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Understanding the zoonotic risks posed by bat coronaviruses (CoVs) is critical for pandemic preparedness. Herein, we generated recombinant vesicular stomatitis viruses (rVSVs) bearing spikes from divergent bat CoVs to investigate their cell entry mechanisms. Unexpectedly, the successful recovery of rVSVs bearing the spike from SHC014-CoV, a SARS-like bat CoV, was associated with the acquisition of a novel substitution in the S2 fusion peptide-proximal region (FPPR). This substitution enhanced viral entry in both VSV and coronavirus contexts by increasing the availability of the spike receptor-binding domain to recognize its cellular receptor, ACE2. A second substitution in the S1 N–terminal domain, uncovered through the rescue and serial passage of a virus bearing the FPPR substitution, further enhanced spike:ACE2 interaction and viral entry. Our findings identify genetic pathways for adaptation by bat CoVs during spillover and host-to-host transmission, fitness trade-offs inherent to these pathways, and potential Achilles' heels that could be targeted with countermeasures. Author summary: The recent emergence of several highly virulent human coronaviruses, SARS-CoV, MERS-CoV and SARS-CoV-2, underscores the risk coronaviruses can pose to the human population. Bat coronaviruses (CoVs) are of particular concern due to their potential to adapt to new hosts. Here, we attempted to generate recombinant vesicular stomatitis viruses (rVSVs) bearing the spike glycoproteins from several SARS-like bat CoVs to study their cell entry mechanisms. We identified two mutations in the SHC014-CoV spike that afforded successful recovery of an rVSV bearing this spike by greatly increasing viral entry. Interestingly, these mutations occur outside the receptor-binding domain (RBD) but enhance spike-receptor interaction nevertheless. These and other results herein establish that these mutations serve to "open" the spike and thereby augment virus-receptor engagement. Our work uncovers new genetic pathways that could contribute to the adaptation of bat CoVs during host spillover. However, these mutations also render the spike more susceptible to neutralizing antibodies that recognize the RBD, pointing to fitness tradeoffs associated with these pathways. [ABSTRACT FROM AUTHOR]

Drawing on theories of aversive racism and colour-blindness, which stress the invisibility of contemporary racism, this article analyses online discussions on taking the knee (TTK) during EURO2020 men's football tournament. While highly visible racist abuse directed at Black English players after losing the final to Italy (dominative racism) received most public attention and repudiation, based on 6,850 English language tweets published on Twitter/X, this article shows how subtle racism and colour-blindness were reinforced in discussions around TTK over the duration of the tournament (aversive racism). The article also shows how individuals online developed a variety of strategies (evidence, othering, critique, and activism) to challenge the main arguments against anti-racist activism in football (identified in four themes: BLM, Marxism, virtue signalling, and woke). The article makes an original contribution by examining the changing intensity of online conversations on TTK over the duration of the tournament. Our analysis identifies key moments in the tournament, political elites' rhetoric, and trends of success and failure as relevant factors that shaped vernacular conversations online. The discussion ultimately argues that investigating the temporal patterns of public discussions on (anti)racism provides valuable insights to understand the contemporary complexity of racism in football and society more broadly. [ABSTRACT FROM AUTHOR]

Atmospheric concentrations of nitrous oxide (N2O), a potent greenhouse gas that is also responsible for significant stratospheric ozone depletion, have increased in response to the intensified use of agricultural fertilizers and other human activities that have accelerated nitrogen cycling processes. Microbial denitrification in soils and sediments is a major source of N2O, produced as an intermediate during the reduction of oxidized forms of nitrogen to dinitrogen gas (N2). Substrate availability (nitrate and organic matter) and environmental factors such as oxygen levels, temperature, moisture, and pH influence rates of denitrification and N2O production. Here we describe the role of physicochemical perturbation (defined here as a change from the ambient environmental conditions) in influencing rates of denitrification and N2O production. Changes in salinity, temperature, moisture, pH, and zinc in agricultural soils induced a short-term perturbation response characterized by lower rates of total denitrification and higher rates of net N2O production. The ratio of N2O to total denitrification (N2O : DNF) increased strongly with physicochemical perturbation. A salinity press experiment on tidal freshwater marsh soils revealed that increased N2O production was likely driven by transcriptional inhibition of the nitrous oxide reductase (nos) gene and that the microbial community adapted to altered salinity over a relatively short time frame (within 1 month). Perturbation appeared to confer resilience to subsequent disturbance, and denitrifiers from an environment without salinity fluctuations (tidal freshwater estuarine sediments) demonstrated a stronger N2O perturbation response than denitrifiers from environments with more variable salinity (oligohaline and mesohaline estuarine sediments), suggesting that the denitrifying community from physicochemically stable environments may have a stronger perturbation response. These findings provide a framework for improving our understanding of the dynamic nature of N2O production in soils and sediments, in which changes in physical and/or chemical conditions initiate a short-term perturbation response that promotes N2O production that moderates over time and with subsequent physicochemical perturbation. [ABSTRACT FROM AUTHOR]

Purpose: Phonological awareness (PA), the awareness of sounds in spoken words, is strongly linked to reading outcomes. However, there is an ongoing debate regarding the effectiveness of PA instruction without including print (i.e. PA without exposure to words or letters). Specifically, is PA-only instruction just as effective in improving reading outcomes when compared to print-based instruction (e.g. phonics)? Method: Robust variance estimation was used to examine the effectiveness of PA-only instruction across 38 independent studies and 293 effect sizes. The sample consisted of 3,880 participants in preschool through first grade. The average age of participants was 5 years 7 months. Moderator analysis were conducted to examine differences in effect across outcomes, comparison conditions and participant characteristics. Results: PA-only instruction had a moderate overall effect (g = 0.57, 95% CI [0.40, 0.74], p <.001) on reading-related outcomes. PA-only instruction was less effective when compared to print-based instruction (g = −0.54, 95% CI [−0.80, −0.27], p <.001) and less effective for word reading outcomes (g = -0.33, 95% CI [−0.66, −0.01], p =.05) than for PA outcomes (g = 0.64, 95% CI [0.44, 0.84], p <.001). Conclusion: PA-only instruction can be beneficial for reading-related outcomes, but the effect varies depending on two important contextual factors: 1) the reading outcome type and 2) the comparison condition. Specifically, PA-only instruction might be less effective in improving word reading outcomes than PA outcomes. In addition, it has less of an effect on reading-related outcomes when compared to print-based instruction like phonics. [ABSTRACT FROM AUTHOR]

The increasing demand for natural products in the United States reflects a cultural shift towards health and sustainability. This trend infiltrates consumer sectors such as the sunscreen industry, amidst concerns about health and environmental impacts of chemical ingredients. The Hawaii Sunscreen Ban has intensified sunscreen formula safety discussions, particularly regarding butylparaben, oxybenzone, and octinoxate. Even at low concentrations, these compounds bleach hard corals eventually leading to their death. As well, these chemicals pose threats to marine ecosystems and raise concerns about human health, particularly systemic absorption and the possibility of causing endocrine disruption. While some argue for chemical-based sunscreens for skin cancer prevention, others advocate for mineral-based alternatives that avoid harmful ingredients. However, public opinion on sunscreen varies, influenced by adverse reactions, socioeconomic status, gender, and cultural perceptions. Future studies should explore diverse demographic perspectives and long-term health and environmental impacts of products containing potentially toxic ingredients. As well, effective communication strategies to promote sunscreen safety and encourage sustainable sun protection practices is needed. [ABSTRACT FROM AUTHOR]

The increasing demand for natural products in the United States reflects a cultural shift towards health and sustainability. This trend infiltrates consumer sectors such as the sunscreen industry, amidst concerns about health and environmental impacts of chemical ingredients. The Hawaii Sunscreen Ban has intensified sunscreen formula safety discussions, particularly regarding butylparaben, oxybenzone, and octinoxate. Even at low concentrations, these compounds bleach hard corals eventually leading to their death. As well, these chemicals pose threats to marine ecosystems and raise concerns about human health, particularly systemic absorption and the possibility of causing endocrine disruption. While some argue for chemical-based sunscreens for skin cancer prevention, others advocate for mineral-based alternatives that avoid harmful ingredients. However, public opinion on sunscreen varies, influenced by adverse reactions, socioeconomic status, gender, and cultural perceptions. Future studies should explore diverse demographic perspectives and long-term health and environmental impacts of products containing potentially toxic ingredients. As well, effective communication strategies to promote sunscreen safety and encourage sustainable sun protection practices is needed. [ABSTRACT FROM AUTHOR]

Background: Music-based intervention has been advocated as a nonpharmacologic approach for the perioperative control of pain and anxiety in surgical patients. However, its impact on patients with preoperative anxiety has not been clearly established. Our study aimed to examine the impact of music-based intervention administered before, during, and after surgery on postoperative opioid consumption and pain levels, as well as preoperative anxiety, depression, and pain catastrophizing. We hypothesized that, compared to a control group, music-based intervention would be effective in reducing opioid requirements and mood disorders. Methods: This study was a single-center, prospective, single-blinded, randomized controlled trial. Inclusion criteria isame-day or observation surgery. Exclusion criteria included American Society of Anesthesiologists physical status IV, use of spinal anesthesia, PROMIS Anxiety T-scores ≤ 57.4 and ≥74.1, preoperative chronic opioid use, transgender surgery, and history of drug or alcohol abuse. Music-based intervention was developed by a certified music therapist. Each patient was randomized to receive standard of care (SC) or SC plus music-based intervention before, during, and after surgery. The primary end point was postoperative oral morphine equivalents (OMEs) over 5 days following surgery using the area under the curve (AUC)Secondary end points were PROMIS Anxiety, PROMIS Depression scores Pain Catastrophizing Scale scores, postoperative nausea and vomiting, time of hospital discharge, and patient satisfaction (0 = totally unsatisfied to 10 = completely satisfied). Results: A total of 75 patients were randomized to a music-based intervention (n = 33) or control (n = 42) group. Patients in the music-based intervention group consumed 56.7% less opioids than those in the control group (AUC was 2.8 in the music-based intervention group vs. 6.4 in the control group, absolute standardized mean difference (aSMD) = 0.34 (−0.17, 0.85)). No difference in pain scores was recorded between groups. Music-based intervention also reduced anxiety on postoperative day (POD)2 (aSMD = 0.38 (−0.16, 0.91)), depression on POD2 (aSMD = 0.31 (−0.23, 0.84)) and POD4 (aSMD = 0.24 (−0.29, 0.77)), and pain catastrophizing on POD1 (aSMD = 0.24 (−0.3, 0.77)). Conclusions: Our data support the use of music-based intervention to reduce postoperative opioid requirements. Music-based intervention may also reduce anxiety, depression, and pain catastrophizing. [ABSTRACT FROM AUTHOR]

The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut–brain axis. The gut–brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation—a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders. [ABSTRACT FROM AUTHOR]

Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery to clinical development to post-marketing activities. Development of standards for how these models are constructed, assessed, and communicated is of active interest to the modeling community and regulators but is complicated by the wide variability in the structures and intended uses of the underlying models and the diverse expertise of QSP modelers. With this in mind, the IQ Consortium conducted a survey across the pharmaceutical/biotech industry to understand current practices for QSP modeling. This article presents the survey results and provides insights into current practices and methods used by QSP practitioners based on model type and the intended use at various stages of drug development. The survey also highlights key areas for future development including better integration with statistical methods, standardization of approaches towards virtual populations, and increased use of QSP models for late-stage clinical development and regulatory submissions. [ABSTRACT FROM AUTHOR]

Understanding how macroalgal forests will respond to environmental change is critical for predicting future impacts on coastal ecosystems. Although measures of adult macroalgae physiological responses to environmental stress are advancing, measures of early life‐stage physiology are rare, in part due to the methodological difficulties associated with their small size. Here we tested a novel, high‐throughput method (rate of oxygen consumption and production; V̇O2$$ \dot{V}{\mathrm{O}}_2 $$) via a sensor dish reader microplate system to rapidly measure physiological rates of the early life stages of three habitat‐forming macroalgae, the kelp Ecklonia radiata and the fucoids Hormosira banksii and Phyllospora comosa. We measured the rate of O2 consumption (respiration) and O2 production (net primary production) to then calculate gross primary production (GPP) under temperatures representing their natural thermal range. The V̇O2$$ \dot{V}{\mathrm{O}}_2 $$ microplate system was suitable for rapidly measuring physiological rates over a temperature gradient to establish thermal performance curves for all species. The V̇O2$$ \dot{V}{\mathrm{O}}_2 $$ microplate system proved efficient for measures of early life stages of macroalgae ranging in size from approximately 50 μm up to 150 mm. This method has the potential for measuring responses of early life stages across a range of environmental factors, species, populations, and developmental stages, vastly increasing the speed, precision, and efficacy of macroalgal physiological measures under future ocean change scenarios. [ABSTRACT FROM AUTHOR]

Background: The high‐sensitivity HEART pathway (hs‐HP) risk stratifies emergency department (ED) patients with chest pain. It is unknown if its safety and effectiveness vary by sex or race. Methods: We conducted a subgroup analysis of the hs‐HP implementation study, a pre−post interrupted time series at five US EDs. The pre‐implementation period (January 2019 to April 2020) utilized the traditional HEART pathway with contemporary troponin (Siemens) and the post‐implementation period (November 2020 to February 2022) used the hs‐HP using hs‐cTnI (Beckman Coulter). Patients were risk‐stratified using the hs‐HP to rule‐out, observation, and rule‐in groups. Safety and effectiveness outcomes were 30‐day all‐cause mortality or myocardial infarction (MI) and 30‐day hospitalization. Results: Twenty‐six thousand and one hundred twenty‐six patients were accrued (12 317 pre‐ and 13 809 post‐implementation), of which 35.3% were non‐White and 52.7% were female. Among 9703 patients with complete hs‐HP assessments, 48.6% of White and 55.4% of non‐White patients were ruled‐out (p < 0.001). Additionally, 47.3% of males and 54.4% of females were ruled‐out (p < 0.001). Among rule‐out patients, 0.3% of White versus 0.3% of non‐White patients (p = 0.98) and 0.3% of females versus males 0.3% (p = 0.90) experienced 30‐day death or MI. Post‐implementation, 30‐day hospitalization decreased 17.2% among White patients (aOR 0.49, 95% CI: 0.45−0.52), 14.1% among non‐White patients (aOR 0.53, 95% CI: 0.48−0.59), 15.6% among females (aOR 0.50, 95% CI: 0.46−0.54), and 16.6% among males (aOR 0.51, 95% CI: 0.47−0.56). The interactions for 30‐day hospitalization between hs‐HP implementation and race (p = 0.10) and sex (p = 0.69) were not significant. Conclusions: The hs‐HP safely decreases 30‐day hospitalizations regardless of sex or race. However, it classifies more non‐White patients and women to the rule‐out group. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) is a globally significant, vector-borne, neglected tropical disease that can result in severe morbidity and disability. As the World Health Organization (WHO) Global Programme to Eliminate Lymphatic Filariasis makes progress towards LF elimination, there is greater need to develop sensitive strategies for post-intervention surveillance. Molecular xenomonitoring (MX), the detection of pathogen DNA in vectors, may provide a sensitive complement to traditional human-based surveillance techniques, including detection of circulating filarial antigen and microfilaraemia (Mf). This study aims to explore the relationship between human Mf prevalence and the prevalence of polymerase chain reaction (PCR)-positive mosquitoes using MX. Methods: This study compared Mf and MX results from a 2019 community-based survey conducted in 35 primary sampling units (PSUs) in Samoa. This study also investigated concordance between presence and absence of PCR-positive mosquitoes and Mf-positive participants at the PSU level, and calculated sensitivity and negative predictive values for each indicator using presence of any Mf-positive infection in humans or PCR-positive mosquitoes as a reference. Correlation between prevalence of filarial DNA in mosquitoes and Mf in humans was estimated at the PSU and household/trap level using mixed-effect Bayesian multilevel regression analysis. Results: Mf-positive individuals were identified in less than half of PSUs in which PCR-positive mosquito pools were present (13 of 28 PSUs). Prevalence of PCR-positive mosquitoes (each species separately) was positively correlated with Mf prevalence in humans at the PSU level. Analysed at the species level, only Aedes polynesiensis demonstrated strong evidence of positive correlation (r) with human Mf prevalence at both PSU (r: 0.5, 95% CrI 0.1–0.8) and trap/household levels (r: 0.6, 95% CrI 0.2–0.9). Conclusions: Findings from this study demonstrate that MX can be a sensitive surveillance method for identifying residual infection in low Mf prevalence settings. MX identified more locations with signals of transmission than Mf-testing. Strong correlation between estimated PCR-positive mosquitoes in the primary vector species and Mf in humans at small spatial scales demonstrates the utility of MX as an indicator for LF prevalence in Samoa and similar settings. Further investigation is needed to develop MX guidelines to strengthen the ability of MX to inform operational decisions. [ABSTRACT FROM AUTHOR]

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During and subsequent to a natural disaster, there is an expectation that certain elements of society will continue to operate with a degree of normalcy. For example, it is expected that emergency medical services will continue to function and remain reliable for the community served. Expectations such as these are based on the presumed reliability of government and the assumption that those responsible for the relevant infrastructure will have made plans to ensure it remains functional and taken steps to mitigate known weaknesses. The COVID-19 pandemic provides a case in point. Specifically, data captured during the pandemic are now the subject of ongoing review and analysis, and the findings from such studies are being used to inform planning and preparedness for the next public health disaster. This particular study was conducted in response to circumstantial evidence indicating that frontline workers in the healthcare profession may share some of the same ambivalence towards transmission mitigation as seen in the general population when confronted with new and emerging communicable diseases. This is a concern, as when medical personnel are either unable or unwilling to take reasonable steps to protect themselves and their patients, it undermines the readiness of the essential service. To explore this situation in greater depth, the study examines the real-time responses from a sample of frontline personnel interviewed during the pandemic. The results indicate that there are a number of opportunities to improve workforce readiness to assure reliable continuity during the next outbreak, epidemic or pandemic. [ABSTRACT FROM AUTHOR]

Aims: Standard neoadjuvant endocrine therapy (NAET) is used for 6–9 months to downstage hormone‐receptor‐positive breast cancer. Bridging ET was introduced during the COVID‐19 pandemic to delay surgical intervention. There are no data in the literature on the effect of short course therapy on tumour response. We aimed to analyse the effect of bridging ET and validate the previously proposed neoadjuvant ET pathological reporting criteria. Methods and Results: This was a multicentre cohort of 256 patients who received bridging ET between March and October 2020. Assessment of paired pre‐ and post‐NAET hormone receptors and HER2 and posttherapy Ki67 expression was done. The median duration of NAET was 45 days. In all, 86% of cases achieved partial pathological response and 9% showed minimal residual disease. Histological response to ET was observed from as early as day 6 posttherapy. Central scarring was noted in 32.8% of cases and lymphocytic infiltrate was seen in 43.4% of cases. Significant changes associated with the duration of ET were observed in tumour grade (21%), with downgrading identified in 12% of tumours (P < 0.001), progesterone receptor (PR) expression with switch to PR‐negative status in 26% of cases (P < 0.001), and HER2 status with a switch from HER2‐low to HER2‐negative status in 32% of cases (P < 0.001). The median patient survival was 475 days, with an overall survival rate of 99.6%. Conclusions: Changes characteristic of tumour regression and significant changes in PR and HER2 occurred following a short course of NAET. The findings support biomarker testing on pretreatment core biopsies and retesting following therapy. [ABSTRACT FROM AUTHOR]

Background: There are limited data on the role of multigene tests and their correlation with immunohistochemistry (IHC), especially on core biopsy. MammaTyper is a quantitative conformite Europeeanne (CE) marked, National Institute for Health and Care excellence (NICE) approved, in in vitro diagnostic quantitative real‐time polymerase chain reaction (RT‐qPCR) test for assessment of mRNA expression of four biomarkers (ESR1, PGR, ERBB2, MKI67). Methods: We evaluated the concordance of MammaTyper with oestrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 by IHC on 133 core needle biopsies of breast cancer. HER2 was positive if IHC 3+ or 2+ and fluorescence in situ hybridization (FISH)‐amplified. Global and hotspot Ki67 expression was analysed using a cutoff of ≥20% assessed manually and by digital image analysis. Agreements were expressed as overall percent agreement (OPA), positive percent agreement (PPA), negative percent agreement (NPA), and Cohen's kappa. Results: RT‐qPCR results of ESR1 were highly concordant with IHC with OPA of 94.7% using 1% cutoff and 91.7% when the low ER‐positive category was included. The PPA and NPA between RT‐qPCR and IHC for PR was 91.5% and 88.0%, respectively, when using the 1% cutoff. For ERBB2/HER2, the OPA was 95% and the PPA was 84.6%. 40 of 72 HER2 IHC score 0 tumours were classified as ERBB2 low. Best concordance between MKI67 by MammaTyper and Ki67 IHC was achieved using hotspot digital image analysis (OPA: 87.2%, PPA: 90.6%, NPA: 80%). Conclusion: RT‐qPCR‐based assessment of the mRNA expression of ESR1, PGR, ERBB2, and MKI67 showed high concordance with IHC, suggesting that the MammaTyper test on core needle biopsies represents a reliable, efficient, and reproducible alternative for breast cancer classification and refining HER2 low categorisation. [ABSTRACT FROM AUTHOR]

We analyse whether US federal aid to state and local governments impacted economic activity through either direct or cross-state spillover effects during the COVID-19 pandemic. Deploying an instrumental-variables framework rooted in the funding advantage of states that are over-represented in Congress, we find that federal assistance had significantly less impact on state and local government employment, as well as broader measures of economic activity, than estimates from prior crisis responses would imply. The modest employment impacts we find stem largely from the direct effect of states' own aid allocation, as opposed to spillovers across state lines. These findings point to an important role for variations in fiscal policy transmission mechanisms, namely that cross-state spillovers are less likely to be important when some of the key mechanisms for such spillovers, like robust interjurisdictional supply chains and patterns of consumption, are muted or shut down. [ABSTRACT FROM AUTHOR]

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2’s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.The evolutionarily conserved SARS-CoV-2 spike’s S2 subunit provides the foundation for its usage as an immunogen in vaccines. Here, the authors use a simulation-driven approach to design S2-only immunogens stabilized in the closed prefusion conformation. [ABSTRACT FROM AUTHOR]

The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological inhibition has not been defined. Triple-negative breast cancer SUM149PT, HCC1937, and MDA-MB-231 cells were used to assess the mechanism of action of the CHD1Li OTI-611. Cytotoxicity as a single agent or in combination with standard-of-care treatments was assessed in tumor organoids. Immunofluorescence was used to assess the translocation of PAR and AIF to the cytoplasm or the nucleus and to study markers of DNA damage or apoptosis. Trapping of PARP1/2 or CHD1L onto chromatin was also assessed by in situ subcellular fractionation and immunofluorescence and validated by Western blot. We show that the inhibition of CHD1L's ATPase activity by OTI-611 is cytotoxic to triple-negative breast cancer tumor organoids and synergizes with PARPi and chemotherapy independently of the BRCA mutation status. The inhibition of the remodeling function blocks the phosphorylation of H2AX, traps CHD1L on chromatin, and leaves PAR chains on PARP1/2 open for hydrolysis. PAR hydrolysis traps PARP1/2 at DNA damage sites and mediates PAR translocation to the cytoplasm, release of AIF from the mitochondria, and induction of PARthanatos. The targeted inhibition of CHD1L's oncogenic function by OTI-611 signifies an innovative therapeutic strategy for breast cancer and other cancers. This approach capitalizes on CHD1L-mediated DNA repair and cell survival vulnerabilities, thereby creating synergy with standard-of-care therapies [ABSTRACT FROM AUTHOR]

Introduction: Aspiration pneumonia (AP) is an infection of the lungs caused by inhalation of material. The reported incidences vary across literature and clinical populations and is associated with high morbidity and mortality. Management of AP is best carried out by a multidisciplinary team. Methods: This aim of this review was to collate and describe the available evidence on AP to develop a greater understanding of the concept of AP as it is represented in the nursing literature. As a collaborative team, we undertook the six stages of a systematic mapping review. We searched for the term aspiration pneumonia in 200 peer reviewed nursing journals across 10 databases, over a ten-year period (2013-2023). Results: In this review, 293 papers were coded. Dysphagia, oral health and tube feeding emerged as the most frequent risk factors for AP, and the most reported factors for preventing this condition. Mortality was the most commonly described consequence of AP, followed by hospitalisations and morbidity. Multiple management approaches were reported including dysphagia assessment, risk evaluation, oral care and texture modification of food and fluids. The role of nurses and interprofessional collaborations were described. Discussion: Despite limited evidence related to the topic of AP in the nursing literature, the complexity of the causes, prevention, management and consequences of AP emerged. Certain factors, such as dysphagia, oral health, and tube feeding, were described under prevention, cause and management of AP. The importance of multidisciplinary approach in the management and prevention of AP was presented. [ABSTRACT FROM AUTHOR]

Presented here is a systematic literature review of what the academic literature asserts about: (1) the stages of the ethical decision-making process (i.e. awareness, reasoning, motivation, and action) that are claimed to be improved or not improved by RI teaching and whether these claims are supported by evidence; (2) the measurements used to determine the effectiveness of RI teaching; and (3) the stage/s of the ethical decision-making process that are difficult to assess. Regarding (1), awareness was the stage most claimed to be amenable to improvement following RI teaching, and with motivation being the stage that is rarely addressed in the academic literature. While few, some sources claimed RI teaching cannot improve specific stages. With behaviour (action) being the stage referenced most, albeit in only 9% of the total sources, for not being amenable to improvement following RI teaching. Finally, most claims were supported by empirical evidence. Regarding (2), measures most frequently used are custom in-house surveys and some validated measures. Additionally, there is much debate in the literature regarding the adequacy of current assessment measures in RI teaching, and even their absence. Such debate warrants caution when we are considering the empirical evidence supplied to support that RI teaching does or does not improve a specific stage of the decision-making process. Regarding (3), only behaviour was discussed as being difficult to assess, if not impossible. In our discussion section we contextualise these results, and following this we derive some recommendations for relevant stakeholders in RI teaching. [ABSTRACT FROM AUTHOR]

Pantoprazole is a proton pump inhibitor indicated for the treatment of gastroesophageal reflux disease, a condition that disproportionately affects children with obesity. Appropriately dosing pantoprazole in children with obesity requires understanding the body size metric that best guides dosing, but pharmacokinetic (PK) trials using traditional techniques are limited by the need for larger sample sizes and frequent blood sampling. Physiologically‐based PK (PBPK) models are an attractive alternative that can account for physiologic‐, genetic‐, and drug‐specific changes without the need for extensive clinical trial data. In this study, we explored the effect of obesity on pantoprazole PK and evaluated label‐suggested dosing in this population. An adult PBPK model for pantoprazole was developed using data from the literature and accounting for genetic variation in CYP2C19. The adult PBPK model was scaled to children without obesity using age‐associated changes in anatomical and physiological parameters. Lastly, the pediatric PBPK model was expanded to children with obesity. Three pantoprazole dosing strategies were evaluated: 1 mg/kg total body weight, 1.2 mg/kg lean body weight, and US Food and Drug Administration‐recommended weight‐tiered dosing. Simulated concentration–time profiles from our model were compared with data from a prospective cohort study (PAN01; NCT02186652). Weight‐tiered dosing resulted in the most (>90%) children with pantoprazole exposures in the reference range, regardless of obesity status or CYP2C19 phenotype, confirming results from previously published population PK models. PBPK models may allow for the efficient study of physiologic and developmental effects of obesity on PK in special populations where clinical trial data may be limited. [ABSTRACT FROM AUTHOR]

Exploring online criticisms of the "take the knee" protest during "Euro 2020", this article examines how alt- and far-right conspiracies were both constructed and communicated via the social media platform, Twitter. By providing a novel exploration of alt-right conspiracies during an international football tournament, a qualitative thematic analysis of 1,388 original tweets relating to Euro 2020 was undertaken. The findings reveal how, in criticisms levelled at both "wokeism" and the Black Lives Matter movement, anti-white criticisms of the "take the knee" protest were embroiled in alt-right conspiracies that exposed an assumed Cultural Marxist, "woke agenda" in the tournament's organisation and mainstream media coverage. In conclusion, it is argued that conspiratorial discourses, associated with the alt-right, provided a framework through which the protest could be understood. This emphasises how the significance of conspiracy functions to promote the wider dissemination of alt-right ideology across popular cultural contexts, such as sport. [ABSTRACT FROM AUTHOR]

We examine Auckland's 'City of Music' (ACM) place branding initiative, outlining its aspirations and gauging its contribution to the vitality of Auckland's underlying music scene. We draw on documentary evidence, media reports, first‐hand observations and a series of interviews with brand advocates and music insiders. The paper highlights tensions between the 'City of Music' brand and the understandings of those whose work, identities, daily lives and lived spaces are appropriated to give it substance. We conclude that ACM has injected resources into the Auckland music 'scene' but fails to represent faithfully its vitality and complex ecology. [ABSTRACT FROM AUTHOR]

We examine how design features influence the experiences of attendees at New Zealand music festivals. Drawing on interviews with festival organisers and attendees, we argue that organisers configure particular atmospheres to provoke affective dispositions. By interrogating how festivals engage in this affective engineering, we argue that festivals are ephemeral spaces where design plays a central role in influencing the thoughts, feelings, behaviours and, ultimately, the place‐experience of attendees. [ABSTRACT FROM AUTHOR]

I investigate intersections between music and mobilities as manifested in songwriter and musician Anthonie Tonnon's Rail Land tour of 2019–20. These concerts celebrated New Zealand's passenger rail heritage through not only performance but also by mobilising the audience to travel by train to the concert venue. The curation of both journey and destination amounted to a subtle activism. In influencing the way people travelled to his shows, Tonnon effectively remobilised a consideration of train travel in which the journey was arguably as memorable as the destination. As such, the artist was contributing to a re‐entwining of music, identity and place. [ABSTRACT FROM AUTHOR]

Purpose of Review: To evaluate the adverse effects of common antihypertensive agents utilized or encountered in the Emergency Department. Recent Findings: All categories of antihypertensive agents may manifest adverse effects, inclusive of adverse drug reactions (ADRs), drug-to-drug interactions, or accidental overdose. Adverse effects, and specifically ADRs, may be stratified into the organ systems affected, might require specific time-sensitive interventions, could pose particular risks to vulnerable populations, and may result in significant morbidity, and potential mortality. Summary: Adverse effects of common antihypertensive agents may be encountered in the ED, necessitating that ED systems of care are poised to prevent, recognize, and intervene when adverse effects arise. [ABSTRACT FROM AUTHOR]

To explore both environmental change and the response of non‐fossilizing phytoplankton across the Cretaceous‐Paleogene (K‐Pg) boundary mass extinction event, we determined changes in organic matter (OM) sources using a range of apolar (n‐alkanes, acyclic isoprenoids, steranes, and hopanes) and polar (BIT index) biomarkers. We analyzed two K‐Pg proximal sections, located in the Mississippi Embayment, Gulf Coastal Plain (USA), covering ∼300 kyrs prior to and ∼3 myrs after the K‐Pg event. The OM abundance and composition changed dramatically across the boundary. The post‐impact ejecta layer and burrowed unit are characterized by an increase in the mass accumulation rate (MAR) of plant and soil biomarkers, including high‐molecular‐weight n‐alkanes and C29 steranes as well as the BIT index, related to an erosive period which transported terrestrial OM to the ocean in the aftermath of the impact event. At the same time, MARs of putative aquatic biomarkers decrease (low‐molecular‐weight n‐alkanes, C27 steranes and pristane and phytane), which suggests a collapse of the marine phytoplankton community. The increase of terrestrial OM to the ocean, during the first 280 kyrs after the Chicxulub impact event, is a combination of reworked kerogen, soil and some plant material. Crucially, within the latter part of this erosion period, only ∼160 kyrs after the K‐Pg do biomarkers return to distributions similar to those in the upper Cretaceous, although not to pre‐impact MARs. Thus, our results suggest a long‐term interval for the full sedimentary and ecological recovery of the non‐fossilizing phytoplankton community after this event. Plain Language Summary: The Cretaceous‐Paleogene (K‐Pg) boundary coincides with the latest of the five major mass extinctions in Earth's history. Determining the nature of the associated rapid environmental change and biotic recovery is critical for knowing the cause and effects of this key event and contributes to our understanding of the ongoing biodiversity crisis. We analyzed biomarkers (molecular fossils) in two K‐Pg sections in the Gulf Coastal Plain (USA) near the impact site, covering ∼300,000 years prior to, and ∼3,000,000 years after the K‐Pg event. The organic matter (OM) abundance and composition changed dramatically after the impact event. In particular, an increase in the concentration of plant and soil biomarkers occurred in the first 280,000 years after the impact and is attributed to an erosive period which transported OM from the land to the ocean. At the same time, the concentrations of marine algal biomarkers decrease, suggesting a collapse of the marine algal community. About 160,000 after the K‐Pg event, marine biomarkers return to distributions similar to those pre‐impact. This suggests an initial recovery of algal communities on the Gulf Coastal Plain, although they never recover to pre‐impact abundances during the studied interval (∼3,000,000 after impact). Key Points: Intense erosive regime after the K‐Pg boundary, coincident with collapse of the marine phytoplankton community on the Gulf Coastal PlainInitial recovery of non‐fossilizing algal communities started ∼160 kyr after the K‐Pg event although with lower mass accumulation rates than pre‐impactSedimentary conditions never return to their pre‐impact state, suggesting a long‐term perturbation to the system [ABSTRACT FROM AUTHOR]

The Canterbury Earthquake Sequence of 2010–2012 was devastating for Christchurch, New Zealand, a city built on a floodplain. The sequence resulted in widespread damage across the central business district (CBD) and residential areas. Alongside, and in contrast to, orthodox planning responses by the New Zealand Government, playful, creative, and temporary projects emerged in vacant spaces. These were designed to bring back life and energy to the city centre, and such types of activity are referred to by scholars as do‐it‐yourself (DIY) urbanism. A primary critique of DIY urbanism in the literature relates to how it has the potential to contribute to gentrification, despite its amateurish appearance and mildly subversive politics. In Christchurch, a venue built from pallets—known as the Pallet Pavilion—was constructed by an organisation known as "Gap Filler" with the help of volunteers. Gap Filler emerged after the first earthquake, inserting creative projects to bring back life and energy to the damaged CBD. By examining the Pallet Pavilion, we show that, despite its potentially gentrifying effects, DIY urbanism interventions may open up a more inclusive politics of the city. Also, and paradoxically, in the case of the Pallet Pavilion, the exercise of privilege made this inclusive politics possible. [ABSTRACT FROM AUTHOR]

Perceptions of neighbourhood change have been an important area of inquiry for several reasons, including for their effects upon place attachment, mobility intentions, and links to mental and physical health. In this article, we take a different perspective by assessing residents' perceptions of neighbourhood compositional changes relating to social class and ethnicity and considering them as potential pathways to other social and psychosocial outcomes. In addition, we examine how these relationships are moderated in situations where policy is a prime cause of neighbourhood change through state-led regeneration. Across deprived areas, perceptions of social mix are positively associated with residential satisfaction, community cohesion, and feelings of empowerment and safety. Perceptions of ethnic diversity are positively associated with empowerment and safety, and negatively with area reputation. In regeneration areas, perceived social mix is positively associated with most outcomes but perceived ethnic mix holds negative associations; neither appears to impact external reputations. [ABSTRACT FROM AUTHOR]

Microbial communities such as biofilms are commonly found at interfaces. However, it is unclear how the physical environment of interfaces may contribute to the development and behavior of surface-associated microbial communities. Combining multimode imaging, single-cell tracking, and numerical simulations, here, we found that activity-induced interface bulging promotes colony biofilm formation in Bacillus subtilis swarms presumably via segregation and enrichment of sessile cells in the bulging area. Specifically, the diffusivity of passive particles is ~50% lower inside the bulging area than elsewhere, which enables a diffusion-trapping mechanism for self-assembly and may account for the enrichment of sessile cells. We also uncovered a quasilinear relation between cell speed and surface-packing density that underlies the process of active interface bulging. Guided by the speed-density relation, we demonstrated reversible formation of liquid bulges by manipulating the speed and local density of cells with light. Over the course of development, the active bulges turned into striped biofilm structures, which eventually give rise to a large-scale ridge pattern. Our findings reveal a unique physical mechanism of biofilm formation at air-solid interface, which is pertinent to engineering living materials and directed self-assembly in active fluids. [ABSTRACT FROM AUTHOR]

Nanomedicine has the potential to increase the biostability of drugs to treat retinal diseases, improving their performance and decreasing the required number of intravitreal injections. However, accurate pharmacokinetic studies of these nanoparticle-drug conjugates, nanoparticle motion across the vitreous humour and interaction with the retinal cell layers still need to be investigated. Existing nanoparticle tracking techniques require fluorescent labels, which can impact cytotoxicity, nanoparticles' motion, protein interactions, and cell internalization. In this study, a real-time label-free tracking technology, for single nanoparticles in an optical microscope based on the optical phenomena of caustics, was used to characterise the diffusion of nanoparticles in agar-hyaluronic acid hydrogels, previously validated as vitreous humour substitutes for in vitro models. The results demonstrated that the diffusion of nanoparticles through these hydrogels was heterogeneous, and that nanoparticle size had an important role in nanoparticle distribution across and within in vitro vitreous substitutes. These findings suggest that nanoparticle diameter is a critical parameter for designing novel therapeutics for retinal diseases. Moreover, nanoparticle charge did not affect nanoparticle diffusion or distribution in these synthetic hydrogels. The use of caustics in optical microscopy has been demonstrated to be a reproducible, inexpensive technique for screening novel therapeutics in eye in vitro models. [ABSTRACT FROM AUTHOR]

Museum genomics provide an opportunity to investigate population demographics of extinct species, especially valuable when research prior to extinction was minimal. The Bachman’s warbler (Vermivora bachmanii) is hypothesized to have gone extinct due to loss of its specialized habitat. However, little is known about other potential contributing factors such as natural rarity or changes to connectivity following habitat fragmentation. We examined mitochondrial DNA (mtDNA) and genome-wide SNPs using specimens collected from breeding and migration sites across the range of the Bachman’s warbler. We found no signals of strong population structuring across the breeding range of Bachman’s warblers in both mtDNA and genome-wide SNPs. Thus, long-term population isolation did not appear to be a significant contributor to the extinction of the Bachman’s warbler. Instead, our findings support the theory that Bachman’s warblers underwent a rapid decline likely driven by habitat destruction, which may have been exacerbated by the natural rarity, habitat specificity and low genetic diversity of the species. [ABSTRACT FROM AUTHOR]

Museum genomics provide an opportunity to investigate population demographics of extinct species, especially valuable when research prior to extinction was minimal. The Bachman’s warbler (Vermivora bachmanii) is hypothesized to have gone extinct due to loss of its specialized habitat. However, little is known about other potential contributing factors such as natural rarity or changes to connectivity following habitat fragmentation. We examined mitochondrial DNA (mtDNA) and genome-wide SNPs using specimens collected from breeding and migration sites across the range of the Bachman’s warbler. We found no signals of strong population structuring across the breeding range of Bachman’s warblers in both mtDNA and genome-wide SNPs. Thus, long-term population isolation did not appear to be a significant contributor to the extinction of the Bachman’s warbler. Instead, our findings support the theory that Bachman’s warblers underwent a rapid decline likely driven by habitat destruction, which may have been exacerbated by the natural rarity, habitat specificity and low genetic diversity of the species. [ABSTRACT FROM AUTHOR]

While the current practice of pilot training relies on flight instructors' subjective assessment, computational cognitive modeling may be used to support future objective assessment and diagnosis of pilot performance. We built two models in a cognitive architecture to simulate pilot flight performance during pre-flight and take-off tasks. Modeling results were compared with human results collected from the same tasks using X-Plane 11 flight simulator. The models were able to capture human pilot performance and workload results from both tasks with good levels of fitness (percentage errors ranging from 0.8% to 13.2%). This work demonstrated the capability and advantage of this theory-driven modeling approach for supporting general aviation pilot training. We expect that this type of cognitive model will be complementary to data-driven machine learning models, and the current work provides the foundation for future work to expand the modeling capability and test practical applications in general aviation. [ABSTRACT FROM AUTHOR]

The Splendid Fairywren Malurus splendens has four distinct phenotypic forms currently recognised as subspecies, although three species have been recognised within the group in the past. Here, we use multilocus nuclear DNA to test the recent hypothesis that the Splendid Fairywren represents three allopatric taxa with little to no modern-day contact, despite phenotypic evidence of periods of past contact and gene flow. Our nuclear dataset is concordant with earlier mtDNA-based data in supporting three distinct genetic groups within M. splendens. These genetic groups align with the three phenotypically distinct forms recently hypothesised to be allopatric and previously described at species-level – western M. splendens, central M. callainus and eastern M. melanotus. Nuclear gene flow does not appear to be rampant between the three forms; however, several individuals show signals of admixed nuclear ancestry, which we cannot distinguish as having resulted from incomplete lineage sorting, poor phylogenetic signal, or gene flow. Given changing modern taxonomic interpretations of the significance of gene flow in speciation, we argue that recognising three distinct species within the M. splendens complex might better represent their evolutionary distinctiveness, rather than continuing to treat these genetically and morphologically distinct forms as subspecies of a widespread polytypic species. Our study highlights the interesting complexity of determining species status when taxa are in the 'grey zone' near the subspecies/species continuum, and the value gained from adding perspectives from nuclear DNA. [ABSTRACT FROM AUTHOR]

Oestrogen receptor (ER)-positive breast cancer (BC) is generally well responsive to endocrine therapy. Neoadjuvant endocrine therapy (NAET) is increasingly being used for downstaging ER-positive tumours. This study aims to analyse the effect of NAET on a well-characterised cohort of ER-positive BC with particular emphasis on receptor expression. This is a retrospective United Kingdom (UK) multicentre study of 391 patients who received NAET between October 2012 and October 2020. Detailed analyses of the paired pre- and post-NAET morphological changes and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression were performed. The median duration of NAET was 86 days, with median survival and overall survival rates of 380 days and 93.4%, respectively. A total of 90.3% of cases achieved a pathological partial response, with a significantly higher rate of response in the HER2-low cancers. Following NAET, BC displayed some pathological changes involving the tumour stroma including central scarring and an increase in tumour infiltrating lymphocytes (TILs) and tumour cell morphology. Significant changes associated with the duration of NAET were observed in tumour grade (30.6% of cases), with downgrading identified in 19.3% of tumours (p < 0.001). The conversion of ER status from positive to low or negative was insignificant. The conversion of progesterone receptor (PR) and HER2 status to negative status was observed in 31.3% and 38.1% of cases, respectively (p < 0.001). HER2-low breast cancer decreased from 63% to 37% following NAET in the paired samples. Significant morphological and biomarker changes involving PR and HER2 expression occurred following NAET. The findings support biomarker testing on pre-treatment core biopsies and post-treatment residual carcinoma. [ABSTRACT FROM AUTHOR]

Probiotics are increasingly used to treat conditions associated with gastrointestinal injury and permeability, including exercise-induced gastrointestinal discomfort. This study assessed safety and efficacy of a probiotic in altering the intestinal milieu and mitigating gastrointestinal symptoms (GIS) in endurance runners. In a double blind, crossover study, 16 runners were randomized to 4 weeks of daily supplementation with a probiotic cocktail containing Pediococcus acidilactici bacteria and Lactobacillus plantarum or placebo. Fasting blood and stool samples were collected for measurement of gut permeability markers, immune parameters, and microbiome analyses. Treadmill run tests were performed before and after treatment; participants ran at 65%–70% of VO2max at 27 °C for a maximum of 90 min or until fatigue/GIS developed. A blood sample was collected after the treadmill run test. In healthy individuals, 4 weeks of probiotic supplementation did not alter health parameters, although a marginal reduction in aspartate aminotransferase levels was observed with probiotic treatment only (p = 0.05). GIS, gut permeability-associated parameters (intestinal fatty acid binding protein, lipopolysaccharide binding protein, zonulin, and cytokines), and intestinal microbial content were not altered by the probiotic supplementation. Post-run measurements of GIS and gut-associated parameters did not differ between groups; however, the observed lack of differences is confounded by an absence of measurable functional outcome as GIS was not sufficiently induced during the run. Under the current study conditions, the probiotic was safe to use, and did not affect gut- or immune-associated parameters, or intestinal symptoms in a healthy population. The probiotic might reduce tissue damage, but more studies are warranted. [ABSTRACT FROM AUTHOR]

Objectives: While terrorism studies were once castigated as atheoretical and unempirical, criminology has been well suited to apply theories of crime to terrorism and to then test those theories with rigorous methods and robust data. The present study takes stock of how criminologists have theorized about terrorism and tested those theories over time in 13 of the discipline's leading journals. Methods: The study systematically examines theoretical framing, hypotheses, methodological approach, focus within criminology and criminal justice, and policy recommendations in terrorism-focused articles. Results: While terrorism has become more central within top journals, sparse attention has been paid to many criminological theories that could help us understand terrorism. Additional qualitative, theoretical, and mixed-methods research is needed. Further, few articles address the making of terrorism laws. We identify other systematic strengths and weaknesses across the literature and highlight domains for future research. Conclusions: Criminological research on terrorism has engaged theories within and beyond the discipline and employed a range of methodologies with diverse data sources to make contributions to both our broader field and to the larger body of scholarship on terrorism. Yet, many opportunities exist for criminologists to expand research on the making, breaking, and reaction to break laws regarding terrorism. [ABSTRACT FROM AUTHOR]

Background and Objective: Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct. Methods: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0–18 years, TBW) or fat-free mass (2–18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity. Results: A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied. Conclusion: Using real-world data and PopPK modeling, enoxaparin's pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity. [ABSTRACT FROM AUTHOR]

Background: Childbirth reserves respect, as emphasized by the World Health Organization in 2018, and the focus towards the need for positive, dignified delivery experiences has become an integral aspect of Respectful Maternity Care (RMC). It is a known fact that RMC is pivotal for favourable birth outcomes and contributes to the satisfaction of maternity care. The absence of RMC negatively affects women's and newborns' rights. The study aimed to explore healthcare providers' perspectives on sustaining RMC actions that mothers previously reported. Methodology: This study was conducted in five hospitals in the Eastern province of Rwanda, involving 5 Focus Group Discussions (FGDs) with midwives and nurses. For interviews, we purposively selected 5-unit managers and five physicians. Additionally, 40 midwives and nurses were recruited for the FGDs. The research utilized the Dream phase of Appreciative Inquiry (AI) for interviews and Focus Groups. Data collection aimed to gain insights into Healthcare Providers' perceptions of how RMC is provided and how to establish and sustain RMC in Rwandan health facilities. Nvivo 12 was employed for organizing codes and creating a codebook, and thematic analysis was applied. Results: Four themes with sub-themes emerged. Namely, 1) Women-centered care, with Compassionate care, Privacy and confidentiality maintenance, Information provision and Liberty in decision making, Effective communication, Family involvement, Cleanliness, and Equality care. 2) Professionalism compliance with Motivated staff, Teamwork, Continuous development, Quality work provision, and Community trust. 3) RMC encounters 4) RMC sustenance. Conclusion and recommendations: The continuous pursuit of high RMC standards in Rwanda involves improving childbirth experiences through utilizing existing resources, ongoing improvement, and sustaining achievements. Key recommended actions in this study for sustaining RMC encompass promoting women-centred care, enhancing healthcare provider attitudes, ensuring professionalism, building community trust, maintaining conducive health facility environments, and involving leadership. [ABSTRACT FROM AUTHOR]

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management. [ABSTRACT FROM AUTHOR]