Earth's ambipolar electrostatic field and its role in ion escape to space.

Cold plasma of ionospheric origin has recently been found to be a much larger contributor to the magnetosphere of Earth than expected1-3. Numerous competing mechanisms have been postulated to drive ion escape to space, including heating and acceleration by wave-particle interactions4 and a global electrostatic field between the ionosphere and space (called the ambipolar or polarization field)5,6. Observations of heated O+ ions in the magnetosphere are consistent with resonant wave-particle interactions7. By contrast, observations of cold supersonic H+ flowing out of the polar ionosphere8,9 (called the polar wind) suggest the presence of an electrostatic field. Here we report the existence of a +0.55 ± 0.09 V electric potential drop between 250 km and 768 km from a planetary electrostatic field (E∥⊕ = 1.09 ± 0.17 µV m-1) generated exclusively by the outward pressure of ionospheric electrons. We experimentally demonstrate that the ambipolar field of Earth controls the structure of the polar ionosphere, boosting the scale height by 271%. We infer that this increases the supply of cold O+ ions to the magnetosphere by more than 3,800%, in which other mechanisms such as wave-particle interactions can heat and further accelerate them to escape velocity. The electrostatic field of Earth is strong enough by itself to drive the polar wind9,10 and is probably the origin of the cold H+ ion population1 that dominates much of the magnetosphere2,3.

Timescales of learning in prefrontal cortex.

The lateral prefrontal cortex (PFC) in humans and other primates is critical for immediate, goal-directed behaviour and working memory, which are classically considered distinct from the cognitive and neural circuits that support long-term learning and memory. Over the past few years, a reconsideration of this textbook perspective has emerged, in that different timescales of memory-guided behaviour are in constant interaction during the pursuit of immediate goals. Here, we will first detail how neural activity related to the shortest timescales of goal-directed behaviour (which requires maintenance of current states and goals in working memory) is sculpted by long-term knowledge and learning - that is, how the past informs present behaviour. Then, we will outline how learning across different timescales (from seconds to years) drives plasticity in the primate lateral PFC, from single neuron firing rates to mesoscale neuroimaging activity patterns. Finally, we will review how, over days and months of learning, dense local and long-range connectivity patterns in PFC facilitate longer-lasting changes in population activity by changing synaptic weights and recruiting additional neural resources to inform future behaviour. Our Review sheds light on how the machinery of plasticity in PFC circuits facilitates the integration of learned experiences across time to best guide adaptive behaviour.

Lipid biosynthesis perturbation impairs endoplasmic reticulum-associated degradation.

The relationship between lipid homeostasis and protein homeostasis (proteostasis) is complex and remains incompletely understood. We conducted a screen for genes required for efficient degradation of Deg1-Sec62, a model aberrant translocon-associated substrate of the endoplasmic reticulum (ER) ubiquitin ligase Hrd1, in Saccharomyces cerevisiae. This screen revealed that INO4 is required for efficient Deg1-Sec62 degradation. INO4 encodes one subunit of the Ino2/Ino4 heterodimeric transcription factor, which regulates expression of genes required for lipid biosynthesis. Deg1-Sec62 degradation was also impaired by mutation of genes encoding several enzymes mediating phospholipid and sterol biosynthesis. The degradation defect in ino4Δ yeast was rescued by supplementation with metabolites whose synthesis and uptake are mediated by Ino2/Ino4 targets. Stabilization of a panel of substrates of the Hrd1 and Doa10 ER ubiquitin ligases by INO4 deletion indicates ER protein quality control is generally sensitive to perturbed lipid homeostasis. Loss of INO4 sensitized yeast to proteotoxic stress, suggesting a broad requirement for lipid homeostasis in maintaining proteostasis. A better understanding of the dynamic relationship between lipid homeostasis and proteostasis may lead to improved understanding and treatment of several human diseases associated with altered lipid biosynthesis.

--Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in Pediatric Human Atrial Tissue.

Nearly 1% of babies are born with congenital heart disease (CHD) - many of whom will require heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate drug therapies, and inform clinical care decisions related to surgical repair and postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we collected right atrial tissue samples from pediatric patients (n=117) undergoing heart surgery. Patients were stratified into five age groups. We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. Enrichment of differentially expressed genes (DEGs) revealed age-dependent changes in several key biological processes (e.g., cell cycle, structural organization), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited age-dependent trends, with changes in calcium handling (INCX) and repolarization (IK1) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We observed a shift in repolarization reserve, with lower IKr expression in younger patients, a finding potentially tied to an increased amplitude of IKs that could be triggered by elevated sympathetic activation in pediatric patients. Collectively, this study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology, shedding light on molecular mechanisms underlying cardiac maturation and function throughout development.

Bidirectional Multiphoton Communication between Remote Superconducting Nodes.

Quantum communication test beds provide a useful resource for experimentally investigating a variety of communication protocols. Here we demonstrate a superconducting circuit test bed with bidirectional multiphoton state transfer capability using time-domain shaped wave packets. The system we use to achieve this comprises two remote nodes, each including a tunable superconducting transmon qubit and a tunable microwave-frequency resonator, linked by a 2 m-long superconducting coplanar waveguide, which serves as a transmission line. We transfer both individual and superposition Fock states between the two remote nodes, and additionally show that this bidirectional state transfer can be done simultaneously, as well as being used to entangle elements in the two nodes.

Sulcal depth in prefrontal cortex: a novel predictor of working memory performance.

The neuroanatomical changes that underpin cognitive development are of major interest in neuroscience. Of the many aspects of neuroanatomy to consider, tertiary sulci are particularly attractive as they emerge last in gestation, show a protracted development after birth, and are either human- or hominoid-specific. Thus, they are ideal targets for exploring morphological-cognitive relationships with cognitive skills that also show protracted development such as working memory (WM). Yet, the relationship between sulcal morphology and WM is unknown-either in development or more generally. To fill this gap, we adopted a data-driven approach with cross-validation to examine the relationship between sulcal depth in lateral prefrontal cortex (LPFC) and verbal WM in 60 children and adolescents between ages 6 and 18. These analyses identified 9 left, and no right, LPFC sulci (of which 7 were tertiary) whose depth predicted verbal WM performance above and beyond the effect of age. Most of these sulci are located within and around contours of previously proposed functional parcellations of LPFC. This sulcal depth model outperformed models with age or cortical thickness. Together, these findings build empirical support for a classic theory that tertiary sulci serve as landmarks in association cortices that contribute to late-maturing human cognitive abilities.

Force Field X: A computational microscope to study genetic variation and organic crystals using theory and experiment.

Force Field X (FFX) is an open-source software package for atomic resolution modeling of genetic variants and organic crystals that leverages advanced potential energy functions and experimental data. FFX currently consists of nine modular packages with novel algorithms that include global optimization via a many-body expansion, acid-base chemistry using polarizable constant-pH molecular dynamics, estimation of free energy differences, generalized Kirkwood implicit solvent models, and many more. Applications of FFX focus on the use and development of a crystal structure prediction pipeline, biomolecular structure refinement against experimental datasets, and estimation of the thermodynamic effects of genetic variants on both proteins and nucleic acids. The use of Parallel Java and OpenMM combines to offer shared memory, message passing, and graphics processing unit parallelization for high performance simulations. Overall, the FFX platform serves as a computational microscope to study systems ranging from organic crystals to solvated biomolecular systems.

Cancer-associated somatic mutations in human phosphofructokinase-1 reveal a critical electrostatic interaction for allosteric regulation of enzyme activity.

Metabolic reprogramming, including increased glucose uptake and lactic acid excretion, is a hallmark of cancer. The glycolytic 'gatekeeper' enzyme phosphofructokinase-1 (PFK1), which catalyzes the step committing glucose to breakdown, is dysregulated in cancers. While altered PFK1 activity and expression in tumors have been demonstrated, little is known about the effects of cancer-associated somatic mutations. Somatic mutations in PFK1 inform our understanding of allosteric regulation by identifying key amino acid residues involved in the regulation of enzyme activity. Here, we characterized mutations disrupting an evolutionarily conserved salt bridge between aspartic acid and arginine in human platelet (PFKP) and liver (PFKL) isoforms. Using purified recombinant proteins, we showed that disruption of the Asp-Arg pair in two PFK1 isoforms decreased enzyme activity and altered allosteric regulation. We determined the crystal structure of PFK1 to 3.6 Šresolution and used molecular dynamic simulations to understand molecular mechanisms of altered allosteric regulation. We showed that PFKP-D564N had a decreased total system energy and changes in the electrostatic surface potential of the effector site. Cells expressing PFKP-D564N demonstrated a decreased rate of glycolysis, while their ability to induce glycolytic flux under conditions of low cellular energy was enhanced compared with cells expressing wild-type PFKP. Taken together, these results suggest that mutations in Arg-Asp pair at the interface of the catalytic-regulatory domains stabilizes the t-state and presents novel mechanistic insight for therapeutic development in cancer.

Semiautomated Hemorrhage Volume Quantification in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The volume of hemorrhage is a crucial factor in predicting outcomes following aneurysmal subarachnoid hemorrhage (aSAH). Although grading scales such as the Fisher score are widely used, they can lead to inaccuracies in quantifying the total blood volume because of their reliance on visual assessment. We analyzed a large cohort of patients with aSAH with a semiautomated software for the precise quantification of hemorrhage volume. The primary aim is to identify clear thresholds that correlate with the likelihood of complications after aSAH, thereby enhancing the predictive accuracy and improving patient management strategies. METHODS: A semiautomated algorithm was developed to analyze noncontrast computed tomography scans of patients with aSAH. The algorithm categorized tissues into blood, gray matter, white matter, and cerebrospinal fluid, isolating the blood for volume quantification. Receiver operating curve analysis was done to establish thresholds for vasospasm, acute hydrocephalus, shunt-dependent hydrocephalus (SDHC), and death within 7 days. RESULTS: A total of 500 patients with aSAH and their respective aneurysms were analyzed. Hemorrhage volume was significantly higher in patients with vasospasm (21.7 [10.9-41.4] vs. 10.7 [4.2-26.9], p < 0.001), acute hydrocephalus (22.7 [9.2-41.8] vs. 5.1 [2.1-13.5], p < 0.001), SDHC (23.8 [11.3-40.7] vs. 11.7 [4.1-28.2], p < 0.001), and those who died before 7 days (52.8 [34.6-90.6] mL vs. 14.8 [5.0-32.4] mL, p < 0.001) compared with their counterparts. Notably, specific hemorrhage thresholds were identified for each complication: 15.16 mL for vasospasm (65% sensitivity and 60% specificity), 9.95 mL for acute hydrocephalus (74% sensitivity and 69% specificity), 16.76 mL for SDHC (63% sensitivity and 60% specificity), and 33.84 mL for death within 7 days (79% sensitivity and 77% specificity). CONCLUSIONS: Semiautomated blood volume quantification tools could aid in stratifying complication risk after aSAH. Established thresholds for hemorrhage volume related to complications could be used in clinical practice to aid in management decisions.

Community events to increase uptake of Indigenous-specific health assessments: a scoping review.

INTRODUCTION: Innovative, culturally safe strategies are required to address the disproportionate level of poorer health outcomes for Indigenous people in Australia compared to non-Indigenous populations. An emerging body of evidence supports the efficacy of Indigenous-specific health assessments, or health checks, despite poor uptake since their introduction in Australia. This poor uptake is attributed to a range of system, patient and provider barriers. Services have begun to deliver preventative health assessments as a community event to address barriers faced by Aboriginal and Torres Strait Islander people in accessing quality preventative care. However, there is a lack of literature exploring how community events have increased the uptake of Indigenous-specific health assessments to date. We expect this review will underpin a larger study to better understand how community engagement supports increased uptake of health checks. The objective of this scoping review was to investigate what is currently known about how community events have been used to increase uptake of Indigenous-specific health assessments. METHODS: A scoping review guided by the Joanna Briggs Institute methodology for scoping reviews was conducted. A search was completed in eight electronic databases using keywords relating to Aboriginal and Torres Strait Islander health, community engagement and preventative health assessments. Published and unpublished sources of evidence were included in the review. As this study aims to explore the entire published literature on the topic, and given there was an expectation that the subject itself is specific, no date ranges were included in the search criteria. Extracted data were reviewed by numerical analysis and conventional content analysis to conduct a narrative synthesis, allowing a summary of the main findings, and addressing the research question. RESULTS: Eighteen sources met the eligibility criteria and were included in the scoping review. Programs varied widely in the characteristics of program design and delivery across geographical location, setting of delivery, program format and target population. Programs employed a range of methods to engage with community, including incentivising participation, identifying and addressing specific community healthcare needs, and utilising cultural or sporting ambassadors to promote the program. The conventional content analysis identified three key themes regarding how community events have been used to increase uptake of health checks: adapting the program to the community; providing a culturally safe participant experience; and prioritising community engagement. DISCUSSION: The findings indicate that an individualised approach to community events is important to their success. Aboriginal Controlled Community Health Services may be best placed to have responsibility for program design and implementation to ensure community control of programs. Aboriginal health workers play a critical role in ensuring the programs deliver culturally safe healthcare, and a clear role for Aboriginal health workers in program delivery is important in their success. An authentic commitment to community engagement is important for program uptake, including the use of passionate cultural ambassadors and individualised cultural programs. CONCLUSION: Community events are a promising and well-regarded strategy to increase uptake of Indigenous-specific health assessments. Future research that explores how specific community supports increase engagement with Health Check Day programs and evaluates the delivery of 715 health check programs will strengthen the capacity of Aboriginal Community Controlled Health Services to delivery this intervention effectively.

Modeling incomplete penetrance in long QT syndrome type 3 through ion channel heterogeneity: an in silico population study.

Many cardiac diseases are characterized by an increased late sodium current, including heart failure, hypertrophic cardiomyopathy, and inherited long QT syndrome type 3 (LQT3). The late sodium current in LQT3 is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5. Despite a well-defined genetic cause of LQT3, treatment remains inconsistent because of incomplete penetrance of the mutation and variability of antiarrhythmic efficacy. Here, we investigate the relationship between LQT3-associated mutation incomplete penetrance and variability in ion channel expression, simulating a population of 1,000 individuals with the O'Hara-Rudy model of the human ventricular myocyte. We first simulate healthy electrical activity (i.e., in the absence of a mutation) and then incorporate heterozygous expression for three LQT3-associated mutations (Y1795C, I1768V, and ΔKPQ), to directly compare the effects of each mutation on individuals across a diverse population. For all mutations, we find that susceptibility, defined by either the presence of an early afterdepolarization (EAD) or prolonged action potential duration (APD), primarily depends on the balance between the conductance of IKr and INa, for which individuals with a higher IKr-to-INa ratio are less susceptible. Furthermore, we find distinct differences across the population, observing individuals susceptible to zero, one, two, or all three mutations. Individuals tend to be less susceptible with an appropriate balance of repolarizing currents, typically via increased IKs or IK1. Interestingly, the more critical repolarizing current is mutation specific. We conclude that the balance between key currents plays a significant role in mutant-specific presentation of the disease phenotype in LQT3.NEW & NOTEWORTHY An in silico population approach investigates the relationship between variability in ion channel expression and gain-of-function mutations in the voltage-gated sodium channel associated with the congenital disorder long QT syndrome type 3 (LQT3). We find that ion channel variability can contribute to incomplete penetrance of the mutation, with mutant-specific differences in ion channel conductances leading to susceptibility to proarrhythmic action potential duration prolongation or early afterdepolarizations.

Radiation Oncology Virtual Education Rotation (ROVER) 2.0 for Residents: Implementation and Outcomes.

The COVID-19 pandemic catalyzed the integration of a virtual education curriculum to support radiation oncologists in training. We report outcomes from Radiation Oncology Virtual Education Rotation (ROVER) 2.0, a supplementary virtual educational curriculum created for radiation oncology residents globally. A prospective cohort of residents completed surveys before and after the live virtual webinar sessions (pre- and post-surveys, respectively). Live sessions were structured as complex gray-zone cases across various core disease sites. Resident demographics and responses were summarized using means, standard deviations, and proportions. Nine ROVER sessions were held from October 2020 to June 2021. A total of 1487 registered residents completed the pre-survey, of which 786 attended the live case discussion and 223 completed post-surveys. A total of 479 unique radiation oncology residents (of which 95, n = 19.8%, were international attendees) from 147 institutions (national, n = 81, 55.1%; international, n = 66, 44.9%) participated in the sessions. There was similar participation across post-graduate year (PGY) 2 through 5 (range n = 86 to n = 105). Of the 122 unique resident post-surveys, nearly all reported learning through the virtual structure as "very easy" or "easy" (97.5%, n = 119). A majority rated the ROVER 2.0 educational sessions to be "valuable or "very valuable" (99.2%, n = 121), and the panelists-attendee interaction as "appropriate" (97.5%, n = 119). Virtual live didactics aimed at radiation oncology residents are feasible. These results suggest that the adoption of the ROVER 2.0 curricula may help improve radiation oncology resident education.

Diagnostic Accuracy of Centrally Restricted Diffusion Sign in Cerebral Metastatic Disease: Differentiating Radiation Necrosis from Tumor Recurrence.

Purpose: The centrally restricted diffusion sign of diffusion-weighted imaging (DWI) is associated with radiation necrosis (RN) in treated gliomas. Our goal was to evaluate its diagnostic accuracy to distinguish RN from tumor recurrence (TR) in treated brain metastases. Methods: Retrospective study of consecutive patients with brain metastases who developed a newly centrally necrotic lesion after radiotherapy (RT). One reader placed regions of interest (ROI) in the enhancing solid lesion and the non-enhancing central necrosis on the apparent diffusion coefficient (ADC) map. Two readers qualitatively assessed the presence of the centrally restricted diffusion sign. The final diagnosis was made by histopathology (n = 39) or imaging follow-up (n = 2). Differences between groups were assessed by Fisher's exact or Mann-Whitney U tests. Diagnostic accuracy and inter-reader agreement were evaluated using receiver operating characteristic (ROC) curve analysis and kappa scores. Results: Forty-one lesions (32 predominant RN; 9 predominant TR) were analyzed. An ADC value ≤ 1220 × 10-6 mm2/s (sensitivity 74%, specificity 89%, area under the curve [AUC] .85 [95% confidence interval {CI}, .70-.94] P < .0001) from the necrosis and an ADC necrosis/enhancement ratio ≤1.37 (sensitivity 74%, specificity 89%, AUC .82 [95% CI, .67-.93] P < .0001) provided the highest performance for RN diagnosis. The qualitative centrally restricted diffusion sign had a sensitivity of 69% (95% CI, .50-.83), specificity of 77% (95% CI, .40-.96), and a moderate (k = .49) inter-reader agreement for RN diagnosis. Conclusions: Radiation necrosis is associated with lower ADC values in the central necrosis than TR. A moderate interobserver agreement might limit the qualitative assessment of the centrally restricted diffusion sign.

A Description and Analysis of Injury and Exercise in Collegiate Rodeo Athletes.

INTRODUCTION: Rodeo constitutes an exciting sporting spectacle enjoyed worldwide by competitors of all ages. College rodeo encompasses nine core events: bull riding, saddle bronc riding, bareback riding, team roping, tie-down roping, breakaway roping, steer wrestling, goat tying, and barrel racing. There is little research on rodeo athletes regarding training habits, injuries during competition and/or practice, or effective injury prevention strategies. The objectives of this study were to 1) characterize the injury profile of collegiate rodeo athletes, 2) describe training practices, and 3) determine if demographic or training factors influence injury risk. METHODS: Demographic, injury, and training data from 71 National Intercollegiate Rodeo Association members was collected via a SurveyMonkey survey. Data was analyzed to determine any association with injury risk, utilizing an ANOVA test for continuous categories and chi-square test for categorical variables. RESULTS: Competing in "roughstock" events (bull riding, saddle bronc riding, and bareback riding) and wearing protective equipment were associated with increased injury risk. Injuries mirrored previous studies of contact sport athletes. Student-athletes spent most of their training in activities directly related to their event but also engaged in exercise not related to their event for a considerable amount of time each week. CONCLUSION: Rodeo competitors constitute a versatile athletic cohort at high injury risk. These findings further define the injury profile of collegiate rodeo athletes and, for the first time, describe their training habits. This information will guide event preparation and rehabilitation of injured rodeo athletes.

Overlooked Tertiary Sulci Serve as a Meso-Scale Link between Microstructural and Functional Properties of Human Lateral Prefrontal Cortex.

Understanding the relationship between neuroanatomy and function in portions of cortex that perform functions largely specific to humans such as lateral prefrontal cortex (LPFC) is of major interest in systems and cognitive neuroscience. When considering neuroanatomical-functional relationships in LPFC, shallow indentations in cortex known as tertiary sulci have been largely unexplored. Here, by implementing a multimodal approach and manually defining 936 neuroanatomical structures in 72 hemispheres (in both males and females), we show that a subset of these overlooked tertiary sulci serve as a meso-scale link between microstructural (myelin content) and functional (network connectivity) properties of human LPFC in individual participants. For example, the posterior middle frontal sulcus (pmfs) is a tertiary sulcus with three components that differ in their myelin content, resting-state connectivity profiles, and engagement across meta-analyses of 83 cognitive tasks. Further, generating microstructural profiles of myelin content across cortical depths for each pmfs component and the surrounding middle frontal gyrus (MFG) shows that both gyral and sulcal components of the MFG have greater myelin content in deeper compared with superficial layers and that the myelin content in superficial layers of the gyral components is greater than sulcal components. These findings support a classic, yet largely unconsidered theory that tertiary sulci may serve as landmarks in association cortices, as well as a modern cognitive neuroscience theory proposing a functional hierarchy in LPFC. As there is a growing need for computational tools that automatically define tertiary sulci throughout cortex, we share pmfs probabilistic sulcal maps with the field.SIGNIFICANCE STATEMENT Lateral prefrontal cortex (LPFC) is critical for functions that are thought to be specific to humans compared with other mammals. However, relationships between fine-scale neuroanatomical structures largely specific to hominoid cortex and functional properties of LPFC remain elusive. Here, we show that these structures, which have been largely unexplored throughout history, surprisingly serve as markers for anatomical and functional organization in human LPFC. These findings have theoretical, methodological, developmental, and evolutionary implications for improved understanding of neuroanatomical-functional relationships not only in LPFC, but also in association cortices more broadly. Finally, these findings ignite new questions regarding how morphological features of these neglected neuroanatomical structures contribute to functions of association cortices that are critical for human-specific aspects of cognition.

Post-Vaccination Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections and Incidence of the Presumptive B.1.427/B.1.429 Variant Among Healthcare Personnel at a Northern California Academic Medical Center.

BACKGROUND: Although mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines report >90% efficacy, breakthrough infections occur. Little is known about their effectiveness against SARS-CoV-2 variants, including the highly prevalent B.1.427/B.1.429 variant. METHODS: In this quality improvement project, we collected demographic and clinical information from post-vaccine SARS-CoV-2 cases (PVSCs), defined as healthcare personnel (HCP) with positive SARS-CoV-2 nucleic acid amplification test after receiving ≥1 vaccine dose. Available specimens were tested for L452R, N501Y, and E484K mutations using reverse-transcription polymerase chain reaction. Mutation prevalence was compared among unvaccinated, early post-vaccinated (≤14 days after dose 1), partially vaccinated (positive test >14 days after dose 1 and <14 days after dose 2), and fully vaccinated (>14 days after dose 2) PVSCs. RESULTS: From December 2020 to April 2021, ≥23 090 HCP received ≥1 dose of an mRNA-based SARS-CoV-2 vaccine, and 660 HCP cases of SARS-CoV-2 occurred, of which 189 were PVSCs. Among the PVSCs, 114 (60.3%), 49 (25.9%), and 26 (13.8%) were early post-vaccination, partially vaccinated, and fully vaccinated, respectively. Of 261 available samples from vaccinated and unvaccinated HCP, 103 (39.5%), including 42 PVSCs (36.5%), had the L452R mutation presumptive of B.1.427/B.1.429. When adjusted for community prevalence of B.1.427/B.1.429, PVSCs did not have significantly elevated risk of B.1.427/B.1.429 compared with unvaccinated HCP. CONCLUSIONS: Most PVSCs occurred prior to expected onset of full, vaccine-derived immunity. Presumptive B.1.427/B.1.429 was not more prevalent in post-vaccine cases than in unvaccinated SARS-CoV-2 HCP. Continued infection control measures, particularly <14 days post-vaccination, and continued variant surveillance in PVSCs are imperative to control future SARS-CoV-2 surges.

Multiplex Epstein-Barr virus BALF2 genotyping detects high-risk variants in plasma for population screening of nasopharyngeal carcinoma.

BACKGROUND: Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) exhibits unusual geographic restriction despite ubiquitous lifelong infection. Screening programs can detect most NPC cases at an early stage, but existing EBV diagnostics are limited by false positives and low positive predictive value (PPV), leading to excess screening endoscopies, MRIs, and repeated testing. Recent EBV genome-wide association studies (GWAS) suggest that EBV BALF2 variants account for more than 80% of attributable NPC risk. We therefore hypothesized that high-risk BALF2 variants could be readily detected in plasma for once-lifetime screening triage. METHODS: We designed and validated a multiplex genotyping assay to detect EBV BALF2 polymorphisms in human plasma. Targeted next-generation sequencing was used to validate this assay, conduct association studies with clinical phenotype, and longitudinally genotype plasma to assess within-host haplotype stability. We examined the association between NPC and BALF2 haplotypes in a large non-endemic population and three prior EBV GWAS. Finally, we estimated NPC mortality reduction, resource utilization, and cost-effectiveness of BALF2 variant-informed screening using a previously-validated cohort model. RESULTS: Following analytical validation, the BALF2 genotyping assay had 99.3% concordance with sequencing in a cohort of 24 NPC cases and 155 non-NPC controls. BALF2 haplotype was highly associated with NPC in this non-endemic population (I613V: odds ratio [OR] 7.9; V317M: OR 178.8). No other candidate BALF2 polymorphisms were significantly associated with NPC or hematologic disorders. Longitudinal genotyping revealed 97.8% within-host haplotype concordance, indicative of lifelong latent infection. In a meta-analysis of 755 NPC cases and 981 non-NPC controls, BALF2 I613V and V317M were significantly associated with NPC in both endemic and non-endemic populations. Modeled variant-informed screening strategies achieved a 46% relative increase in PPV with 7% decrease in effective screening sensitivity, thereby averting nearly half of screening endoscopies/MRIs among endemic populations in east/southeast Asia. CONCLUSIONS: EBV BALF2 haplotypes are temporally stable within hosts and can be readily detected in plasma via an inexpensive multiplex genotyping assay that offers near-perfect sequencing concordance. In endemic and non-endemic populations, I613V and V317M were highly associated with NPC and could be leveraged to develop variant-informed screening programs that mitigate false positives with small reductions in screening sensitivity.

Evaluation of a Rapid and Accessible Reverse Transcription-Quantitative PCR Approach for SARS-CoV-2 Variant of Concern Identification.

The ability to distinguish between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) is of ongoing interest due to differences in transmissibility, responses to vaccination, clinical prognosis, and therapy. Although detailed genetic characterization requires whole-genome sequencing (WGS), targeted nucleic acid amplification tests can serve a complementary role in clinical settings, as they are more rapid and accessible than sequencing in most laboratories. We designed and analytically validated a two-reaction multiplex reverse transcription-quantitative PCR (RT-qPCR) assay targeting spike protein mutations L452R, E484K, and N501Y in reaction 1 and del69-70, K417N, and T478K in reaction 2. This assay had 95 to 100% agreement with WGS for 502 upper respiratory tract swab samples collected between 26 April 2021 and 1 August 2021, consisting of 43 Alpha, 2 Beta, 20 Gamma, 378 Delta, and 59 non-VOC infections. Validation in a separate group of 230 WGS-confirmed Omicron variant samples collected in December 2021 and January 2022 demonstrated 100% agreement. This RT-qPCR-based approach can be implemented in clinical laboratories already performing SARS-CoV-2 nucleic acid amplification tests to assist in local epidemiological surveillance and clinical decision-making.

Management Options for Congenitally Corrected Transposition: Which, When, and for Whom?

Management strategies for congenitally corrected transposition of the great arteries (ccTGA) historically consisted of a physiologic repair, resulting in the morphologic right ventricle (mRV) supporting systemic circulation. This strategy persisted despite the development of heart failure by middle age because of the reasonable short-term outcomes, and the natural history of some patients with favorable anatomy (felt to demonstrate the mRV's ability to function in the long-term), and due to the less-than-optimal outcomes associated with anatomical repair. As outcomes with anatomical repair improved, and the long-term risk of systemic mRV dysfunction became apparent, more have begun to realize its advantages. In addition to the decision on whether or not to pursue anatomical repair, and the optimal timing, studies demonstrating the nuance to morphologic left ventricle retraining have demonstrated its feasibility. Further considerations in ccTGA have begun to be better understood, including: the management of a poorly functioning mRV, systemic tricuspid valve regurgitation, the utility of morphologic left ventricle outflow tract obstruction (native or surgically created) and pacing strategies. While some considerations are apparent: biventricular pacing is superior to univentricular, tricuspid regurgitation must be managed early with either progression towards anatomical repair (pulmonary artery banding if needed for retraining) or tricuspid replacement (not repair) based on the patient's age; others remain to be completely elucidated. Overall, the heterogeneity of ccTGA, as well as the unique presentation with each patient regarding ventricular and valvular function and center-to-center variability in management strategies has made the interpretation of published data difficult. That said, more recent long-term outcomes favor anatomical repair in most situations.

Paediatrician's guide to post-operative care for biventricular CHD: a review.

IMPORTANCE: Paediatricians play an integral role in the lifelong care of children with CHD, many of whom will undergo cardiac surgery. There is a paucity of literature for the paediatrician regarding the post-operative care of such patients. OBSERVATIONS: The aim of this manuscript is to summarise essential principles and pertinent lesion-specific context for the care of patients who have undergone surgery or intervention resulting in a biventricular circulation. CONCLUSIONS AND RELEVANCE: Familiarity with common issues following cardiac surgery or intervention, as well as key details regarding specific lesions and surgeries, will aid the paediatrician in providing optimal care for these patients.