. Periodontitis severity was measured using the periodontal inflamed surface area (PISA). Blood was drawn to measure the haemostatic (Factor VIII, von Willebrand factor [VWF], endogenous thrombin potential, d-dimer, clot lysis time) and cardiovascular risk (C-reactive protein [CRP], lipid profile) parameters, prior to and 12 weeks post-extraction. The results were analysed group-wise. Results: The mean VWF and CRP levels were higher and the high-density lipoprotein levels were lower in the individuals prior to extraction compared to the controls. The VWF was significantly correlated with the PISA (a 21% unit increase in VWF per 1000 mm2 increase in PISA, 95%CI: 6–36%, p = 0.01). The other analyses were comparable between the individuals and controls, and did not change in the individuals after the extraction. Conclusion: VWF levels are associated with periodontitis severity; they do not improve after full-mouth extraction. Severe periodontitis in control individuals does not induce substantial changes in their haemostatic or inflammatory systems. Clinical relevance: Treatment of periodontitis has been shown to improve the cardiometabolic blood profile of patients with established cardiometabolic disease. However, whether periodontitis treatment improves cardiometabolic and haemostatic profiles in people without cardiometabolic disease is uncertain. [ABSTRACT FROM AUTHOR]

This paper presents the results of a systematic scoping literature review of higher education mathematics and statistics support (MSS) evaluation focusing on its impact on students. MSS is defined as any additional organised mathematical and/or statistical aid offered to higher education students outside of their regular programme of teaching by parties within the students' institution specifically assigned to give mathematical and/or statistical support. The objective of this review is to establish how MSS researchers investigate the effect of MSS on students and what that impact is. Based on a predefined protocol, five databases, the proceedings of eight conferences, two previous MSS literature reviews' reference lists, and six mathematics education or MSS networks' websites and reports were searched for publications in English since 2000. A two-round screening process resulted in 148 publications being included in the review which featured research from 12 countries. Ten formats of MSS, seven data sources (e.g., surveys), and 14 types of data (e.g., institution attainment, usage data) were identified with a range of analysis methods. Potential biases in MSS research were also considered. The synthesised results and discussion of this review include the mostly positive impact of MSS, issues in MSS evaluation research thus far, and rich opportunities for collaboration. The role MSS has and can play in mathematics education research is highlighted, looking towards the future of MSS evaluation research. Future directions suggested include more targeted systematic reviews, rigorous study design development, and greater cross-disciplinary and international collaboration. [ABSTRACT FROM AUTHOR]

With a decade passing since the release of the Next Generation Science Standards (NGSS), it is timely to reflect and consider the extent to which the promise of science teaching and learning that values and centers learners' varied epistemologies for scientific sensemaking has been realized. We argue that this potential, in part, lies in the hands of our science education research community becoming aware and intentional with how we situate learners' language-related resources and practices in our work. Hoping to achieve a more inclusive and expansive future where science is for and by all—re-imagining what is possible in science education—we propose science education research move toward a language for science perspective. When taking up this perspective, researchers center the diverse ways that learners adopt and draw upon wide-ranging language resources and practices to explore phenomena, engage in scientific sensemaking and express evolving understandings about our natural world. In this commentary, we describe how we conceptualize a language for science perspective and why we believe such a perspective is critical for carrying out transformative equity-oriented research. We also illustrate one way that this perspective might be taken up, specifically in the context of science education research that integrates translanguaging theory and pedagogy to explore multilingual learners' scientific sensemaking experiences. Though our commentary is framed within the context of realizing reform-oriented science teaching and learning in the USA, the argument we make is central to the discipline of science and thus is relevant for science education research conducted across the globe. [ABSTRACT FROM AUTHOR]