Search

Chemical mechanisms describe the atmospheric transformations of organic and inorganic species and connect air emissions to secondary species such as ozone, fine particles, and hazardous air pollutants (HAPs) like formaldehyde. Recent advances in our understanding of several chemical systems and shifts in the drivers of atmospheric chemistry warrant updates to mechanisms used in chemical transport models such as the Community Multiscale Air Quality (CMAQ) modeling system. This work builds on the Regional Atmospheric Chemistry Mechanism version 2 (RACM2) and develops the Community Regional Atmospheric Chemistry Multiphase Mechanism (CRACMM) version 1.0, which demonstrates a fully coupled representation of chemistry leading to ozone and secondary organic aerosol (SOA) with consideration of HAPs. CRACMMv1.0 includes 178 gas-phase species, 51 particulate species, and 508 reactions spanning gas-phase and heterogeneous pathways. To support estimation of health risks associated with HAPs, nine species in CRACMM cover 50 % of the total cancer and 60 % of the total non-cancer emission-weighted toxicity estimated for primary HAPs from anthropogenic and biomass burning sources in the US, with the coverage of toxicity higher (> 80 %) when secondary formaldehyde and acrolein are considered. In addition, new mechanism species were added based on the importance of their emissions for the ozone, organic aerosol, or atmospheric burden of total reactive organic carbon (ROC): sesquiterpenes, furans, propylene glycol, alkane-like low- to intermediate-volatility organic compounds (9 species), low- to intermediate-volatility oxygenated species (16 species), intermediate-volatility aromatic hydrocarbons (2 species), and slowly reacting organic carbon. Intermediate- and lower-volatility organic compounds were estimated to increase the coverage of anthropogenic and biomass burning ROC emissions by 40 % compared to current operational mechanisms. Autoxidation, a gas-phase reaction particularly effective in producing SOA, was added for C10 and larger alkanes, aromatic hydrocarbons, sesquiterpenes, and monoterpene systems including second-generation aldehydes. Integrating the radical and SOA chemistry put additional constraints on both systems and enabled the implementation of previously unconsidered SOA pathways from phenolic and furanone compounds, which were predicted to account for ∼ 30 % of total aromatic hydrocarbon SOA under typical atmospheric conditions. CRACMM organic aerosol species were found to span the atmospherically relevant range of species carbon number, number of oxygens per carbon, and oxidation state with a slight high bias in the number of hydrogens per carbon. In total, 11 new emitted species were implemented as precursors to SOA compared to current CMAQv5.3.3 representations, resulting in a bottom-up prediction of SOA, which is required for accurate source attribution and the design of control strategies. CRACMMv1.0 is available in CMAQv5.4.

We present Arm's efforts in verifying the specification and prototype reference implementation of the Realm Management Monitor (RMM), an essential firmware component of Arm Confidential Computing Architecture (Arm CCA), the recently-announced Confidential Computing technologies incorporated in the Armv9-A architecture. Arm CCA introduced the Realm Management Extension (RME), an architectural extension for Armv9-A, and a technology that will eventually be deployed in hundreds of millions of devices. Given the security-critical nature of the RMM, and its taxing threat model, we use a combination of interactive theorem proving, model checking, and concurrency-aware testing to validate and verify security and safety properties of both the specification and a prototype implementation of the RMM. Crucially, our verification efforts were, and are still being, developed and refined contemporaneously with active development of both specification and implementation, and have been adopted by Arm's product teams. We describe our major achievements, realized through the application of formal techniques, as well as challenges that remain for future work. We believe that the work reported in this paper is the most thorough application of formal techniques to the design and implementation of any current commercially-viable Confidential Computing implementation, setting a new high-water mark for work in this area.

Background: Organising alcohol retail systems with more or less public ownership has implications for health and the economy. The aim of the present study was to estimate the economic, health, and social impacts of alcohol use in Finland in 2018 (baseline), and in two alternative scenarios in which current partial public ownership of alcohol retail sales is either increased or fully privatised. Methods: Baseline alcohol-attributable harms and costs were estimated across five categories of death, disability, and criminal justice. Two alternate alcohol retail systems were defined as privately owned stores selling: (1) only low strength alcoholic beverages (public ownership scenario, similar to Sweden); or (2) all beverages (private ownership scenario). Policy analyses were conducted to estimate changes in alcohol use per capita. Health and economic impacts were modelled using administrative data and epidemiological modelling. Results: In Finland in 2018, alcohol use was estimated to be responsible for €1.51 billion (95% Uncertainty Estimates: €1.43 billion, €1.58 billion) in social cost, 3,846 deaths, and 270,652 criminal justice events. In the public ownership scenario, it was estimated that alcohol use would decline by 15.8% (11.8%, 19.7%) and social cost by €384.3 million (€189.5 million, €559.2 million). Full privatisation was associated with an increase in alcohol use of 9.0% (6.2%, 11.8%) and an increase in social cost of €289.7 million (€140.8 million, €439.5 million). Conclusion: The outcome from applying a novel analytical approach suggests that more public ownership of the alcohol retail system may lead to significant decreases in alcohol-caused death, disability, crime, and social costs. Conversely, full privatisation of the ownership model would lead to increased harm and costs.

Although it is well established that Huntington's disease (HD) is mainly caused by polyglutamine-expanded mutant huntingtin (mHTT), the molecular mechanism of mHTT-mediated actions is not fully understood. Here, we showed that expression of the N-terminal fragment containing the expanded polyglutamine (HTTQ94) of mHTT is able to promote both the ACSL4-dependent and the ACSL4-independent ferroptosis. Surprisingly, inactivation of the ACSL4-dependent ferroptosis fails to show any effect on the life span of Huntington's disease mice. Moreover, by using RNAi-mediated screening, we identified ALOX5 as a major factor required for the ACSL4-independent ferroptosis induced by HTTQ94. Although ALOX5 is not required for the ferroptotic responses triggered by common ferroptosis inducers such as erastin, loss of ALOX5 expression abolishes HTTQ94-mediated ferroptosis upon reactive oxygen species (ROS)-induced stress. Interestingly, ALOX5 is also required for HTTQ94-mediated ferroptosis in neuronal cells upon high levels of glutamate. Mechanistically, HTTQ94 activates ALOX5-mediated ferroptosis by stabilizing FLAP, an essential cofactor of ALOX5-mediated lipoxygenase activity. Notably, inactivation of theAlox5gene abrogates the ferroptosis activity in the striatal neurons from the HD mice; more importantly, loss of ALOX5 significantly ameliorates the pathological phenotypes and extends the life spans of these HD mice. Taken together, these results demonstrate that ALOX5 is critical for mHTT-mediated ferroptosis and suggest that ALOX5 is a potential new target for Huntington's disease.

Background Text messages can be an effective and low-cost mechanism for patient reminders; however, they are yet to be consistently integrated into pediatric primary care. Objective The aim of this study was to explore pediatric primary care clinician and staff perceptions of pediatric office text message communication with families. Methods As part of the National Institutes of Health–funded Flu2Text randomized controlled trial of second-dose influenza vaccine text message reminders, we conducted 7 focus groups and 4 individual interviews in July–August 2019 with primary care pediatric clinicians and staff (n = 39). Overall, 10 Pediatric Research in Office Settings (PROS) pediatric practices in 10 states were selected using stratified sampling. Semi-structured discussion guides included perspectives on possible uses, perceived usefulness, and ease of use of text messages; practices' current text messaging infrastructure; and perceived barriers/facilitators to future use of texting. Two investigators independently coded and analyzed transcripts based on the technology acceptance model using NVIVO 12 Plus (intercoder reliability, K = 0.86). Results Overall, participants were supportive of text reminders for the second-dose influenza vaccine, other vaccines, and appointments and perceived texting as a preferred method of communication for caregivers. Health information privacy and patient confidentiality were the main concerns cited. Only respondents from practices with no internal appointment text message reminder system prior to the study expressed concerns about technology implementation logistics, time, and cost. Conclusion Text message reminders, for various uses, appear to be well accepted among a group of geographically widespread pediatric practices after participation in a trial of influenza vaccine text message reminders. Privacy, confidentiality, and resource barriers need to be addressed to facilitate successful implementation.

We describe the characterization and field deployment of chemical ionization mass spectrometry (CIMS) using a recently developed focusing ion-molecule reactor (FIMR) and ammonium–water cluster (NH4+⋅H2O) as the reagent ion (denoted as NH4+ CIMS). We show that NH4+⋅H2O is a highly versatile reagent ion for measurements of a wide range of oxygenated organic compounds. The major product ion is the cluster with NH4+ produced via ligand-switching reactions. Other product ions (e.g., protonated ion, cluster ion with NH4+⋅H2O, with H3O+, and with H3O+⋅H2O) are also produced, but with minor fractions for most of the oxygenated compounds studied here. The instrument sensitivities (ion counts per second per part per billion by volume, cps ppbv−1) and product distributions are strongly dependent on the instrument operating conditions, including the ratio of ammonia (NH3) and H2O flows and the drift voltages, which should be carefully selected to ensure NH4+⋅H2O as the predominant reagent ion and to optimize sensitivities. For monofunctional analytes, the NH4+⋅H2O chemistry exhibits high sensitivity (i.e., >1000 cps ppbv−1) to ketones, moderate sensitivity (i.e., between 100 and 1000 cps ppbv−1) to aldehydes, alcohols, organic acids, and monoterpenes, low sensitivity (i.e., between 10 and 100 cps ppbv−1) to isoprene and C1 and C2 organics, and negligible sensitivity (i.e., cps ppbv−1) to reduced aromatics. The instrumental sensitivities of analytes depend on the binding energy of the analyte–NH4+ cluster, which can be estimated using voltage scanning. This offers the possibility to constrain the sensitivity of analytes for which no calibration standards exist. This instrument was deployed in the RECAP campaign (Re-Evaluating the Chemistry of Air Pollutants in California) in Pasadena, California, during summer 2021. Measurement comparisons against co-located mass spectrometers show that the NH4+ CIMS is capable of detecting compounds from a wide range of chemical classes. The NH4+ CIMS is valuable for quantification of oxygenated volatile organic compounds (VOCs) and is complementary to existing chemical ionization schemes.

Millions of children have tested positive for SARS-CoV-2, and over 1000 children have died in the US. However, vaccination rates for children 5 to 11 years old are low.Starting in August 2020, we conducted a prospective SARS-CoV-2 household surveillance study in Spanish and English-speaking households in New York City and Utah. From October 21 to 25, 2021, we asked caregivers about their likelihood of getting COVID-19 vaccine for their child, and reasons that they might or might not vaccinate that child. We compared intent to vaccinate by site, demographic characteristics, SARS-CoV-2 infection detected by study surveillance, and parents' COVID-19 vaccination status using Chi-square tests and a multivariable logistic regression model, accounting for within-household clustering.Among parents or caregivers of 309 children (0 to 11 years) in 172 households, 87% were very or somewhat likely to intend to vaccinate their child. The most prevalent reasons for intending to vaccinate were to protect family and friends and the community; individual prevention was mentioned less often. The most prevalent reasons for not intending to vaccinate were side effect concerns and wanting to wait and see.In multivariable analysis, parents had much lower odds of intending to vaccinate if someone in the household had tested SARS-CoV-2-positive during the study (adjusted odds ratio = 0.09; 95% confidence interval, 0.03-0.3).This study highlighted several themes for clinicians and public health officials to consider including the importance and safety of vaccination for this age-group even if infected previously, and the benefits of vaccination to protect family, friends, and community.

There is growing interest in faecal microbiota transplantation (FMT) as a treatment for recurrent Clostridioides difficile infection (CDI), but evidence on the diverse requirements for safe, effective and accessible services is fragmented and limited.To identify key components of FMT provision relating to the patient care pathway, stool donor pathway and wider healthcare system, and to explore variation in practice METHODS: We conducted a narrative review of the literature and consultations with key clinical experts in the field. Evidence is drawn from high-income country contexts, with an emphasis on Australia, Canada, Italy and the United Kingdom as case example countries.We identify and discuss key challenges to do with healthcare capacity (workforce, FMT and stool banking facilities), donors and donations, patient access and choice of FMT delivery routes, regulation, costs and reimbursement. We also identify improvement opportunities to increase awareness of FMT and referral processes, physician training, maintaining patient registries and outcome monitoring metrics, in-country regulatory harmonisation and tackling reimbursement challenges and discuss future research needs.Effectively bringing FMT to patients in a healthcare system requires much more than just the existence of a clinically effective procedure. With FMT being a potentially effective treatment option for recurrent CDI for many patients, a well-rounded understanding of how appropriate FMT capacity can be built and nurtured is important for both healthcare providers and policymakers seeking to improve patient care.

As molecular genetic techniques improve and sequence data becomes available for more fungal species, taxonomic classifications historically based upon growth morphology alone are being revisited and occasionally reclassified. Herein, we present such an instance for the fungal pathogen that causes dry berry disease of caneberries. The organism was previously described as the basidiomycete fungus Rhizoctonia rubi based upon the pathogen’s production of Rhizoctonia-like angular branching hyphae. Utilizing molecular genetic techniques unavailable when the pathogen was first characterized in 1959, three housekeeping gene regions (ITS, β-tubulin, and G3PDH) were sequenced across 13 contemporary dry berry isolates, as well as the original 1959 R. rubi type strain, CBS382.59. The resulting neighbor-joining, maximum likelihood, and Bayesian phylogenies for single and multilocus sequences provide strong evidence that the dry berry pathogen was misclassified. This data, in addition to revisiting in vivo macroscopic and microscopic growth morphology, again comparing contemporary dry berry isolates to the CBS382.59 type strain, suggests that the causal organism is a new species within the genus Monilinia that we propose be classified as Monilinia rubi. A transition from designation as a basidiomycete fungus to an ascomycete fungus could have implications on chemical management decisions, as well as the assumptions made about cell structure and the pathogen’s putative life cycle.

This article examines several recent theorizations of the concept “world” from within or in proximity to the field of world literature, and argues that these theorizations all suffer from a missed engagement with the work of Jean-Luc Nancy, the most important contemporary thinker of the concept. Focusing on recent books by Emily Apter, Debjani Ganguly, and Pheng Cheah, this article argues that while these theorists all make reference to Nancy, they do so in ways that miss essential aspects of his thinking. The article argues that the theoretical frameworks put forth by these thinkers prevent them from engaging with what Nancy called the “sense of the world.” The article concludes with a reflection on the place of joy in the text of Nancy to which all three of these thinkers make reference: The Creation of the World or Globalization.

This article takes its cue from David Miall’s influential 2011 paper, ‘Enacting the other: towards an aesthetics of feeling in literary reading’, in Elisabeth Schellekens and Peter Goldie (eds) The Aesthetic Mind: Philosophy and Psychology, Oxford: Oxford University Press, pp. 285–298. There, Miall considers the workings of readerly empathy with fictional people. He draws on work from philosophy, psychology, cognitive poetics, and both empirical and textual analysis to explore the complexities of how real readerly minds interact with fictional minds and the minds of real but remote authors. In this article, I revisit these arguments with the benefit of recent insights into the cognition of fictional minds. The key mechanism underlying characterisation, empathy, hostility, and engagement, I argue, is mind-modelling. With its origins in Theory of Mind, but extrapolated far from that simple phenomenon, mind-modelling captures the aesthetic and ethical relationships between minds both fictional and natural. I consider literary reading as a broader ecosystem: the reading mind as being embodied, enacted, and extended to include the imagined authorial mind. In recognition of Miall’s literary critical work, I will present a particular example from the poem ‘Ode on a Grecian Urn’ by John Keats – not only for the analytical demonstration but also in order to show the echoes between Romantic notions of holistic engagement with nature and recent work in cognition and literature. The analysis suggests a solution to a literary critical debate around its ending. An approach situated in mind-modelling offers a principled exploration of both fictional, poetic minds as well as authorial positioning.

Context Agricultural land-use conversion has fragmented prairie wetland habitats in the Prairie Pothole Region (PPR), an area with one of the most wetland dense regions in the world. This fragmentation can lead to negative consequences for wetland obligate organisms, heightening risk of local extinction and reducing evolutionary potential for populations to adapt to changing environments. Objectives This study models biotic connectivity of prairie-pothole wetlands using landscape genetic analyses of the northern leopard frog (Rana pipiens) to (1) identify population structure and (2) determine landscape factors driving genetic differentiation and possibly leading to population fragmentation. Methods Frogs from 22 sites in the James River and Lake Oahe river basins in North Dakota were genotyped using Best-RAD sequencing at 2868 bi-allelic single nucleotide polymorphisms (SNPs). Population structure was assessed using STRUCTURE, DAPC, and fineSTRUCTURE. Circuitscape was used to model resistance values for ten landscape variables that could affect habitat connectivity. Results STRUCTURE results suggested a panmictic population, but other more sensitive clustering methods identified six spatially organized clusters. Circuit theory-based landscape resistance analysis suggested land use, including cultivated crop agriculture, and topography were the primary influences on genetic differentiation. Conclusion While the R. pipiens populations appear to have high gene flow, we found a difference in the patterns of connectivity between the eastern portion of our study area which was dominated by cultivated crop agriculture, versus the western portion where topographic roughness played a greater role. This information can help identify amphibian dispersal corridors and prioritize lands for conservation or restoration.

Government alcohol sales data were used to examine whether age 15+ per-capita alcohol consumption (PCAC) (i) changed during COVID-19 and (ii) predicted COVID-19 infections 2-5 weeks later.Interrupted time-series analyses were applied to panels of data before and after COVID-19 restrictions were introduced in Canada.The populations, aged 15+, of the provinces of Ontario (ON), British Columbia (BC) and Nova Scotia (NS), Canada.Expansion of home delivery options and hours of trading for liquor stores while restrictions on travel, social and economic activities were imposed by governments during COVID-19 from 17 March 2020 until 29 March 2021.Weekly estimates of (i) age 15+ PCAC using sales data supplied by provincial government alcohol distributors for liquor stores, bars and restaurants, (ii) stringency of public health measures assessed by the Public Health Agency of Canada (PHAC) and (iii) new COVID-19 infections reported by PHAC.PCAC increased by 7.10% (P = 0.013) during the pandemic versus previous years, with increased private liquor store sales partly offset by reduced bar/restaurant sales. Consumption was positively associated with stringency of public health measures. Weekly PCAC was positively associated with new COVID-19 infections 2 weeks later (+6.34% for a one drink/week increase, P 0.001). Lagged associations with COVID-19 infections 2 or 3 weeks later were observed for PCAC from all sales channels, with larger effect sizes per standard drink/person/week increase for on-premise outlets (+77.27% week 2, P = 0.009) than government liquor stores (+6.49%, week 2, P 0.001) or private liquor stores (+7.13%, week 4, P 0.001).Alcohol consumption increased in three Canadian provinces during COVID-19 to degrees corresponding to the extent of the strictness of measures imposed to prevent viral spread. Increased consumption of alcohol was associated with increased COVID-19 infection rates 2 weeks later.

Freshwater whitefishes, Salmonidae Coregoninae, are cold stenothermic fishes of ecological and socio-economic importance in northern hemisphere lakes that are warming in response to climate change. To address the effect of warming waters on coregonine reproduction we experimentally evaluated different embryo incubation temperatures on post-hatching survival, growth, and critical thermal maximum of larval cisco (Coregonus artedi) sampled from lakes Superior and Ontario. Embryos were incubated at water temperatures of 2.0, 4.4, 6.9, and 8.9°C to simulate present and increased winter temperatures, and hatched larvae were reared in a common environment. For both populations, larval survival and critical thermal maximum were negatively related to incubation temperature, and larval growth was positively related to incubation temperature. The magnitude of change across incubation temperatures was greater in the population sampled from Lake Superior than Lake Ontario for all traits examined. The more rapid decrease in survival and critical thermal maximum across incubation temperatures for larval cisco in Lake Superior, compared to those from Lake Ontario, suggests that Lake Superior larvae may possess a more limited ability to acclimate to and cope with increasing winter water temperatures. However, the rapid increase in growth rates across incubation temperatures in Lake Superior larvae suggests they could recover better from hatching at a small length induced by warm winters, as compared to Lake Ontario larvae. Our results suggest propagation and restoration programs may want to consider integrating natural habitat preferences and maximizing phenotypic variability to ensure offspring are set up for success upon stocking.

Glutamine synthase 2 (GLS2) is a key regulator of glutaminolysis and has been previously implicated in activities consistent with tumor suppression. Here we generated Gls2 knockout (KO) mice that develop late-occurring B-cell lymphomas and hepatocellular carcinomas (HCC). Further, Gls2 KO mice subjected to the hepatocarcinogenic Stelic Animal Model (STAM) protocol produce larger HCC tumors than seen in wild-type (WT) mice. GLS2 has been shown to promote ferroptosis, a form of cell death characterized by iron-dependent accumulation of lipid peroxides. In line with this, GLS2 deficiency, either in cells derived from Gls2 KO mice or in human cancer cells depleted of GLS2, conferred significant resistance to ferroptosis. Mechanistically, GLS2, but not GLS1, increased lipid reactive oxygen species (ROS) production by facilitating the conversion of glutamate to α-ketoglutarate (αKG), thereby promoting ferroptosis. Ectopic expression of WT GLS2 in a human hepatic adenocarcinoma xenograft model significantly reduced tumor size; this effect was nullified by either expressing a catalytically inactive form of GLS2 or by blocking ferroptosis. Furthermore, analysis of cancer patient datasets supported a role for GLS2-mediated regulation of ferroptosis in human tumor suppression. These data suggest that GLS2 is a bona fide tumor suppressor and that its ability to favor ferroptosis by regulating glutaminolysis contributes to its tumor suppressive function. Significance: This study demonstrates that the key regulator of glutaminolysis, GLS2, can limit HCC in vivo by promoting ferroptosis through αKG-dependent lipid ROS, which in turn might lay the foundation for a novel therapeutic approach.

The Omicron variant (B.1.1.529) of SARS-CoV-2, the virus that causes COVID-19, was first identified in the United States in November 2021, with the BA.1 sublineage (including BA.1.1) causing the largest surge in COVID-19 cases to date. Omicron sublineages BA.2 and BA.2.12.1 emerged later and by late April 2022, accounted for most cases.* Estimates of COVID-19 vaccine effectiveness (VE) can be reduced by newly emerging variants or sublineages that evade vaccine-induced immunity (1), protection from previous SARS-CoV-2 infection in unvaccinated persons (2), or increasing time since vaccination (3). Real-world data comparing VE during the periods when the BA.1 and BA.2/BA.2.12.1 predominated (BA.1 period and BA.2/BA.2.12.1 period, respectively) are limited. The VISION network

Hospitals rely on voluntary event reporting (VER) for adverse event (AE) identification, although it captures fewer events than a trigger tool, such as Global Assessment of Pediatric Patient Safety (GAPPS). Medical providers exhibit bias based on patient weight status, race, and English proficiency. We compared the AE rate identified by VER with that identified using the GAPPS between hospitalized children by weight category, race, and English proficiency.We identified a cohort of patients 2 years to younger than 18 years consecutively discharged from an academic children's hospital between June and October 2018. We collected data on patient weight status from age, sex, height, and weight, race/ethnicity by self-report, and limited English proficiency by record of interpreter use. We reviewed each chart with the GAPPS to identify AEs and reviewed VER entries for each encounter. We calculated an AE rate per 1000 patient-days using each method and compared these using analysis of variance.We reviewed 834 encounters in 680 subjects; 262 (38.5%) had overweight or obesity, 144 (21.2%) identified as Black, and 112 (16.5%) identified as Hispanic; 82 (9.8%) of encounters involved an interpreter. We identified 288 total AEs, 270 (93.8%) by the GAPPS and 18 (6.3%) by VER. A disparity in AE reporting was found for children with limited English proficiency, with fewer AEs by VER ( P = 0.03) compared with no difference in AEs by GAPPS. No disparities were found by weight category or race.Voluntary event reporting may systematically underreport AEs in hospitalized children with limited English proficiency.

Autistic students experience strengths and challenges that can impact their full inclusion in higher education, including stigma. A participatory team of autistic and non-autistic scholars developed an autism and universal design (UD) training. This participatory approach centered the voices of autistic collaborators in training design and evaluation. Ninety-eight educators from 53 institutions across five countries completed assessments before training (pre-tests), 89 completed post-tests (after training), and 82 completed maintenance assessments (a month after post-test). Pre-test autism stigma was heightened among males, educators with less autism knowledge, and those who reported heightened social dominance orientation. Autism knowledge, autism stigma, and attitudes toward UD improved with training. Improvements remained apparent a month after post-test but were somewhat attenuated for knowledge and stigma. To the best of our knowledge, this is the first evidence of maintenance of benefits of an autism training over time. Participants’ main reason for enrolling in the study was to gain a better understanding about neurodiversity. Feedback indicates that this goal was reached by most with the added benefit of gaining understanding about UD. Results suggest that interest in one type of diversity (e.g. autism) can motivate faculty to learn UD-aligned teaching strategies that benefit diverse students more generally. Lay abstract Autistic university students have many strengths. They also go through difficulties that professors may not understand. Professors may not understand what college life is like for autistic students. They might judge autistic students. A team of autistic and non-autistic researchers made a training to help professors understand autistic students better. This training also gave professors ideas to help them teach all of their students. Ninety-eight professors did an online survey before the autism training. They shared how they felt about autism and teaching. Before our training, professors who knew more about autism appreciated autism more. Professors who thought people should be equal and women also appreciated autism more. Then, 89 of the professors did our training and another survey after the training. This helped us see what they learned from the training. They did one more survey a month later. This helped us see what they remembered. Our training helped professors understand and value autism. It also helped them understand how they can teach all students better. The professors remembered a lot of what we taught them. This study shows that a training that autistic people helped make can help professors understand their autistic students better.

This paper discusses how to implement ‘Skills-Based Grading’ (SBG) in linguistics, with a university-level course in formal semantics as a case study. Particular focus is given to transitioning to SBG from traditional grading. Regardless, of the grading system, all courses start out from a set of desired learning objectives, with final grades intended to reflect the extent to which these objectives have been achieved. Traditionally, grades are determined by a series of mandatory assessments and tests, for which somewhere between partial and full credit is awarded. In this paper, we illustrate how mastery of learning outcomes can be more directly measured by re-packaging them as “skills”. In SBG, students are given multiple opportunities to demonstrate full mastery of each skill. However, grading is all-or-nothing, with no partial credit awarded. SBG has been shown to improve student learning, encourage effective study, lower student stress, and achieve more equitable outcomes, and has been successfully adapted for linguistics courses in phonology (Zuraw et al. 2019) and semantics (O’Leary & Stockwell 2021). Here, we offer step-by-step instructions for creating an SBG course, covering skill types, skill groupings, opportunities, grading, and assessments.

The epidemiology, clinical features, and socioeconomic burden associated with detection of rhinoviruses (RV)/enteroviruses (EV) from individuals in the community with acute respiratory infections (ARIs) are not fully understood.To assess the clinical and socioeconomic burden associated with RV/EV, a secondary analysis of data collected during a prospective, community-based ARI surveillance study was performed. From December 2012 to September 2017, adult and pediatric participants with ARIs had nasopharyngeal specimens obtained and tested by multiplex polymerase chain reaction assay. Characteristics and socioeconomic burden including missed school or work and/or antibiotic use among participants who did and did not seek medical care and among participants with and without co-detection of another respiratory pathogen with RV/EV were compared.Throughout the study period, RV/EV was detected in 54.7% (885/1617) of ARIs with a respiratory pathogen detected. Most ARI episodes associated with RV/EV occurred in females (59.1%) and children ≤17 years old (64.2%). Those ≤17 years were more likely to seek medical care. Compared to those not seeking medical care (n = 686), those seeking medical care (n = 199) had a longer duration of illness (5 vs. 7 days) and were more likely to miss work/school (16.4% vs. 47.7%) and/or use antibiotics (3.6% vs. 34.2%). Co-detection occurred in 8% of ARIs of which 81% occurred in children. Co-detection was not associated with longer illness, more missed work/or school, or antibiotic use.Non-medically attended and medically attended ARIs associated with RV/EV resulted in clinical and socioeconomic burden, regardless of co-detection of other respiratory pathogens.

CDC recommends that all persons aged ≥18 years receive a single COVID-19 vaccine booster dose ≥2 months after receipt of an Ad.26.COV2.S (Janssen [JohnsonJohnson]) adenovirus vector-based primary series vaccine; a heterologous COVID-19 mRNA vaccine is preferred over a homologous (matching) Janssen vaccine for booster vaccination. This recommendation was made in light of the risks for rare but serious adverse events following receipt of a Janssen vaccine, including thrombosis with thrombocytopenia syndrome and Guillain-Barré syndrome

The symptom of cognitive fatigue is reported as one of the longest lasting and most debilitating symptoms of traumatic brain injury (TBI). Virtual reality may be one of the most suitable technologies for neurorehabilitation, able to integrate evidence-based neuroscientific principles into motivating rehabilitation simulations. The purpose of this study was to seek perspectives of individuals with lived experience of TBI and experienced rehabilitation clinicians in the co-design of a novel technology-based tool for cognitive fatigue after TBI.Co-design focus groups with a sample of clinicians and individuals with lived experience of TBI were used to identify the design parameters. A prototype was developed using inter-disciplinary design iterations. Focus groups were repeated with participants testing the prototype. Qualitative data were analysed using a general inductive approach.Feasibility of VR in this population was well tolerated. The focus groups guided development of domains including environment, tasks, level progression, outcome measures and considerations about clinical implementation of VR.By merging advancements in VR science with a translational approach, a co-designed virtual reality tool to increase awareness and self-management of cognitive fatigue has been developed, suitable for use in persons with TBI.Implications for rehabilitationImmersive virtual reality tools show promise for addressing awareness of cognitive fatigue after traumatic brain injury in rehabilitation settings.Early engagement with consumers is recommended to produce a usable rehabilitation product.

Emerging evidence suggests that zooplankton production is affected by physiological and nutritional constraints due to climate change and eutrophication, which in turn could have broad implications for food-web dynamics and fisheries production. In this study, we developed a resource-based zooplankton production dynamics model that causally links freshwater cladoceran and copepod daily production-to-biomass (P/B) ratios with water temperature, phytoplankton biomass and community composition, and zooplankton feeding selectivity. This model was used to evaluate constraints on zooplankton growth under four hypothetical scenarios: involving natural plankton community seasonal succession; lake fertilization to enhance fisheries production; eutrophication; and climatic warming. Our novel modeling approach predicts zooplankton production is strongly dependent on seasonal variation in resource availability and quality, which results in more complex zooplankton dynamics than predicted by simpler temperature-dependent models. For mesotrophic and hypereutrophic lakes, our study suggests that the ultimate control over zooplankton P/B ratios shifts from physiological control during colder periods to strong resource control during warmer periods. Our resource-based model provides important insights into the nature of biophysical control of zooplankton under a changing climate that has crucial implications for food web energy transfer and fisheries production.

BackgroundThe natural history of SARS-CoV-2 infection and transmission dynamics may have changed as SARS-CoV-2 has evolved and population immunity has shifted.MethodsHousehold contacts, enrolled from two multi-site case-ascertained household transmission studies (April 2020–April 2021 and September 2021–September 2022), were followed for 10–14 days after enrollment with daily collection of nasal swabs and/or saliva for SARS-CoV-2 testing and symptom diaries. SARS-CoV-2 virus lineage was determined by whole genome sequencing, with multiple imputation where sequences could not be recovered. Adjusted infection risks were estimated using modified Poisson regression.Findings858 primary cases with 1473 household contacts were examined. Among unvaccinated household contacts, the infection risk adjusted for presence of prior infection and age was 58% (95% confidence interval [CI]: 49–68%) in households currently exposed to pre-Delta lineages and 90% (95% CI: 74–100%) among those exposed to Omicron BA.5 (detected May – September 2022). The fraction of infected household contacts reporting any symptom was similarly high between pre-Delta (86%, 95% CI: 81–91%) and Omicron lineages (77%, 70–85%). Among Omicron BA.5-infected contacts, 48% (41–56%) reported fever, 63% (56–71%) cough, 22% (17–28%) shortness of breath, and 20% (15–27%) loss of/change in taste/smell.InterpretationThe risk of infection among household contacts exposed to SARS-CoV-2 is high and increasing with more recent SARS-CoV-2 lineages. This high infection risk highlights the importance of vaccination to prevent severe disease.FundingFunded by the Centers for Disease Control and Prevention and the Food and Drug Administration.Key points-Monitoring the transmissibility and symptomatology of SARS-CoV-2 lineages is important for informing public health practice and understanding the epidemiology of COVID-19; household transmission studies contribute to our understanding of the natural history of SARS-CoV-2 infections and the transmissibility of SARS-CoV-2 variants.-The Omicron BA.5 sub-lineage is highly transmissible, similar to previous Omicron sub-lineages.-Over 80% of infected household contacts reported at least 1 symptom during their infection and the proportion of household contacts with asymptomatic infection did not differ by SARS-CoV-2 variant. The most common symptom was cough. Change in taste or smell was more common in Omicron BA.5 infections, compared to previous Omicron sub-lineages, but less common compared to pre-Delta lineages.-The high infection risk among household contacts supports the recommendations that individuals maintain up-to-date and lineage-specific vaccinations to mitigate further risks of severe disease.

Background Early coronavirus disease 2019 (COVID-19) vaccine trials excluded pregnant women, resulting in limited data about immunogenicity and maternal–fetal antibody transfer, particularly by gestational timing of vaccination. Methods In this multicenter observational immunogenicity study, pregnant and nonpregnant women receiving COVID-19 vaccines were prospectively enrolled. Participants had sera collected before vaccination, at 14–28 days after each vaccine dose, at delivery (umbilical cord and peripheral), and from their infants at 3 and 6 months. Geometric mean titers (GMTs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ID50 neutralizing antibody (nAb) against D614G-like viruses were compared by participant characteristics. Results Overall, 23 nonpregnant and 85 pregnant participants (trimester of first vaccine dose: 10 first, 47 second, 28 third) were enrolled. Ninety-three percent (76/82 with blood samples) of pregnant participants had detectable SARS-CoV-2 nAb after 2 vaccine doses, but GMTs (95% confidence intervals) were lower in pregnant participants than nonpregnant participants (1722 [1136–2612] vs 4419 [2012–9703]; P = .04). By 3 and 6 months, 28% and 74% of infants, respectively, of vaccinated participants had no detectable nAb to D614G-like viruses. Among the 71 pregnant participants without detectable nAb before vaccination, cord blood GMTs at delivery were 5-fold higher among participants vaccinated during the third versus first trimester, and cord blood nAb titers appeared inversely correlated with weeks since first vaccine dose (R2 = 0.06, P = .06). Conclusions Though most pregnant women develop nAb after 2 doses of mRNA COVID-19 vaccines, this analysis suggests that infant protection from maternal vaccination varies by gestational timing of vaccination and wanes. Additional prevention strategies such as caregiver vaccination may warrant consideration to optimize infant protection.

OBJECTIVES We assessed BNT162b2 vaccine effectiveness (VE) against mild to moderate and severe coronavirus disease 2019 (COVID-19) in children and adolescents through the Omicron BA.4/BA.5 period. METHODS Using VISION Network records from April 2021 to September 2022, we conducted a test-negative, case-control study assessing VE against COVID-19-associated emergency department/urgent care (ED/UC) encounters and hospitalizations using logistic regression, conditioned on month and site, adjusted for covariates. RESULTS We compared 9800 ED/UC cases with 70 232 controls, and 305 hospitalized cases with 2612 controls. During Delta, 2-dose VE against ED/UC encounters at 12 to 15 years was initially 93% (95% confidence interval 89 to 95), waning to 77% (69% to 84%) after ≥150 days. At ages 16 to 17, VE was initially 93% (86% to 97%), waning to 72% (63% to 79%) after ≥150 days. During Omicron, VE at ages 12 to 15 was initially 64% (44% to 77%), waning to 13% (3% to 23%) after ≥150 days; at ages 16 to 17 VE was 31% (10% to 47%) during days 60 to 149, waning to 7% (−8 to 20%) after 150 days. A monovalent booster increased VE to 54% (40% to 65%) at ages 12 to 15 and 46% (30% to 58%) at ages 16 to 17. At ages 5 to 11, 2-dose VE was 49% (33% to 61%) initially and 41% (29% to 51%) after 150 days. During Delta, VE against hospitalizations at ages 12 to 17 was high (>97%), and at ages 16 to 17 remained 98% (73% to 100%) beyond 150 days; during Omicron, hospitalizations were too infrequent to precisely estimate VE. CONCLUSIONS BNT162b2 protected children and adolescents against mild to moderate and severe COVID-19. VE was lower during Omicron predominance including BA.4/BA.5, waned after dose 2 but increased after a monovalent booster. Children and adolescents should receive all recommended COVID-19 vaccinations.

SummaryDevelopment of functional neurons is a complex orchestration of several signaling pathways controlling cell proliferation, differentiation, and homeostasis1. However, details about the involved factors are not fully understood. The balance of antioxidants and vitamins is important for neuronal survival, synaptic plasticity, and early neuronal development; thus, we hypothesized that ferroptosis—a lipid peroxidation dependent cell death modality that is inhibited by antioxidanats2,3—needs to be suppressed to gain neurons. Our study shows that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids. Intriguingly, impaired neuronal development in conditions lacking antioxidants can be fully restored when ferroptosis is specifically inhibited by ferrostatin-1, or neuronal differentiation occurs in the presence of sufficient amounts of vitamin A. Mechanistically, vitamin A activates the heterodimeric nuclear receptor complex Retinoic Acid Receptor (RAR)/Retinoid X Receptor (RXR)4, which upregulates expression of the ferroptosis regulators GPX4, FSP1, GCH1, and ACSL3, amongst others. Therefore, our study reveals that above a certain threshold, vitamin A increases expression of essential cellular gatekeepers of lipid peroxidation. This study uncovers a critical process during early neuronal development, where suppression of ferroptosis by radical-trapping antioxidants or vitamin A is required to obtain maturing neurons and proper laminar organization in cortical organoids.

Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5′-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse.Significance:Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL.This article is highlighted in the In This Issue feature, p. 2483

Heart rate is an extremely important physiological parameter to measure in critically unwell infants, as it is the main physiological marker that changes in response to a change in infant condition. Heart rate is routinely measured peripherally on a limb with a pulse oximeter. However, when infants are critically unwell, the blood supply to these peripheries is reduced in preference for central perfusion of vital organs such as the brain and heart. Measurement of heart rate with a reflection mode photoplethysmogram (PPG) sensor on the forehead could help minimise this problem and make it easier for other important medical equipment, such as cannulas, to be placed on the limbs. This study compares heart rates measured with a forehead-based PPG sensor against a wrist-based PPG sensor in 19 critically unwell infants in neonatal intensive care collecting 198 h of data. The two heart rates were compared using positive percentage agreement, Spearman’s correlation coefficient and Bland-Altman analysis. The forehead PPG sensor showed good agreement with the wrist-based PPG sensor with limits of agreement of 8.44 bpm, bias of −0.22 bpm; positive percentage agreement of 98.87%; and Spearman’s correlation coefficient of 0.9816. The analysis demonstrates that the forehead is a reliable alternative location for measuring vital signs using the PPG.

Supplementary Figure from Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia

Supplementary Table from Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia

Perspective on this Article from Chromoendoscopy Detects More Adenomas than Colonoscopy Using Intensive Inspection without Dye Spraying

PDF file - 102K