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Both men and women who violate gender stereotypes incur backlashes, or penalties, for these transgressions. However, men who engage in warm, communal behaviors occasionally receive a boost (or benefit) for this female‐stereotyped behavior. To understand how and why warmth and gender interact to predict backlashes or boosts, we integrate uncertainty reduction theory with the stereotype content model and examine warmth by gender interactions. In our first study (a field examination of job seekers), we find that men receive a boost in hireability (i.e., an increased likelihood of obtaining a job offer) for exhibiting gender incongruent (i.e., high) levels of warmth, but women do not receive a backlash in hireability for exhibiting gender incongruent (i.e., low) levels of warmth. In our second study (a laboratory experiment), we replicate and extend these findings by elucidating why they occur: warmth reduces relational uncertainty for male, but not female, applicants. In our third study (another laboratory experiment), we again replicate and extend our findings by identifying when these effects are stronger: in male‐dominated roles. Our investigation suggests that the valence of the gender stereotype violation matters when it comes to hiring decisions. Indeed, we find that displaying warmth appears to promote, rather than impede, career outcomes for men. [ABSTRACT FROM AUTHOR]

Summary: HbSC disease is a common form of sickle cell disease with significant morbidity and early mortality. Whether hydroxyurea is beneficial for HbSC disease is unknown. Prospective Identification of Variables as Outcomes for Treatment (PIVOT, Trial ID PACTR202108893981080) is a double‐blind, randomised, placebo‐controlled phase II trial of hydroxyurea for people with HbSC, age 5–50 years, in Ghana. After screening, participants were randomised to placebo (standard of care) or hydroxyurea. The primary outcome is the cumulative incidence of haematological toxicities during 12 months of blinded treatment; secondary outcomes include multiple laboratory and clinical assessments. Between April 2022 and June 2023, 112 children and 102 adults were randomised, including 44% females and average age 21.6 ± 14.5 years. Participants had substantial morbidity including previous hospitalisations (93%), vaso‐occlusive events (86%), malaria (79%), often received transfusions (20%), with baseline haemoglobin 11.0 ± 1.2 g/dL and foetal haemoglobin 1.8% ± 1.5%. The spleen was palpable in six children and one adult, and ultrasonographic volumes were collected. Proliferative sickle retinopathy was common (30% children, 75% adults), but proteinuria was less common (3% children, 8% adults). Whole blood viscosity, ektacytometry, point‐of‐sickling, transcranial Doppler, near‐infrared spectrometry (NIRS), 6‐minute walk, and quality of life were also measured. Now fully enrolled, PIVOT will document the safety and potential benefits of hydroxyurea on clinical and laboratory outcomes in HbSC disease. [ABSTRACT FROM AUTHOR]

To help ensure a prosperous future on Earth for coming generations, academia and industry need to transform the way they plan and carry out the synthesis of novel materials to make them more environmentally sustainable. In particular, the field of reticular materials, i.e., metal‐organic frameworks, zeolitic imidazolate frameworks, and covalent organic frameworks, has great potential to outperform other materials and revolutionize various fields of applications. This review highlights several key aspects from the choice of their starting materials, solvents and synthetic methodologies that fall under the umbrella of the Green Chemistry principles, and incorporates a Circular Economy perspective by providing relevant strategies such as reuse, regeneration, or recycling to maximize the value of the Earth's available resources. Moreover, it will shed light on the life cycle assessment results of selected reticular materials and consider how constraints imposed by Green Chemistry principles, life cycle assessment metrics, and circular patterns will shape the future rational sustainable design and discovery of reticular materials. [ABSTRACT FROM AUTHOR]

Shrinking saline lakes provide irreplaceable habitat for waterbird species globally. Disentangling the effects of wetland habitat loss from other drivers of waterbird population dynamics is critical for protecting these species in the face of unprecedented changes to saline lake ecosystems, ideally through decision‐making frameworks that identify effective management options and their potential outcomes. Here, we develop a framework to assess the effects of hypothesized population drivers and identify potential future outcomes of plausible management scenarios on a saline lake‐reliant waterbird species. We use 36 years of monitoring data to quantify the effects of environmental conditions on the population size of a regionally important breeding colony of American white pelicans (Pelecanus erythrorhynchos) at Great Salt Lake, Utah, US, then forecast colony abundance under various management scenarios. We found that low lake levels, which allow terrestrial predators access to the colony, are probable drivers of recent colony declines. Without local management efforts, we predicted colony abundance could likely decline approximately 37.3% by 2040, although recent colony observations suggest population declines may be more extreme than predicted. Results from our population projection scenarios suggested that proactive approaches to preventing predator colony access and reversing saline lake declines are crucial for the persistence of the Great Salt Lake pelican colony. Increasing wetland habitat and preventing predator access to the colony together provided the most effective protection, increasing abundance 145.4% above projections where no management actions are taken, according to our population projection scenarios. Given the importance of water levels to the persistence of island‐nesting colonial species, proactive approaches to reversing saline lake declines could likely benefit pelicans as well as other avian species reliant on these unique ecosystems. [ABSTRACT FROM AUTHOR]

Purpose: While potential harm from high doses of systemic dexamethasone for clinical management of COVID‐19 is an important concern, little is known about real world dexamethasone dosing in patients hospitalized with COVID‐19 in the United States. Methods: Descriptive study to assess dexamethasone daily dose in adults with COVID‐19 in a large US hospital network, overall and by respiratory support requirements, extracted using semi‐ structured nursing notes. Results: Of 332 430 hospitalizations with a COVID‐19 diagnosis, 201 637 (60.7%) hospitalizations included dexamethasone administration. The mean age of recipients was 63 years, 53.0% were male, and 64.5% White. Median time from admission to dexamethasone administration was 0 day (interquartile range [IQR], 0–1 days) and median duration of use was 5 (IQR, 3–9) days. Almost 80% of hospitalizations received standard daily doses (≤ 6 mg daily), 12.7% moderately high daily doses (> 6– ≤ 10 mg daily), and 8.1% high (> 10– ≤ 20 mg daily) or very high daily dose (> 20 mg daily). Over 20% of COVID‐19 hospitalizations requiring no oxygen or simple oxygen received high doses of systemic dexamethasone. Conclusions: Given the findings from the UK RECOVERY trial, and the general uncertainty around safety of higher dexamethasone doses in those requiring more intense respiratory support, standard daily dexamethasone doses of 6 mg or less for hospitalized COVID‐19 requiring supplemental oxygen are recommended. [ABSTRACT FROM AUTHOR]

Background: The College of Surgeons of East, Central, and Southern Africa (COSECSA) comprises 14 countries, many of which currently grapple with an increasing burden of cardiothoracic surgical (CTS) diseases. Health and economic implications of unaddressed CTS conditions are profound and require a robust regional response. This study aimed to define the status of CTS specialist training in the region (including the density of specialists, facilities, and active training posts), examine implications, and proffer recommendations. Methods: A desk review of COSECSA secretariat documents and program accreditation records triangulated with information from surgical societies was performed in May 2022 and September 2023 as part of education quality improvement. A modified nominal group process involving contextual experts was used to develop a relevant action framework. Results: Only 6 of 14 (43%) of COSECSA countries offered active training programs with annual intake of only 18 trainees. Significant training gaps existed in Burundi, Botswana, Malawi, Rwanda, South Sudan, Zambia, and Zimbabwe. Country specialist density ranged from 1 per 400,000 (Namibia) to 1 per 8,000,000 (Ethiopia). Overall, the region had 0.2 CTS specialists per million population as compared with 7.15 surgeons per million in High‐Income Countries. Surgical education experts proposed an action framework to address the training crisis including increasing investments in CTS education, establishing regional centers of excellence, retention incentives and opportunities for women, and leveraging international partnerships. Conclusion: Proactive investments in infrastructure, human resources, training, and collaborative efforts by national governments, regional intergovernmental organizations, and international partners are critical to expanding regional CTS training. [ABSTRACT FROM AUTHOR]

Hydroxyurea treatment for children with sickle cell anemia (SCA) is effective and life‐saving. Stepwise escalation to maximum tolerated dose (MTD) provides optimal benefits, but is logistically challenging and time‐consuming, especially in low‐income countries where most people with SCA live. Model‐informed precision dosing (MIPD) of hydroxyurea expedites MTD determination and improves outcomes compared with trial‐and‐error dose adjustments. HdxSim, a user‐friendly, online, clinical decision support tool was developed to facilitate hydroxyurea MIPD and evaluated using real‐world pharmacokinetic (PK) data. First‐dose hydroxyurea PK profiles were analyzed from two clinical trial datasets (Hydroxyurea Study of Long‐Term Effects (HUSTLE), NCT00305175 and Therapeutic Response Evaluation and Adherence Trial (TREAT), NCT02286154). Areas under the concentration‐time curve (AUC) estimated by HdxSim were compared with those determined using traditional trapezoidal methodology and PK software (MWPharm‐DOS). The doses predicted by HdxSim and MWPharm‐DOS were compared with the observed clinical MTD. For HUSTLE participants, HdxSim accurately estimated hydroxyurea AUC compared with the trapezoidal method, with < 20% variance. The average (mean ± SD) AUC for TREAT participants estimated with HdxSim (68.6 ± 18.0 mg*hour/L) was lower than MWPharm‐DOS (78.6 ± 20.7 mg*hour/L, P = 0.012), but the average recommended doses were not different (425 vs. 423 mg/day, P = 0.97). Moreover, HdxSim was non‐inferior to MWPharm‐DOS at predicting clinical MTD (absolute difference 3.9 ± 5.8 vs. 4.9 ± 8.2 mg/kg/day, P = 0.19). HdxSim accurately estimates hydroxyurea exposure and is noninferior to traditional PK approaches at predicting the clinical hydroxyurea MTD. Hydroxyurea dosing based on target exposure leads to improved outcomes in children with SCA, and has the potential to make PK‐guided hydroxyurea dosing more accessible to this neglected population globally. [ABSTRACT FROM AUTHOR]

Summary: The mechanisms of action of l‐glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three‐week, dose‐ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK–PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK–PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit‐to‐viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK–PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK‐optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use. [ABSTRACT FROM AUTHOR]

In this Technical Advance, we describe a novel method to improve ecological interpretation of remotely sensed vegetation greenness measurements that involved sampling 24,395 Landsat pixels (30 m) across 639 km of Alaska's central Brooks Range. The method goes well beyond the spatial scale of traditional plot‐based sampling and thereby more thoroughly relates ground‐based observations to satellite measurements. Our example dataset illustrates that, along the boreal‐Arctic boundary, vegetation with the greatest Landsat Normalized Difference Vegetation Index (NDVI) is taller than 1 m, woody, and deciduous; whereas vegetation with lower NDVI tends to be shorter, evergreen, or non‐woody. The field methods and associated analyses advance efforts to inform satellite data with ground‐based vegetation observations using field samples collected at spatial scales that closely match the resolution of remotely sensed imagery. [ABSTRACT FROM AUTHOR]

Introduction: During the COVID‐19 pandemic, inpatient electronic health records (EHRs) have been used to conduct public health surveillance and assess treatments and outcomes. Invasive mechanical ventilation (MV) and supplemental oxygen (O2) use are markers of severe illness in hospitalized COVID‐19 patients. In a large US system (n = 142 hospitals), we assessed documentation of MV and O2 use during COVID‐19 hospitalization in administrative data versus nursing documentation. Methods: We identified 319 553 adult hospitalizations with a COVID‐19 diagnosis, February 2020–October 2022, and extracted coded, administrative data for MV or O2. Separately, we developed classification rules for MV or O2 supplementation from semi‐structured nursing documentation. We assessed MV and O2 supplementation in administrative data versus nursing documentation and calculated ordinal endpoints of decreasing COVID‐19 disease severity. Nursing documentation was considered the gold standard in sensitivity and positive predictive value (PPV) analyses. Results: In nursing documentation, the prevalence of MV and O2 supplementation among COVID‐19 hospitalizations was 14% and 75%, respectively. The sensitivity of administrative data was 83% for MV and 41% for O2, with both PPVs above 91%. Concordance between sources was 97% for MV (κ = 0.85), and 54% for O2 (κ = 0.21). For ordinal endpoints, administrative data accurately identified intensive care and MV but underestimated hospitalizations with O2 requirements (42% vs. 18%). Conclusions: In comparison to nursing documentation, administrative data under‐ascertained O2 supplementation but accurately estimated severe endpoints such as MV. Nursing documentation improved ascertainment of O2 among COVID‐19 hospitalizations and can capture oxygen requirements in adults hospitalized with COVID‐19 or other respiratory illnesses. [ABSTRACT FROM AUTHOR]

Research Summary: This study explores how digital transformation can promote organizational resilience when incumbent firms face crises. We examine the intersection of digital transformation and resilience-seeking processes through two longitudinal case studies of incumbent firms designated as "essential businesses" during the COVID-19 pandemic. We analyze 72 crisis adaptations the firms implemented during the crisis to understand how previously underutilized digital capabilities upgraded each firm's ability to adapt to mitigate stakeholder risks and engage in resilience-seeking rather than advantage- or opportunity-seeking. We identify five digital capabilities--virtual access, virtual collaboration, data-driven decision-making, algorithmic reprogrammability, and assisted decision-making--that arose from technologies acquired to enable digital transformation before the crisis.We discuss the concept of resilience opportunities and contribute to the literatures on digital transformation and organizational resilience. Managerial Summary: While studying the digital transformation of incumbent firms, we found that digital capabilities helped firms adapt during the COVID-19 pandemic in ways that crisis management plans did not anticipate. As a result, these adaptations accelerated digital transformation initiatives that years of strategic planning had failed to achieve. We explain why the quantum leap in digital transformation helped these firms not only adapt during crisis, but digital adaptation also enabled them to bounce back more resilient and competitive than before the crisis. We show how the pursuit of organizational resilience can be a vital justification for investments in digital transformation. Strategic leaders play a critical role in not only adopting new technologies, but also in helping firms become more adaptive by combining new and legacy technologies. [ABSTRACT FROM AUTHOR]

Background: Operative experience is a necessary part of surgical training. The College of Surgeons of East, Central, and Southern Africa (COSECSA), which oversees general surgery training programs in the region, has implemented guidelines for the minimum necessary case volumes upon completion of two (Membership) and five (Fellowship) years of surgical training. We aimed to review trainee experience to determine whether guidelines are being met and examine the variation of cases between countries. Methods: Operative procedures were categorized from a cohort of COSECSA general surgery trainees and compared to the guideline minimum case volumes for Membership and Fellowship levels. The primary and secondary outcomes were total observed case volumes and cases within defined categories. Variations by country and development indices were explored. Results: One hundred ninety-four trainees performed 69,283 unique procedures related to general surgery training. The review included 70 accredited hospitals and sixteen countries within Africa. Eighty percent of MCS trainees met the guideline minimum of 200 overall cases; however, numerous trainees did not meet the guideline minimum for each procedure. All FCS trainees met the volume target for total cases and orthopedics; however, many did not meet the guideline minimums for other categories, especially breast, head and neck, urology, and vascular surgery. The operative experience of trainees varied significantly by location and national income level. Conclusions: Surgical trainees in East, Central, and Southern Africa have diverse operative training experience. Most trainees fulfill the overall case volume requirements; however, further exploration of how to meet the demands of specific categories and procedures is necessary. [ABSTRACT FROM AUTHOR]

Triazole antifungals (i.e., fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) are commonly used in clinical practice to prevent or treat invasive fungal infections. Most triazole antifungals require therapeutic drug monitoring (TDM) due to highly variable pharmacokinetics, known drug interactions, and established relationships between exposure and response. On behalf of the Society of Infectious Diseases Pharmacists (SIDP), this insight describes the pharmacokinetic principles and pharmacodynamic targets of commonly used triazole antifungals and provides the rationale for utility of TDM within each agent. [ABSTRACT FROM AUTHOR]

Advances in digital manufacturing technologies have not only altered R&D processes for new product development (NPD), but they have also opened new possibilities for user innovators to engage in traditionally closed innovation processes. However, incorporating external sources of user innovation—through design challenges or crowdsourcing, for example—can introduce competing logics into exploratory innovation processes. Using the lens of complexity, we conduct an ethnographic study of the competing logics at work in the NPD processes of a corporate makerspace launched by a large firm in the consumer appliances industry. The makerspace was founded with a hybrid logic, intended to combine the community logic of makers with the corporate logic of the parent organization. We analyze the conflicts that arose between logics and how the hybrid logic evolved through four iterations of the NPD process. We identify how managing multiple logics led to structural and identity changes, and we explain how two mechanisms—structural bridging and stakeholder identity linking—enabled the makerspace to innovate with a hybrid logic and overcome the constraints of a dominant logic on the NPD process. The results offer insights into dynamic organizational responses to complexity, how new business initiatives can be structured to act as exploratory units for corporate parents, and how corporate makerspaces can help incorporate external sources of innovation. [ABSTRACT FROM AUTHOR]

Sickle cell anemia (SCA) is a life‐threatening genetic condition contributing to high‐risk pregnancies affecting both the mother and fetus. With improved management of children with SCA, this life‐threatening hematological disorder has evolved into a chronic disease of adults, and consequently parenthood has now become a possible and important life goal for many patients. Providing continuous management with healthy red blood cell function and avoiding SCA‐associated complications, such as pain crises, acute chest syndrome, and stroke, are crucial for a healthy pregnancy. Despite its excellent safety profile in non‐pregnant adults and children, and based on theoretical concerns derived from data using animal models and supraphysiological dosing, hydroxyurea is currently contraindicated for pregnant and lactating women with SCA. Clinical experience of hydroxyurea use during pregnancy is increasingly reported, however, and has shown inconsistent results of fetal or infant adverse effects. How the hydroxyurea exposure level may correlate with pregnancy outcomes is still unclear. Accordingly, efforts should be made to systemically evaluate exposure and safety of hydroxyurea treatment during pregnancy and lactation. Novel approaches such as physiologically based pharmacokinetic (PBPK) modeling, coupled with the ex vivo human placental cotyledon perfusion assay, provide opportunities to understand hydroxyurea exposure not only in pregnant women but also in the developing fetus. Combined with animal data, research using these approaches might be able to define safe and effective hydroxyurea dosing regimens for pregnant and lactating women with SCA, when the benefits of continuing hydroxyurea treatment likely outweigh the risks of non‐treatment, by avoiding substantial morbidity and even mortality for both mothers and infants. [ABSTRACT FROM AUTHOR]

Accurate laboratory screening for sickle cell disease and other haemoglobin disorders is expanding worldwide. Two new reports describe different methods and strategies for screening in Mali and Denmark, respectively, and their encouraging results suggest that countries should tailor their screening programmes according to local needs, resources and opportunities. Commentary on: Guindo et al. Potential for a large‐scale newborn screening strategy for sickle cell disease in Mali: a comparative diagnostic performance study of two rapid diagnostic tests (SickleScan® and HemotypeSC®) on cord blood. Br J Haematol 2024;204:337–345 and Gravholt et al. The Danish national haemoglobinopathy screening programme: report from 16 years of screening in a low‐prevalence, non‐endemic region. Br J Haematol 2024;204:329–336. [ABSTRACT FROM AUTHOR]

Background: Digital cognitive assessment solutions can overcome some barriers to cognitive screening in primary care by providing rapidly‐obtained objective insights without requiring specialty‐trained examiners. The Linus Health Digital Clock and Recall (DCR™) is a three‐part test consisting of three‐word immediate verbal acquisition, the Digital Clock Test (DCTclock™), and delayed recall of the three words. Our objective was to compare performance on the DCR to the Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) and the Saint Louis University Mental Status (SLUMS; Tariq et al., 2006), two commonly used screening tests in primary care. Method: Comparative analyses of DCR, MoCA (Total Score and Memory Index Score [MIS]), and SLUMS results were conducted among 80 primary care patients – 65 years and older presenting for any reason – whose DCR performance was indicative of cognitive impairment. Result: Of the 80 patients (mean age 74.0 [±7.8]; 60% female) performing as impaired or borderline impaired on the DCR, 67 completed the MoCA and 13 completed the SLUMS. Comparison between the DCR and MoCA Total Score included 78% (52/67) concordance for identifying impairment (cutoff <26). While the remaining 15 of 67 patients (22%) had normal MoCA Total Scores (≥26), 13 (87%) missed points in at least one MoCA cognitive domain and 8 (53%) missed points in multiple MoCA domains (often language and delayed recall). Comparison between DCR and SLUMS revealed that all 13 patients receiving SLUMS assessment had DCR scores 0‐1 and SLUMS scores <27 (indicating cognitive impairment). See Tables 1 and 2 for breakdown of MoCA, MIS, and SLUMS stratified by DCR performance. Logistic regression found that DCTclock metrics of information processing (z = 2.00, p =.045) and spatial reasoning (z = 2.82 p =.005) discriminated cognitive impairment on MoCA Total Score (cutoff <26). Overall, ROC analysis revealed good accuracy of DCR to identify MoCA performance (AUC =.84; Figure 1). Conclusion: Screening in primary care using the DCR is feasible, takes less time to administer than MoCA or SLUMS, and shows concordant results with these more established screening tools in detecting cognitive impairment. Future research aims to investigate the criterion validity of the DCR among biomarkers for neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Background: Increased brain docosahexaenoic acid (DHA) uptake reflects a compensatory mechanism for maintaining brain DHA homeostasis and can be captured through PET‐MRI scan uptake studies using radiolabeled DHA. It has been previously shown that APOE4 status and alcohol intake alter brain DHA uptake in mice. Whether a change in DHA intake affects the brain DHA incorporation coefficient (K*) however is not known. Method: Four‐month‐old C57BL/6J mice were fed either a diet rich in DHA (15 kcal% Fat, 1.7 g/kg ALA, and 7g/kg DHA) or deficient in DHA (15 kcal% Fat and 0.9 mg/kg ALA) for 4 months. At 8 months, anesthetized mice were subjected to dynamic PET‐MRI for 30 min following i.v. injection of 22‐[18F]fluorodocosahexaenoic acid ([18F]FDHA), prepared in‐house through radiosynthesis. Using an image‐derived cardiac input function, brain uptake was assessed by estimating [18F]FDHA K* values using both the Patlak model approach and the irreversible two‐tissue compartmental model (Irr2TCM) with and without correction of the brain radioactivity for radioactive spillover from the skull. Mice were then sacrificed, and the plasma and brains were analyzed using liquid chromatography‐mass spectrometry (LC‐MS) to evaluate differences in the unlabeled concentrations of fatty acids into phospholipids, triglycerides, and other lipids. Result: There was no significant difference in the [18F]FDHA K* estimates (with either Patlak or Irr2TCM) between mice fed a DHA‐rich or a DHA‐deficient diet. LC‐MS based lipidomic analysis showed that the DHA‐rich diet significantly increased DHA concentration in triglycerides in plasma and in phosphatidylethanolamine in the brain. Conclusion: These results suggest that under physiological conditions, increased dietary intake of DHA in wild‐type mice increases DHA in brain phosphatidylethanolamine and in plasma triglycerides without changing the DHA K*. The net effect likely is increased brain DHA uptake, equal to the product of unesterified DHA plasma concentration and K*. Imaging brain DHA with dynamic [18F]FDHA PET‐MRI is a potentially useful tool not only to investigate the APOE4 phenotype, which promotes DHA dysregulation, but also to assess dietary and pharmacological interventions that affect brain DHA homeostasis as well as to guide future treatments. [ABSTRACT FROM AUTHOR]

Summary: Ischaemic stroke is a common complication of sickle cell disease (SCD) and without intervention can affect 11% of children with SCD before the age of 20. Within the Trans‐Omics for Precision Medicine (TOPMed), a genome‐wide association study (GWAS) of ischaemic stroke was performed on 1333 individuals with SCD from Brazil (178 cases, 1155 controls). Via a novel Cox proportional‐hazards analysis, we searched for variants associated with ischaemic stroke occurring at younger ages. Variants at genome‐wide significance (p < 5 × 10−8) include two near genes previously linked to non‐SCD early‐onset stroke (<65 years): ADAMTS2 (rs147625068, p = 3.70 × 10−9) and CDK18 (rs12144136, p = 2.38 × 10−9). Meta‐analysis, which included the independent SCD cohorts Walk‐PHaSST and PUSH, exhibited consistent association for variants rs1209987 near gene TBC1D32 (p = 3.36 × 10−10), rs188599171 near CUX1 (p = 5.89 × 10−11), rs77900855 near BTG1 (p = 4.66 × 10−8), and rs141674494 near VPS13C (1.68 × 10−9). Findings from this study support a multivariant model of early ischaemic stroke risk and possibly a shared genetic architecture between SCD individuals and non‐SCD individuals younger than 65 years. [ABSTRACT FROM AUTHOR]

Hydroxyurea is approved for treating children and adults with sickle cell anemia (SCA). Despite its proven efficacy, concerns remain about its mutagenic and carcinogenic potential that hamper its widespread use. Cell culture‐ and animal‐based investigations indicate that hydroxyurea's genotoxic effects are due to indirect clastogenicity in select cell types when high dose and time thresholds are exceeded (reviewed by Ware & Dertinger, 2021). The current study extends these preclinical observations to pediatric patients receiving hydroxyurea for treatment of SCA. First, proof‐of‐principle experiments with testicular cancer patients exposed to a cisplatin‐based regimen validated the ability of flow cytometric blood‐based micronucleated reticulocyte (MN‐RET) and PIG‐A mutant reticulocyte (MUT RET) assays to detect clastogenicity and gene mutations, respectively. Second, these biomarkers were measured in a cross‐sectional study with 26 SCA patients receiving hydroxyurea and 13 SCA patients without exposure. Finally, a prospective study was conducted with 10 SCA patients using pretreatment blood samples and after 6 or 12 months of therapy. Cancer patients exposed to cisplatin exhibited increased MN‐RET within days of exposure, while the MUT RET endpoint required more time to reach maximal levels. In SCA patients, hydroxyurea induced MN‐RET in both the cross‐sectional and prospective studies. However, no evidence of PIG‐A gene mutation was found in hydroxyurea‐treated children, despite the fact that the two assays use the same rapidly‐dividing, highly‐exposed cell type. Collectively, these results reinforce the complementary nature of MN‐RET and MUT RET biomarkers, and indicate that hydroxyurea can be clastogenic but was not mutagenic in young patients with SCA. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EV) are important mediators of cell communication and physiology. EVs are frequently investigated by transiently transfecting cells with plasmid DNA to produce EVs modified with protein(s) or nucleic acid(s) of interest. DNA‐transfection reagent complexes (DTC) are approximately the same size as EVs, raising the possibility that some purification procedures may fail to separate these two species and activity arising from carryover DTC may be improperly attributed to EVs. We find that differential ultracentrifugation, a commonly employed EV isolation procedure, does not separate EVs from DTC present in the cell culture supernatant of transiently transfected cells. We demonstrate that the biological activity of an EV‐directed Cre recombinase is due to contaminating plasmid DNA and not EV‐mediated delivery of Cre protein. Moreover, steps commonly taken to remove plasmid DNA from EV samples, such as media exchanges and treatment with nucleases, are ineffective at avoiding this artefact. Due to the pernicious nature of plasmid DNA in these cellular assays, some reports of EV function are likely artefacts produced by contaminating DTC. EVs and DTC can be separated by density gradient ultracentrifugation, highlighting the importance of validating elimination of DTC when using transient transfection of EV‐producing cells to interrogate EV function. [ABSTRACT FROM AUTHOR]

Resource‐based theories posit that exerting self‐control to regulate one's thoughts, feelings, and behaviors depletes people's available self‐regulatory resources, leaving them depleted and less able to exert self‐control in subsequent activities. Although the detrimental effects of depletion are well‐established, we challenge this prevailing view by proposing that depletion can have unexpected beneficial effects. Across multiple studies, our current research provides evidence that depletion shifts consumers' attention on benefits of creativity, and in turn influences their subsequent creative engagement. Specifically, we found that depletion increases consumers' persistence in creative activity, and this beneficial effect of depletion on creative engagement is explained by their attention on benefits of creativity. Furthermore, we explore a boundary conditions of this depletion‐creative engagement effect by demonstrating that the effect could be attenuated for individuals who are not open to new experiences. [ABSTRACT FROM AUTHOR]

Manganese‐enhanced magnetic resonance imaging (MEMRI) holds exceptional promise for preclinical studies of brain‐wide physiology in awake‐behaving animals. The objectives of this review are to update the current information regarding MEMRI and to inform new investigators as to its potential. Mn(II) is a powerful contrast agent for two main reasons: (1) high signal intensity at low doses; and (2) biological interactions, such as projection tracing and neural activity mapping via entry into electrically active neurons in the living brain. High‐spin Mn(II) reduces the relaxation time of water protons: at Mn(II) concentrations typically encountered in MEMRI, robust hyperintensity is obtained without adverse effects. By selectively entering neurons through voltage‐gated calcium channels, Mn(II) highlights active neurons. Safe doses may be repeated over weeks to allow for longitudinal imaging of brain‐wide dynamics in the same individual across time. When delivered by stereotactic intracerebral injection, Mn(II) enters active neurons at the injection site and then travels inside axons for long distances, tracing neuronal projection anatomy. Rates of axonal transport within the brain were measured for the first time in "time‐lapse" MEMRI. When delivered systemically, Mn(II) enters active neurons throughout the brain via voltage‐sensitive calcium channels and clears slowly. Thus behavior can be monitored during Mn(II) uptake and hyperintense signals due to Mn(II) uptake captured retrospectively, allowing pairing of behavior with neural activity maps for the first time. Here we review critical information gained from MEMRI projection mapping about human neuropsychological disorders. We then discuss results from neural activity mapping from systemic Mn(II) imaged longitudinally that have illuminated development of the tonotopic map in the inferior colliculus as well as brain‐wide responses to acute threat and how it evolves over time. MEMRI posed specific challenges for image data analysis that have recently been transcended. We predict a bright future for longitudinal MEMRI in pursuit of solutions to the brain‐behavior mystery. [ABSTRACT FROM AUTHOR]

Conjugated alkali metal dicarboxylates have recently received attention for applications as organic anode materials in lithium‐ and sodium‐ion batteries. In order to understand and optimise these materials, it is important to be able to characterise both the long‐range and local aspects of the crystal structure, which may change during battery cycling. Furthermore, some materials can display polymorphism or hydration behaviour. NMR crystallography, which combines long‐range crystallographic information from diffraction with local information from solid‐state NMR via interpretation aided by DFT calculations, is one such approach, but this has not yet been widely applied to conjugated dicarboxylates. In this work, we evaluate the application of NMR crystallography for a set of model lithium and sodium dicarboxylate salts. We investigate the effect of different DFT geometry optimisation strategies and find that the calculated NMR parameters are not systematically affected by the choice of optimisation method, although the inclusion of dispersion correction schemes is important to accurately reproduce the experimental unit cell parameters. We also observe hydration behaviour for two of the sodium salts and provide insight into the structure of an as‐yet uncharacterised structure of sodium naphthalenedicarboxylate. This highlights the importance of sample preparation and characterisation for organic sodium‐ion battery anode materials in particular. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the performance of 4-dimensional computed tomography (4D-CT) in assessing upper airway obstruction (UAO) in patients with Robin sequence (RS) and compare the accuracy and reliability of 4D-CT and flexible fiber-optic laryngoscopy (FFL). Study Design: Prospective survey of retrospective clinical data. Setting: Single, tertiary care pediatric hospital. Methods: At initial and 30-day time points, a multidisciplinary group of 11 clinicians who treat RS rated UAO severity in 32 sets of 4D-CT visualizations and FFL videos (dynamic modalities) and static CT images. Raters assessed UAO at the velopharynx and oropharynx (1 = none to 5 = complete) and noted confidence levels of each rating. Intraclass correlation and Krippendorff alpha were used to assess intra- and interrater reliability, respectively. Accuracy was assessed by comparing clinician ratings with quantitative percentage constriction (QPC) ratings, calculated based on 4D-CT airway cross-sectional area. Results were compared using Wilcoxon rank-sum and signed-rank tests. Results: There was similar intrarater agreement (moderate to substantial) with 4D-CT and FFL, and both demonstrated fair interrater agreement. Both modalities underestimated UAO severity, although 4D-CT ratings were significantly more accurate, as determined by QPC similarity, than FFL (−1.06 and −1.46 vs QPC ratings, P =.004). Overall confidence levels were similar for 4D-CT and FFL, but other specialists were significantly less confident in FFL ratings than were otolaryngologists (2.25 and 3.92, P <.0001). Conclusion: Although 4D-CT may be more accurate in assessing the degree of UAO in patients with RS, 4D-CT and FFL assessments demonstrate similar reliability. Additionally, 4D-CT may be interpreted with greater confidence by nonotolaryngologists who care for these patients. [ABSTRACT FROM AUTHOR]

Mindfulness has received increasing attention from scholars and practitioners, and considerable research has demonstrated the intrapersonal effects of mindfulness at work or at home. Research to date, however, has overlooked potential interpersonal effects of mindfulness across the work and family domains. Drawing on the spillover‐crossover model and the mindfulness literature, we investigate the effects of spouse mindfulness at home on employee work and family outcomes. We test our model using dyadic experience‐sampling data collected from 125 focal employees and their spouses over 10 consecutive workdays. The results indicated that, at the within‐person level, spouse mindfulness at home was positively associated with employee authentic emotional sharing at home, which, in turn, was positively associated with employee positive effect at home but negatively associated with employee negative affect at home. The results also indicated that spouse mindfulness at home had a positive indirect effect on family satisfaction at home and work engagement during the next morning through enhancing employee authentic emotional sharing at home. We discuss the implications of these findings and directions for the mindfulness research. [ABSTRACT FROM AUTHOR]

Background: We assessed the ability to identify key data relevant to influenza and other respiratory virus surveillance in a large‐scale US‐based hospital electronic medical record (EMR) dataset using seasonal influenza as a use case. We describe characteristics and outcomes of hospitalized influenza cases across three seasons. Methods: We identified patients with an influenza diagnosis between March 2017 and March 2020 in 140 US hospitals as part of the US FDA's Sentinel System. We calculated descriptive statistics on the presence of high‐risk conditions, influenza antiviral administrations, and severity endpoints. Results: Among 5.1 million hospitalizations, we identified 29,520 hospitalizations with an influenza diagnosis; 64% were treated with an influenza antiviral within 2 days of admission, and 25% were treated >2 days after admission. Patients treated >2 days after admission had more comorbidities than patients treated within 2 days of admission. Patients never treated during hospitalization had more documentation of cardiovascular and other diseases than treated patients. We observed more severe endpoints in patients never treated (death = 3%, mechanical ventilation [MV] = 9%, intensive care unit [ICU] = 26%) or patients treated >2 days after admission (death = 2%, MV = 14%, ICU = 32%) than in patients treated earlier (treated on admission: death = 1%, MV = 5%, ICU = 23%, treated within 2 days of admission: death = 1%, MV = 7%, ICU = 27%). Conclusions: We identified important trends in influenza severity related to treatment timing in a large inpatient dataset, laying the groundwork for the use of this and other inpatient EMR data for influenza and other respiratory virus surveillance. [ABSTRACT FROM AUTHOR]

Vietnamese smallholder dairy cows (VDC) are the result of crossbreeding between different zebu (ZEB) and taurine dairy breeds through many undefined generations. Thus, the predominant breed composition of VDC is currently unknown. This study aimed to evaluate the level of genetic diversity and breed composition of VDC. The SNP data of 344 animals from 32 farms located across four dairy regions of Vietnam were collected and merged with genomic reference data, which included three ZEB breeds: Red Sindhi, Sahiwal and Brahman, three taurine breeds: Holstein (HOL), Jersey (JER) and Brown Swiss (BSW), and a composite breed: Chinese Yellow cattle. Diversity and admixture analyses were applied to the merged data set. The VDC were not excessively inbred, as indicated by very low inbreeding coefficients (Wright's FIS ranged from −0.017 to 0.003). The genetic fractions in the test herds suggested that the VDC are primarily composed of HOL (85.0%); however, JER (6.0%), BSW 5.3%) and ZEB (4.5%) had also contributed. Furthermore, major genotype groupings in the test herds were pure HOL (48%), B3:15/16HOL_1/16ZEB (22%) and B2:7/8HOL_1/8ZEB (12%). The genetic makeup of the VDC is mainly components of various dairy breeds but also has a small percentage of ZEB; thus, the VDC could be a good genetic base for selecting high milk‐producing cows with some degree of adaptation to tropical conditions. [ABSTRACT FROM AUTHOR]

Gene therapy for sickle cell disease has recently been approved by regulatory agencies in the United Kingdom, United States, and European Union. This marks the beginning of a new era for sickle cell disease treatment, offering transformative or curative options for a marginalized patient population. However, the benefits, risks, and costs of gene therapy still need to be better understood, and issues of access and affordability must be addressed for equitable implementation. Sickle cell disease is a common form of inherited anemia that disproportionately affects marginalized groups globally. While gene therapy holds promise, there are still questions about its effectiveness, labeling, costs, durability, and accessibility, particularly in low-resource settings. [Extracted from the article]

Background: Polyunsaturated fatty acids (PUFAs) are the precursors of various lipid mediators of inflammation. Brain imaging techniques for monitoring the brain's uptake of PUFAs would not only uncover the effects of risk factors for excessive neuroinflammation associated with Alzheimer's disease (AD) and related dementia but also direct the development of methods to prevent or treat AD. Radiosynthesized 11C‐docosahexaenoic acid (DHA) and 11C‐arachidonic acid (AA) have already been utilized in positron emission tomography (PET) studies in humans [1, 2]. Because 18F has a longer half‐life than 11C, fluorinated PUFA derivatives would be more favorable alternatives for PET studies of brain uptake. Methods: We prepared 18F‐fluorinated analogues of DHA (18F‐FDHA) and AA (18F‐FAA) as PUFA PET tracers. Radiosynthesis was performed via a nucleophilic fluorination scheme using the tosylate ester derivatives as precursors. We then performed bolus injection of each tracer into 16‐month‐old APOE4 knock‐in mice and scanned them by dynamic PET‐MRI over 45 min to assess region‐specific uptake. PUFA uptake kinetics in the cerebral region was evaluated using the time‐dependent activity in the lumen of the right ventricle as the image‐derived input function and using an irreversible two‐tissue compartment model to calculate the incorporation coefficient (Ki). Results: Both 18F‐FDHA and 18F‐FAA were successfully synthesized in high radiochemical purity (≥98%) and were found to be stable in the formulation and mouse serum for 2 hr. The mean Ki values for the cerebral region were determined to be 6.31 ± 0.98 µL mL‐1 min‐1 for 18F‐FDHA (n = 4) and 6.75 ± 0.68 µL mL‐1 min‐1 for 18F‐FAA (n = 5). Conclusion: Using an image‐based method with 18F‐fluorinated PUFA tracers, we were able to determine Ki values for both AA and DHA. The use of these PUFA PET tracers has the potential to elucidate deleterious changes in PUFA metabolism during various phases of AD as well as effects due to dietary interventions and drug treatment. References 1. Yassine, H.N. et al. (2017). DHA brain uptake and APOE4 status: a PET study with [1‐11C]‐DHA. Alzheimers Res Ther 9, 23. 2. Zanderigo, F. et al. (2018). [11C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use. Synapse 72. [ABSTRACT FROM AUTHOR]

Sodium‐ion batteries are commanding increasing attention owing to their promising electrochemical performance and sustainability. Organic electrode materials (OEMs) complement such technologies as they can be sourced from biomass and recycling them is environmentally friendly. Organic anodes based on sodium carboxylates have exhibited immense potential, except the limitation of current synthesis methods concerning upscaling and energy costs. In this work, a rapid and energy efficient microwave‐assisted synthesis for organic anodes is presented using sodium naphthalene‐2,6‐dicarboxylate as a model compound. Optimizing the synthesis and electrode composition enables the compound to deliver a reversible initial capacity of ≈250 mAh g–1 at a current density of 25 mA g–1 with a high initial Coulombic efficiency (≈78%). The capacity is stable over 400 cycles and the compound also exhibits good rate performance. The successful demonstration of this rapid synthesis may facilitate the transition to preparing organic battery materials by scalable, efficient methods. [ABSTRACT FROM AUTHOR]

Summary: EXpanding Treatment for Existing Neurological Disease (EXTEND) investigated whether hydroxycarbamide lowers transcranial Doppler (TCD) velocities in Jamaican children with sickle cell anaemia (SCA) and elevated TCD velocity with or without previous stroke. Forty‐three children (age 2–17 years) with baseline maximum time‐averaged mean velocity (TAMV) ≥ 170 cm/s were stratified into three risk categories based on treatment status and stroke history: Group 1 (no history of stroke, on hydroxycarbamide, n = 12); and Groups 2 (no stroke, no hydroxycarbamide, n = 21) and 3 (previous stroke, no hydroxycarbamide, n = 10). Open‐label hydroxycarbamide at 20 mg/kg/day was commenced, with escalation to maximum tolerated dose (MTD) based on mild marrow suppression (average dose 25·4 ± 4·5 mg/kg/day). TCD was performed every six months with brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) at baseline and after 18‐months of hydroxycarbamide. The maximum TAMV decreased significantly compared to baseline (24 ± 30 cm/s, P < 0·0001), with similar declines in all groups. Clinical stroke occurred in five children, one in Group 1, none in Group 2, and four in Group 3, P = 0·0032, comparing group incidence rates. Brain MRI/MRA was stable in children without clinical stroke. EXTEND documents the feasibility and benefits of hydroxycarbamide at MTD to lower TCD velocities and reduce stroke risk in children with SCA and no history of primary stroke in low‐resource settings without transfusion management. [ABSTRACT FROM AUTHOR]

Aim: Diabetes has been identified as a risk factor for poor outcomes in patients with COVID‐19. We examined the association of hyperglycaemia, both in the presence and absence of pre‐existing diabetes, with severity and outcomes in COVID‐19 patients. Methods: Data from 74,148 COVID‐19‐positive inpatients with at least one recorded glucose measurement during their inpatient episode were analysed for presence of pre‐existing diabetes diagnosis and any glucose values in the hyperglycaemic range (>180 mg/dl). Results: Among patients with and without a pre‐existing diabetes diagnosis on admission, mortality was substantially higher in the presence of high glucose measurements versus all measurements in the normal range (70–180 mg/dl) in both groups (non‐diabetics: 21.7% vs. 3.3%; diabetics 14.4% vs. 4.3%). When adjusting for patient age, BMI, severity on admission and oxygen saturation on admission, this increased risk of mortality persisted and varied by diabetes diagnosis. Among patients with a pre‐existing diabetes diagnosis, any hyperglycaemic value during the episode was associated with a substantial increase in the odds of mortality (OR: 1.77, 95% CI: 1.52–2.07); among patients without a pre‐existing diabetes diagnosis, this risk nearly doubled (OR: 3.07, 95% CI: 2.79–3.37). Conclusion: This retrospective analysis identified hyperglycaemia in COVID‐19 patients as an independent risk factor for mortality after adjusting for the presence of diabetes and other known risk factors. This indicates that the extent of glucose control could serve as a mechanism for modifying the risk of COVID‐19 morality in the inpatient environment. [ABSTRACT FROM AUTHOR]

Summary: There is an immediate need to address long‐standing questions about the reproductive health of girls and women with sickle cell disease (SCD). There are many SCD‐related reproductive risks and uncertainties across girls' and women's reproductive life span, with particularly outstanding concerns about menstruation, contraception, fertility and pregnancy. Extant literature addressing women's reproductive health topics is mostly descriptive; there are few high‐quality interventional studies. In 2020, the Centers for Disease Control and Prevention and the Foundation for Women and Girls with Blood Disorders convened an expert panel to assess the knowledge gaps in women's reproductive health in SCD. The panel identified significant limitations to clinical care due to the need for research. The panel also identified prominent barriers to research and care. In this report, we frame these issues, providing a roadmap for investigators, funding agencies, and policy makers to advance care for girls and women with SCD. [ABSTRACT FROM AUTHOR]

The mechanical properties of electrospun fibers play an important role in determining their applications. Most of the reported literature measures the mechanical properties of electrospun mats, scaffolds, or films instead of single fibers; however, a basic understanding of the relationship between the mechanical properties of the single fiber and that of the mat is critical to obtain precise information for choosing their application. This Review aims to evaluate the reported mechanical properties of electrospun fibers and the variables that influence those properties. An overview on the recent inputs in the development of mechanical properties of electrospun fibers is given, illustrating attempts to tailor mechanical properties of the fibers and/or mats. The necessity of determining flexible and reliable testing methods to establish testing standards for obtaining consistent and reliable data for both electrospun fibers and mats is also highlighted. [ABSTRACT FROM AUTHOR]

Summary: Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF‐containing cells (F‐cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics‐guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F‐cells (near‐pancellular), and almost half had ≥90% F‐cells (pancellular). The mean HbF/F‐cell content was ~12 pg. Earlier age of initiation and better medication adherence were associated with high F‐cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics‐guided starting doses at predicted MTD can achieve sustained near‐pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov). [ABSTRACT FROM AUTHOR]

The covid‐19 pandemic has revealed the need for alternative production approaches with low startup costs like electrospinning for filter needs, the most imperative element of the personal protective equipment (PPE). Current attempts in advancing melt electrospinning deal with developing strategies for fiber diameter attenuation toward sub‐micron scale. Here, the attunement in the spinning‐zone temperature known as ''spin‐line temperature profile'' was utilized as a baseline for fiber diameter reduction. The mechanical performance of the melt‐electrospun linear low‐density polyethylene (LLDPE) fibers is reported to characterize their structural transformation with respect to various spin‐line temperature profiles. With an increase in the spin‐line temperature to above 100°C in the area of cone formation, an increased tensile and yield strength along with fiber diameter reduction by four‐folds was demonstrated. A significant increase in toughness, by almost three times, without compromising the stiffness and Young's modulus was observed. The dynamic mechanical analysis revealed that spinning in high temperatures produces changes in the alpha (α) relaxation, contributing to the significant increase in strain at break. These results are significant because polyolefin fibers are an imperative element of medical textiles and PPE. Therefore, developing a correlation for process‐structure‐properties for emerging production techniques like melt electrospinning becomes critical. [ABSTRACT FROM AUTHOR]

Summary: Hydroxyurea (hydroxycarbamide) is approved for treating both children and adults with sickle cell anaemia (SCA). Fetal haemoglobin (HbF) induction is the primary treatment response, along with improved anaemia, reduced haemolysis, myelosuppression and decreased endothelial inflammation. Hydroxyurea has proven clinical efficacy for SCA — treatment significantly reduces disease manifestations and prolongs survival. Despite these recognised benefits, long‐standing concerns regarding the risks of mutagenic and potentially carcinogenic drug exposure have hampered efforts for broad hydroxyurea use in SCA, although these are based largely on outdated experimental models and treatment experiences with myeloproliferative neoplasms. Consequently, many patients with SCA are not receiving this highly effective disease‐modifying therapy. In this review, we describe the concept of genotoxicity and its laboratory measurements, summarise hydroxyurea‐associated data from both preclinical and clinical studies, and discuss carcinogenic potential. The genotoxicity results clearly demonstrate that hydroxyurea does not directly bind DNA and is not mutagenic. Rather, its genotoxic effects are limited to indirect clastogenicity occurring in select cell types, and only when high dose and time thresholds are exceeded. This absence of mutagenic activity is consistent with the observed lack of any compelling carcinogenic potential. Since hydroxyurea therapy for SCA carries minimal carcinogenic risks, the current drug labelling should be modified accordingly, and prescribing practices should be broadened to allow better access and increased utilisation of this highly effective drug. [ABSTRACT FROM AUTHOR]

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post‐market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID‐19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID‐19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi‐pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID‐19, validated a diagnosis‐code based algorithm for identifying patients with COVID‐19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID‐19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID‐19 prevention and treatment. [ABSTRACT FROM AUTHOR]

Metal‐organic frameworks (MOFs) are promising materials for many potential applications, spacing from gas storage to catalysis. However, the powder form they are generally made of is not suitable, mainly because of the low packing density. Powder compaction is therefore necessary, but also challenging because of its typical mechanical fragility. Indeed, generally, MOF powders undergo irreversibly damages upon densification processes, for example partially or totally loosing microporosity and catalytic activity. In this work, we have deeply studied the compaction effects on the flexible Cu(II)‐based MOF STAM‐17‐OEt (Cu(C10O5H8) ⋅ 1.6 H2O), whose chemical composition is close to that of HKUST‐1, obtaining that, by contrast, STAM‐17‐OEt is extremely suitable for mechanical compaction processes with pressures up to 200 MPa, which increase its packing density and its catalytic activity, and then also preserve the characteristic porosity, flexibility and water stability of STAM‐17‐OEt. The results are supported by many experimental techniques including EPR spectroscopy, PXRD diffraction, CO2 isotherms studies and catalytic tests. [ABSTRACT FROM AUTHOR]

The size of single crystals of the metal‐organic framework CPO‐27‐Ni was incrementally increased through a series of modulated syntheses. A novel linker modulated synthesis using 2,5‐dihydroxyterephthalic acid and the isomeric ligand 4,6‐dihydroxyisophthalic acid yielded large single crystals of CPO‐27‐Ni (∼70 μm). All materials were shown to have high crystallinity and phase purity through powder X‐ray diffraction, electron microscopy methods, thermogravimetry, and compositional analysis. For the first time single‐crystal structure analyses were carried out on CPO‐27‐Ni. High BET surface areas and nitric oxide (NO) release efficiencies were recorded for all materials. Large single crystals of CPO‐27‐Ni showed a prolonged NO release and proved suitable for in situ single‐crystal diffraction experiments to follow the NO adsorption. An efficient activation protocol was developed, leading to a dehydrated structure after just 4 h, which subsequently was NO‐loaded, leading to a first NO loaded single‐crystal structural model of CPO‐27‐Ni. [ABSTRACT FROM AUTHOR]