An expedited screening platform for the discovery of anti-ageing compounds in vitro and in vivo.

BACKGROUND: Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. METHODS: Using Illumina methylation arrays, we monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. Finally, we bench mark our epigenetic clock with other available epigenetic clocks to consolidate its usefulness and specialisation for primary cells in culture. RESULTS: We developed a novel epigenetic clock, the CellPopAge Clock, to accurately monitor the age of a population of adult human primary cells. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo. CONCLUSIONS: Our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.

Child sexual abuse and social identity loss: A qualitative analysis of survivors' public accounts.

Emerging evidence suggests that social identities are an important determinant of adaptation following traumatic life experiences. In this paper, we analyse accounts of people who experienced child sexual abuse. Using publicly available talk of people who waived their right to anonymity following successful conviction of perpetrators, we conducted a thematic analysis focusing on trauma-related changes in their social identities. Analysis of these accounts highlighted two themes. The first highlights the acquisition in these accounts of unwanted and damaging identity labels. The second presents child sexual abuse as a key destructive force in terms of important identity work during childhood. Discussion of this analysis centres on the pathological consequences of social identity change. Both the loss of valued identities and the acquisition of aberrant and isolating identities are experienced and constructed as devastating by those affected by child sexual abuse. This has important implications, not only for those impacted by child sexual abuse but for how abuse is discussed in society, and how it is approached by policy makers, educators and individuals working with survivors and their families.

Comparison of Clinical Decision Support Tools to Improve Pediatric Lipid Screening.

OBJECTIVE: To test whether different clinical decision support tools increase clinician orders and patient completions relative to standard practice and each other. STUDY DESIGN: A pragmatic, patient-randomized clinical trial in the electronic health record was conducted between October 2019 and April 2020 at Geisinger Health System in Pennsylvania, with 4 arms: care gap-a passive listing recommending screening; alert-a panel promoting and enabling lipid screen orders; both; and a standard practice-no guideline-based notification-control arm. Data were analyzed for 13 346 9- to 11-year-old patients seen within Geisinger primary care, cardiology, urgent care, or nutrition clinics, or who had an endocrinology visit. Principal outcomes were lipid screening orders by clinicians and completions by patients within 1 week of orders. RESULTS: Active (care gap and/or alert) vs control arm patients were significantly more likely (P < .05) to have lipid screening tests ordered and completed, with ORs ranging from 1.67 (95% CI 1.28-2.19) to 5.73 (95% CI 4.46-7.36) for orders and 1.54 (95% CI 1.04-2.27) to 2.90 (95% CI 2.02-4.15) for completions. Alerts, with or without care gaps listed, outperformed care gaps alone on orders, with odds ratios ranging from 2.92 (95% CI 2.32-3.66) to 3.43 (95% CI 2.73-4.29). CONCLUSIONS: Electronic alerts can increase lipid screening orders and completions, suggesting clinical decision support can improve guideline-concordant screening. The study also highlights electronic record-based patient randomization as a way to determine relative effectiveness of support tools. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04118348.

Memory of Fictional Information: A Theoretical Framework.

Much of the information people encounter in everyday life is not factual; it originates from fictional sources, such as movies, novels, and video games, and from direct experience such as pretense, role-playing, and everyday conversation. Despite the recent increase in research on fiction, there is no theoretical account of how memory of fictional information is related to other types of memory or of which mechanisms allow people to separate fact and fiction in memory. We present a theoretical framework that places memory of fiction in relation to other cognitive phenomena as a distinct construct and argue that it is an essential component for any general theory of human memory. We show how fictionality can be integrated in an existing memory model by extending Rubin's dimensional conceptual memory model. By this means, our model can account for explicit and implicit memory of fictional information of events, places, characters, and objects. Further, we propose a set of mechanisms involving various degrees of complexity and levels of conscious processing that mostly keep fact and fiction separated but also allow information from fiction to influence real-world attitudes and beliefs: content-based reasoning, source monitoring, and an associative link from the memory to the concept of fiction.

Acute Ischemic Stroke in a Teenage Patient: Are We "MIS-C"ing Something?

The reported annual incidence of acute ischemic stroke (AIS) among pediatric and young adults is 1-13/100,000. In adults, ischemic stroke is attributed to several risk factors such as smoking, hypertension, atherosclerosis, and diabetes. Alternatively, pediatric ischemic stroke is associated with a broad spectrum of etiologies including prematurity, congenital heart disease, arteriopathies like moyamoya, chronic inflammatory disease, sickle cell, hypercoagulability, and malignancy. In rare cases, AIS has been associated with multisystem inflammatory syndrome in children (MIS-C), a Kawasaki-like inflammatory disease affecting patients younger than 21 years of age. This recently recognized and rare condition has been linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and presentations can vary widely in terms of severity and systemic involvement. While the exact reason behind this association is unknown, there is a growing body of evidence in adult literature that links SARS-CoV-2 infection to hypercoagulability and immune-mediated thrombosis. In pediatric patients, this association is not very clear. We report a case of a 17-year-old, previously healthy male who presented with acute-onset expressive aphasia, right-sided hemiparesis, and facial droop after two weeks from experiencing coronavirus disease 2019 (COVID-19)-like symptoms. A non-contrast head CT revealed an acute left M2 territory infarct while serum workup was consistent with MIS-C. Providers must maintain a high degree of suspicion and consider AIS in pediatric patients presenting with even mild neurological changes and a recent history of SARS-CoV-2 infection.

Equine conjunctival haemangiosarcoma: Clinical presentation, management, and outcome of seven cases in the United Kingdom.

Background: Only 27 cases of equine conjunctival haemangiosarcoma have been reported in the literature over the past 37 years. Out of these, 22% of cases were lost to follow-up, 52% were euthanized, and 26% survived. A scarcity of cases and information is available for this rarely seen conjunctival tumour. Aim: To describe the clinical features, management, and outcome of conjunctival hemangiosarcoma in seven horses in the UK. Methods: Optivet medical records were reviewed for equine cases seen or advised on with a histopathological diagnosis of conjunctival haemangiosarcoma between January 2013 and March 2023. Medical records were accessed for details of signalment, history, management, and follow-up. Histopathology was used to confirm the diagnosis of haemangiosarcoma and assess the surgical margins. Immunohistochemistry was performed in a minority of cases with poorly differentiated solid tumours to support vascular lineage. Results: Seven eyes from seven horses (five geldings and two mares) with a mean age of 16 years and median of 18 years (range 10-21 years) met the criteria. Serosanguinous discharge was seen in six eyes. All eyes were managed surgically; 4 by exenteration and 3 by conjunctivectomy/keratectomy. Adjunctive cryotherapy was performed in two eyes. Metastatic disease in the ipsilateral parotid salivary gland, confirmed with histopathology, was seen in one horse. Surgical margins were clear in all but one eye. Solar elastosis was noted in five eyes. All horses were healthy at the last follow-up (0.2-5 years, mean 2.9 years, and median 2 years). Conclusion: Equine conjunctival haemangiosarcoma is rare. Serosanguinous ocular discharge is a common clinical sign. Early surgical excision is highly effective. Solar elastosis is a common histopathological feature, suggesting a role for UV-light in the pathogenesis.

Diagnosis, management, and outcome of an intralenticular foreign body in a dog: A case report.

Background: Intra-lenticular foreign bodies are rare in veterinary medicine and uncommon in human medicine. Approximately 50% of perforating ocular injuries in canines have lenticular involvement. Treatment choices include conservative management and surgical options. Retained intra-lenticular foreign body with delayed removal has not been reported in animals. Case Description: A 3-year-old male neutered Lurcher presented with right-sided ocular discomfort and a sealed full-thickness corneal perforation. The full ophthalmic examination could not be performed at the initial presentation due to miosis. Recrudescence of anterior uveitis was seen post-drug cessation. Re-evaluation of the eye with a mydriatic pupil revealed an intra-lenticular foreign body. Surgical removal via phacoemulsification was performed 8 weeks after the initial perforating injury. The eye remains visual, comfortable, and normotensive 50 months post-operatively. Conclusion: This is the first report of an encapsulated, retained intra-lenticular foreign body with delayed removal in a dog. Mydriasis and repeat examinations are of crucial importance when evaluating eyes post-perforation.

3D printable adhesive elastomers with dynamic covalent bond rearrangement.

Repairable adhesive elastomers are emerging materials employed in compelling applications such as soft robotics, biosensing, tissue regeneration, and wearable electronics. Facilitating adhesion requires strong interactions, while self-healing requires bond dynamicity. This contrast in desired bond characteristics presents a challenge in the design of healable adhesive elastomers. Furthermore, 3D printability of this novel class of materials has received limited attention, restricting the potential design space of as-built geometries. Here, we report a series of 3D-printable elastomeric materials with self-healing ability and adhesive properties. Repairability is obtained using Thiol-Michael dynamic crosslinkers incorporated into the polymer backbone, while adhesion is facilitated with acrylate monomers. Elastomeric materials with excellent elongation up to 2000%, self-healing stress recovery >95%, and strong adhesion with metallic and polymeric surfaces are demonstrated. Complex functional structures are successfully 3D printed using a commercial digital light processing (DLP) printer. Shape-selective lifting of low surface energy poly(tetrafluoroethylene) objects is achieved using soft robotic actuators with interchangeable 3D-printed adhesive end effectors, wherein tailored contour matching leads to increased adhesion and successful lifting capacity. The demonstrated utility of these adhesive elastomers provides unique capabilities to easily program soft robot functionality.

RCSB Protein Data Bank: Efficient Searching and Simultaneous Access to One Million Computed Structure Models Alongside the PDB Structures Enabled by Architectural Advances.

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) provides open access to experimentally-determined three-dimensional (3D) structures of biomolecules. The RCSB PDB RCSB.org research-focused web portal is used annually by many millions of users around the world. They access biostructure information, run complex queries utilizing various search services (e.g., full-text, structural and chemical attribute, chemical, sequence, and structure similarity searches), and visualize macromolecules in 3D, all at no charge and with no limitations on data usage. Notwithstanding more than 24,000-fold growth of the PDB over the past five decades, experimentally-determined structures are only available for a small subset of the millions of proteins of known sequence. Recently developed machine learning software tools can predict 3D structures of proteins at accuracies comparable to lower-resolution experimental methods. The RCSB PDB now provides access to ∼1,000,000 Computed Structure Models (CSMs) of proteins coming from AlphaFold DB and the ModelArchive alongside ∼200,000 experimentally-determined PDB structures. Both CSMs and PDB structures are available on RCSB.org and via well-established RCSB PDB Data, Search, and 1D-Coordinates application programming interfaces (APIs). Simultaneous delivery of PDB data and CSMs provides users with access to complementary structural information across the human proteome and those of model organisms and selected pathogens. API enhancements are backwards-compatible and programmatic users can "opt in" to access CSMs with minimal effort. Herein, we describe modifications to RCSB PDB cyberinfrastructure required to support sixfold scaling of 3D biostructure data delivery and lay the groundwork for scaling to accommodate hundreds of millions of CSMs.

A cross-national study of predrinking motives in Spain and the UK: Cross-sectional associations with risk-taking and alcohol consumption.

This study contrasts young people's predrinking in two European cultural contexts: Spain and the UK. Whilst UK predrinking typically occurs amongst small groups of individuals who already know one another, the distinctive Spanish context of the Botellón details a far larger gathering in which participants may be less likely to know each other. As such, predrinking motives which drive consumption and risk-taking may be expected to vary between these cultures. An online questionnaire (N = 397; UK = 167, Spain = 230) was used to examine a variety of drinking behaviours and associated beliefs/motivations including predrinking motivations, drinking behaviour, and risk taking. Path analysis was used to analyse both direct and indirect relationships between the measures with the aim of predicting problem alcohol consumption with the most parsimonious model. Varying (in)direct paths were observed between predrinking motives and alcohol consumption between the cultures. Most notably and pointing towards inconsistency in the drivers of young adults' drinking, fun predrinking motives featured prominently among Spanish respondents and predicted their reported consumption (not so in the UK), while conviviality was a more prevalent predrinking motive in the UK sample and associated with alcohol consumption (not the case in Spain). Further, (personal) risky behaviour and risk-taking predicted consumption in both samples, suggesting the importance of group norms and behaviours in predrinking activity, irrespective of alcohol consumption. These findings highlight the potential importance of the environment in which young people predrink. Given their importance in shaping alcohol consumption and risk taking in young people, cultural differences in predrinking contexts and motives warrant further investigation.

An idea to explore: How an interdisciplinary undergraduate course exploring a global health challenge in molecular detail enabled science communication and collaboration in diverse audiences.

Communication and collaboration are key science competencies that support sharing of scientific knowledge with experts and non-experts alike. On the one hand, they facilitate interdisciplinary conversations between students, educators, and researchers, while on the other they improve public awareness, enable informed choices, and impact policy decisions. Herein, we describe an interdisciplinary undergraduate course focused on using data from various bioinformatics data resources to explore the molecular underpinnings of diabetes mellitus (Types 1 and 2) and introducing students to science communication. Building on course materials and original student-generated artifacts, a series of collaborative activities engaged students, educators, researchers, healthcare professionals and community members in exploring, learning about, and discussing the molecular bases of diabetes. These collaborations generated novel educational materials and approaches to learning and presenting complex ideas about major global health challenges in formats accessible to diverse audiences.

RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning.

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB), founding member of the Worldwide Protein Data Bank (wwPDB), is the US data center for the open-access PDB archive. As wwPDB-designated Archive Keeper, RCSB PDB is also responsible for PDB data security. Annually, RCSB PDB serves >10 000 depositors of three-dimensional (3D) biostructures working on all permanently inhabited continents. RCSB PDB delivers data from its research-focused RCSB.org web portal to many millions of PDB data consumers based in virtually every United Nations-recognized country, territory, etc. This Database Issue contribution describes upgrades to the research-focused RCSB.org web portal that created a one-stop-shop for open access to ∼200 000 experimentally-determined PDB structures of biological macromolecules alongside >1 000 000 incorporated Computed Structure Models (CSMs) predicted using artificial intelligence/machine learning methods. RCSB.org is a 'living data resource.' Every PDB structure and CSM is integrated weekly with related functional annotations from external biodata resources, providing up-to-date information for the entire corpus of 3D biostructure data freely available from RCSB.org with no usage limitations. Within RCSB.org, PDB structures and the CSMs are clearly identified as to their provenance and reliability. Both are fully searchable, and can be analyzed and visualized using the full complement of RCSB.org web portal capabilities.

Chromatin accessibility-based characterisation of brain gene regulatory networks in three distinct honey bee polyphenisms.

The honey bee genome has the capacity to produce three phenotypically distinct organisms (two diploid female castes: queen and worker, and a haploid male drone). Previous studies have implicated metabolic flux acting via epigenetic regulation in directing nutrition-driven phenotypic plasticity in the honey bee. However, the cis-acting DNA regulatory elements that establish tissue and polyphenism -specific epigenomes and gene expression programmes, remain unclear. Using a high resolution multiomic approach including assay for transposase-accessible chromatin by sequencing (ATAC-seq), RNA-seq and ChIP-seq, we produce the first genome-wide maps of the regulatory landscape across all three adult honey bee phenotypes identifying > 5000 regulatory regions in queen, 7500 in worker and 6500 in drone, with the vast majority of these sites located within intronic regions. These regions are defined by positive enrichment of H3K27ac and depletion of H3K4me3 and show a positive correlation with gene expression. Using ATAC-seq footprinting we determine queen, worker and drone -specific transcription factor occupancy and uncover novel phenotype-specific regulatory networks identifying two key nuclear receptors that have previously been implicated in caste-determination and adult behavioural maturation in honey bees; ecdysone receptor and ultraspiracle. Collectively, this study provides novel insights into key gene regulatory networks that are associated with these distinct polyphenisms in the honey bee.

Protein Data Bank: A Comprehensive Review of 3D Structure Holdings and Worldwide Utilization by Researchers, Educators, and Students.

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB), funded by the United States National Science Foundation, National Institutes of Health, and Department of Energy, supports structural biologists and Protein Data Bank (PDB) data users around the world. The RCSB PDB, a founding member of the Worldwide Protein Data Bank (wwPDB) partnership, serves as the US data center for the global PDB archive housing experimentally-determined three-dimensional (3D) structure data for biological macromolecules. As the wwPDB-designated Archive Keeper, RCSB PDB is also responsible for the security of PDB data and weekly update of the archive. RCSB PDB serves tens of thousands of data depositors (using macromolecular crystallography, nuclear magnetic resonance spectroscopy, electron microscopy, and micro-electron diffraction) annually working on all permanently inhabited continents. RCSB PDB makes PDB data available from its research-focused web portal at no charge and without usage restrictions to many millions of PDB data consumers around the globe. It also provides educators, students, and the general public with an introduction to the PDB and related training materials through its outreach and education-focused web portal. This review article describes growth of the PDB, examines evolution of experimental methods for structure determination viewed through the lens of the PDB archive, and provides a detailed accounting of PDB archival holdings and their utilization by researchers, educators, and students worldwide.

RCSB Protein Data bank: Tools for visualizing and understanding biological macromolecules in 3D.

Now in its 52nd year of continuous operations, the Protein Data Bank (PDB) is the premiere open-access global archive housing three-dimensional (3D) biomolecular structure data. It is jointly managed by the Worldwide Protein Data Bank (wwPDB) partnership. The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) is funded by the National Science Foundation, National Institutes of Health, and US Department of Energy and serves as the US data center for the wwPDB. RCSB PDB is also responsible for the security of PDB data in its role as wwPDB-designated Archive Keeper. Every year, RCSB PDB serves tens of thousands of depositors of 3D macromolecular structure data (coming from macromolecular crystallography, nuclear magnetic resonance spectroscopy, electron microscopy, and micro-electron diffraction). The RCSB PDB research-focused web portal (RCSB.org) makes PDB data available at no charge and without usage restrictions to many millions of PDB data consumers around the world. The RCSB PDB training, outreach, and education web portal (PDB101.RCSB.org) serves nearly 700 K educators, students, and members of the public worldwide. This invited Tools Issue contribution describes how RCSB PDB (i) is organized; (ii) works with wwPDB partners to process new depositions; (iii) serves as the wwPDB-designated Archive Keeper; (iv) enables exploration and 3D visualization of PDB data via RCSB.org; and (v) supports training, outreach, and education via PDB101.RCSB.org. New tools and features at RCSB.org are presented using examples drawn from high-resolution structural studies of proteins relevant to treatment of human cancers by targeting immune checkpoints.

Systemic corticosteroids for radicular and non-radicular low back pain.

BACKGROUND: Corticosteroids are medications with anti-inflammatory and immunosuppressant properties. Systemic corticosteroids administered through the oral, intravenous, or intramuscular routes have been used to treat various types of low back pain, including radicular back pain (not due to spinal stenosis), non-radicular back pain, and spinal stenosis. However, there is uncertainty about the benefits and harms of systemic corticosteroids for low back pain. OBJECTIVES: To evaluate the benefits and harms of systemic corticosteroids versus placebo or no corticosteroid for radicular low back pain, non-radicular low back pain, and symptomatic spinal stenosis in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was September 2021. SELECTION CRITERIA: We included randomized and quasi-randomized trials in adults of systematic corticosteroids versus placebo or no corticosteroid. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The major outcomes were pain, function, need for surgery, serious adverse effect, and presence of hyperglycemia. The minor outcomes were quality of life, successful outcomes, non-serious adverse events, and withdrawal due to adverse events. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: Thirteen trials (1047 participants) met the inclusion criteria. Nine trials included participants with radicular low back pain, two trial with low back pain, and two trials with spinal stenosis. All trials blinded participants to receipt of systemic corticosteroids. Seven trials were at low risk of bias, five at unclear risk, and one at high risk of selection bias. Two trials were at high risk of attrition bias. Doses and duration of systemic corticosteroid therapy varied. Radicular low back pain For radicular low back pain, moderate-certainty evidence indicated that systemic corticosteroids probably slightly decrease pain versus placebo at short-term follow-up (mean difference (MD) 0.56 points better, 95% confidence interval (CI) 1.08 to 0.04 on a 0 to 10 scale) and may slightly increase the likelihood of experiencing improvement in pain at short-term follow-up (risk ratio (RR) 1.21, 95% CI 0.88 to 1.66; absolute effect 5% better (95% CI 5% worse to 15% better). Systemic corticosteroids may not improve function at short-term follow-up (standardized mean difference (SMD) 0.14 better; range 0.49 better to 0.21 worse) and probably increase the likelihood of improvement in function at short-term follow-up (RR 1.52, 95% CI 1.22 to 1.91; absolute effect 19% better, 95% CI 8% better to 30% better). Systemic corticosteroids were associated with greater improvement in function versus placebo at long-term follow-up (MD -7.40, 95% CI -12.55 to -2.25 on the 0 to 100 Oswestry Disability Index) and greater likelihood of functional improvement (RR 1.29, 95% CI 1.06 to 1.56), based on a single trial. There was no difference in likelihood of surgery (RR 1.00, 95% CI 0.68 to 1.47). Evidence indicated that systemic corticosteroids (administered as a single dose or as a short course of therapy) are not associated with increased risk of any adverse event, serious adverse events, withdrawal due to adverse events, or hyperglycemia, but estimates were imprecise as some trials did not report harms, and harms reporting was suboptimal in trials that did provide data. Limitations included variability across trials in interventions (e.g. corticosteroid used, dose and duration of treatment), clinical settings, and participants (e.g. duration of symptoms, methods for diagnosis); limited utility of subgroup analyses due to small numbers of trials; methodologic limitations or suboptimal reporting of methods by some trials; and too few trials to formally assess for publication bias using graphical or statistical tests for small sample effects. Non-radicular low back pain Evidence on systemic corticosteroids versus placebo for non-radicular pain was limited and suggested that systemic corticosteroids may be associated with slightly worse short-term pain but slightly better function. Spinal stenosis For spinal stenosis, limited evidence indicated that systemic corticosteroids are probably no more effective than placebo for short-term pain or function. AUTHORS' CONCLUSIONS: Systemic corticosteroids appear to be slightly effective at improving short-term pain and function in people with radicular low back pain not due to spinal stenosis, and might slightly improve long-term function. The effects of systemic corticosteroids in people with non-radicular low back pain are unclear and systemic corticosteroids are probably ineffective for spinal stenosis. A single dose or short course of systemic corticosteroids for low back pain does not appear to cause serious harms, but evidence is limited.

Severe Pertussis Infection With Hyperleukocytosis in a 10-Month-Old Unvaccinated Amish Female: A Case Report.

Bordetella pertussis (B. pertussis) commonly infects individuals of all ages. However, pertussis, the disease caused by B. pertussis infection, is most severe in young infants. Severe pertussis, defined by the presence of refractory hypoxemia, pneumonia, cardiogenic shock, and hyperleukocytosis, is associated with significant morbidity and mortality. Both hyperleukocytosis and pulmonary hypertension have been found to be predictive of mortality in young infants. Leukoreductive strategies such as leukapheresis and exchange transfusion have been employed to treat these complications. Pulmonary hypertension is thought to be a result of aggregation of white blood cells in pulmonary vasculature; however, studies have suggested that the mechanism of pulmonary hypertension is multifactorial. We report a case of a 10-month-old unvaccinated Amish female with pertussis complicated by an initial hyperleukocytosis of 204,900 103/uL successfully treated with leukapheresis in our pediatric intensive care unit. This infant never showed signs of pulmonary hypertension, which is often associated with hyperleukocytosis in severe or fatal cases of pertussis in infants and neonates. To our knowledge, this is the most significant degree of hyperleukocytosis reported in pertussis. The findings in this case support the clinical utility of leukoreductive therapy in severe pertussis and provide some evidence that the mechanism of pulmonary hypertension in these patients is multifactorial.

Outcomes of the National Heart, Lung, and Blood Institute K12 program in emergency care research: 7-year follow-up.

BACKGROUND: Long-term follow-up for clinician-scientist training programs is sparse. We describe the outcomes of clinician-scientist scholars in the National Heart Lung and Blood Institute (NHLBI) K12 program in emergency care research up to 8.7 years after matriculation in the program. METHODS: This was a cohort study of faculty clinician-scientist scholars enrolled in a NHLBI K12 research training program at 6 sites across the US, with median follow-up 7.7 years (range 5.7-8.7 years) from the date of matriculation. Scholars completed electronic surveys in 2017 and 2019, with the 2019 survey collecting information for their current work setting, percent time for research, and grant funding from all sources. We used NIH RePorter and online resources to verify federal grants through March 2021. The primary outcome was a funded career development award (CDA) or research project grant (RPG) where the scholar was principal investigator. We included funding from all federal sources and national foundations. RESULTS: There were 43 scholars, including 16 (37%) women. Over the follow-up period, 32 (74%) received an individual CDA or RPG, with a median of 36 months (range 9-83 months) after entering the program. Of the 43 scholars, 23 (54%) received a CDA and 22 (51%) received an RPG, 7 (16%) of which were R01s. Of the 23 scholars who received a CDA, 13 (56%) subsequently had an RPG funded. Time to CDA or RPG did not differ by sex (women vs. men log-rank test p = 0.27) or specialty training (emergency medicine versus other specialties, p = 0.59). CONCLUSIONS: After 7 years of follow-up for this NHLBI K12 emergency care research training program, three quarters of clinician-scientist scholars had obtained CDA or RPG funding, with no notable differences by sex or clinical training.