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Aerodynamic canopy height (ha) is the effective height of vegetation canopy for its influence on atmospheric fluxes and is a key parameter of surface-atmosphere coupling. However, methods to estimate ha from data are limited. This synthesis evaluates the applicability and robustness of the calculation of ha from eddy covariance momentum-flux data. At 69 forest sites, annual ha robustly predicted site-to-site and year-to-year differences in canopy heights (R2 = 0.88, 111 site-years). At 23 cropland/grassland sites, weekly ha successfully captured the dynamics of vegetation canopies over growing seasons (R2 > 0.70 in 74 site-years). Our results demonstrate the potential of flux-derived ha determination for tracking the seasonal, interannual, and/or decadal dynamics of vegetation canopies including growth, harvest, land use change, and disturbance. The large-scale and time-varying ha derived from flux networks worldwide provides a new benchmark for regional and global Earth system models and satellite remote sensing of canopy structure.

Abstract: There are no agreed upon terminology to define "refractory" pediatric immune thrombocytopenia (ITP). Guidelines are therefore limited to arbitrary and outdated definitions. The Pediatric ITP Consortium of North America held a meeting in 2023 to define this entity. With 100% agreement, the faculty established that pediatric ITP that is refractory to emergent therapy could be defined as no platelet response after treatment with all eligible emergent pharmacotherapies. With 100% agreement, the working group established that pediatric patients with ITP that continue to demonstrate high disease burden and/or no platelet response despite treatment with multiple classes of disease-modifying therapies represent a challenging subset of ITP. These patients are at higher risk of ongoing disease burden and merit additional investigation as well as consideration for clinical trials or novel therapies. Future efforts to define disease burden and disease response will be completed in collaboration with the ITP International Working Group., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable efficacy in cancer treatment. Still, most patients receiving CAR T cells relapse within 5 years of treatment. CAR-mediated trogocytosis (CMT) is a potential tumor escape mechanism in which cell surface proteins transfer from tumor cells to CAR T cells. CMT results in the emergence of antigen-negative tumor cells, which can evade future CAR detection, and antigen-positive CAR T cells, which has been suggested to cause CAR T cell fratricide and exhaustion. Whether CMT indeed causes CAR T cell dysfunction and the molecular mechanisms conferring CMT remain unknown. Using a selective degrader of trogocytosed antigen in CAR T cells, we show that the presence of trogocytosed antigen on the CAR T cell surface directly causes CAR T cell fratricide and exhaustion. By performing a small molecule screening using a custom high throughput CMT-screening assay, we found that the cysteine protease cathepsin B (CTSB) is essential for CMT and that inhibition of CTSB is sufficient to prevent CAR T cell fratricide and exhaustion. Our data demonstrate that it is feasible to separate CMT from cytotoxic activity and that CAR T cell persistence, a key factor associated with clinical CAR T cell efficacy, is directly linked to CTSB activity in CAR T cells.

Background Aims: Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies have revolutionized the treatment of B-cell lymphomas. Unfortunately, relapses after CD19-targeted CAR-T are relatively common and, therefore, there is a critical need for assays able to assess the function and potency of CAR-T products pre-infusion, which will hopefully help to optimize CAR-T therapies. We developed a novel multicolor fluorescent spot assay (MFSA) for the functional assessment of CAR-T products on a single-cell level, combining the numerical assessment of CAR-T products with their functional characterization., Methods: We first used a standard single-cell interferon (IFN)-γ enzyme-linked immune absorbent spot assay to measure CD19-targeted CAR-T responses to CD19-coated beads. We then developed, optimized and validated an MFSA that simultaneously measures the secretion of combinations of different cytokines on a single CAR-T level., Results: We identified IFN-γ/tumor necrosis factor-α/granzyme B as the most relevant cytokine combination, and we used our novel MFSA to functionally and numerically characterize two clinical-grade CAR-T products., Conclusions: In conclusion, we have developed a novel assay for the quantitative and functional potency assessment of CAR-T products. Our optimized MFSA is cost-effective, easy to perform, reliable, can be performed overnight, allowing for a fast delivery of the product to the patient, and requires relatively minimal maintenance and training. The clinical value of our novel assay will be assessed in studies correlating the pre-infusion assessment of CAR-T products with the patients' outcome in a prospective fashion., Competing Interests: Declaration of Competing Interest SD serves on advisory boards for Bristol-Myers Squibb, Incyte and Atara Biotherapeutics. The remaining authors declare that they do not have any competing interests., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

During October 2021-June 2023, a total of 392 cases of acute hepatitis of unknown etiology in children in the United States were reported to Centers for Disease Control and Prevention as part of national surveillance. We describe demographic and clinical characteristics, including potential involvement of adenovirus in development of acute hepatitis, of 8 fatally ill children who met reporting criteria. The children had diverse courses of illness. Two children were immunocompromised when initially brought for care. Four children tested positive for adenovirus in multiple specimen types, including 2 for whom typing was completed. One adenovirus-positive child had no known underlying conditions, supporting a potential relationship between adenovirus and acute hepatitis in previously healthy children. Our findings emphasize the importance of continued investigation to determine the mechanism of liver injury and appropriate treatment. Testing for adenovirus in similar cases could elucidate the role of the virus.

Background: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported., Methods: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity., Results: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4 + central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells., Conclusions: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR) T cells are an effective treatment for some blood cancers. However, the lack of tumor-specific surface antigens limits their wider use. We identified a set of surface antigens that are limited in their expression to cancer and the central nervous system (CNS). We developed CAR T cells against one of these antigens, LINGO1, which is widely expressed in Ewing sarcoma (ES). To prevent CNS targeting, we engineered LINGO1 CAR T cells lacking integrin α 4 (A4 ko ), an adhesion molecule essential for migration across the blood-brain barrier. A4 ko LINGO1 CAR T cells were efficiently excluded from the CNS but retained efficacy against ES. We show that altering adhesion behavior expands the set of surface antigens targetable by CAR T cells., Competing Interests: CONFLICTS OF INTEREST EAM, DA, and TL are inventors on U.S. patent application 63/285843 describing the use of LINGO1 CAR T cells and knockout of integrin α4 for the treatment of ES. The other authors are not declaring any conflicts of interest.

Background: Early life exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment from infancy to adolescence. In our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort, we previously reported that residential proximity to OP use during pregnancy was associated with altered cortical activation using functional near infrared spectroscopy (fNIRS) in a small subset (n = 95) of participants at age 16 years., Methods: We administered fNIRS to 291 CHAMACOS young adults at the 18-year visit. Using covariate-adjusted regression models, we estimated associations of prenatal and childhood urinary dialkylphosphates (DAPs), non-specific OP metabolites, with cortical activation in the frontal, temporal, and parietal regions of the brain during tasks of executive function and semantic language., Results: There were some suggestive associations for prenatal DAPs with altered activation patterns in both the inferior frontal and inferior parietal lobes of the left hemisphere during a task of cognitive flexibility (β per ten-fold increase in DAPs = 3.37; 95% CI: -0.02, 6.77 and β = 3.43; 95% CI: 0.64, 6.22, respectively) and the inferior and superior frontal pole/dorsolateral prefrontal cortex of the right hemisphere during the letter retrieval working memory task (β = -3.10; 95% CI: -6.43, 0.22 and β = -3.67; 95% CI: -7.94, 0.59, respectively). We did not observe alterations in cortical activation with prenatal DAPs during a semantic language task or with childhood DAPs during any task., Discussion: We observed associations of prenatal OP concentrations with mild alterations in cortical activation during tasks of executive function. Associations with childhood exposure were null. This is reasonably consistent with studies of prenatal OPs and neuropsychological measures of attention and executive function found in CHAMACOS and other birth cohorts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Asa Bradman reports a relationship with The Organic Center that includes: board membership., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA 1,2 . Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA 3-7 , although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Iron deficiency anemia (IDA) is a common problem in toddlers. The cause of IDA is multifactorial but is often from excessive consumption of cow's milk. The prevalence and at times devastating consequences of IDA are under recognized. There are increasing numbers of toddlers presenting with severe IDA. We urge all paediatric primary care givers to help prevent severe IDA through adherence to the 2019 CPS Guidelines on iron requirements, early diagnosis, and adequate treatment., Competing Interests: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Critically ill patients routinely receive antibiotics with activity against anaerobic gut bacteria. However, in other disease states and animal models, gut anaerobes are protective against pneumonia, organ failure and mortality. We therefore designed a translational series of analyses and experiments to determine the effects of anti-anaerobic antibiotics on the risk of adverse clinical outcomes among critically ill patients., Methods: We conducted a retrospective single-centre cohort study of 3032 critically ill patients, comparing patients who did and did not receive early anti-anaerobic antibiotics. We compared intensive care unit outcomes (ventilator-associated pneumonia (VAP)-free survival, infection-free survival and overall survival) in all patients and changes in gut microbiota in a subcohort of 116 patients. In murine models, we studied the effects of anaerobe depletion in infectious ( Klebsiella pneumoniae and Staphylococcus aureus pneumonia) and noninfectious (hyperoxia) injury models., Results: Early administration of anti-anaerobic antibiotics was associated with decreased VAP-free survival (hazard ratio (HR) 1.24, 95% CI 1.06-1.45), infection-free survival (HR 1.22, 95% CI 1.09-1.38) and overall survival (HR 1.14, 95% CI 1.02-1.28). Patients who received anti-anaerobic antibiotics had decreased initial gut bacterial density (p=0.00038), increased microbiome expansion during hospitalisation (p=0.011) and domination by Enterobacteriaceae spp. (p=0.045). Enterobacteriaceae were also enriched among respiratory pathogens in anti-anaerobic-treated patients (p<2.2×10 -16 ). In murine models, treatment with anti-anaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia (p<0.05) and increased the lethality of hyperoxia (p=0.0002)., Conclusions: In critically ill patients, early treatment with anti-anaerobic antibiotics is associated with increased mortality. Mechanisms may include enrichment of the gut with respiratory pathogens, but increased mortality is incompletely explained by infections alone. Given consistent clinical and experimental evidence of harm, the widespread use of anti-anaerobic antibiotics should be reconsidered., Competing Interests: Conflict of interest: All authors have nothing to disclose., (The content of this work is not subject to copyright. Design and branding are copyright ©ERS 2023.)

Children are capable of initiating COVID-19 transmission into households, but many questions remain about the impact of vaccination on transmission. Data from a COVID-19 Delta variant outbreak at an overnight camp in Texas during June 23-27, 2021, were analyzed. The camp had 451 attendees, including 364 youths aged  < 18 years and 87 adults. Detailed interviews were conducted with 92 (20.4%) of consenting attendees and 117 household members of interviewed attendees with COVID-19. Among 450 attendees with known case status, the attack rate was 41%, including 42% among youths; attack rates were lower among vaccinated (13%) than among unvaccinated youths (48%). The secondary attack rate was 51% among 115 household contacts of 55 interviewed index patients. Secondary infections occurred in 67% of unvaccinated household members and 33% of fully or partially vaccinated household members. Analyses suggested that household member vaccination and camp attendee masking at home protected against household transmission., (Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society 2022.)

The composition of proanthocyanidins in the testa (seed coat) of bread wheat was analyzed by thiolysis of PA oligomers from developing grain and found to consist of (+)-catechin monomers, with a small amount of (+)-gallocatechin. The average chain length of soluble PA stayed relatively constant between 10 and 20 days post-anthesis, whereas that of unextractable PA increased over the same period, suggesting that increases in chain length might account for the insolubility of PAs from mature wheat grain. We carried out RNA-Seq followed by differential expression analysis from dissected tissues of developing grain from red- and white-grained near-isogenic lines differing in the presence of an active R gene that encodes a MYB transcription factor involved in control of PA biosynthesis. In addition to genes already identified encoding chalcone synthase, chalcone isomerase, flavanone 3-hydroxylase, and dihydroxyflavonoid 4-reductase, we showed that wheat genes encoding phenylalanine ammonia lyase, flavonoid 3',5'-hydroxylase, leucoanthocyanidin reductase, and a glutathione S -transferase (the orthologue of maize Bronze-2 ) were more highly expressed in the red NIL. We also identified candidate orthologues of other catalytic and regulatory components of flavonoid biosynthesis in wheat., Competing Interests: The authors did not report any conflicts of interest., (© 2022 The Authors. Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Epidemiological studies suggest that exposure to p,p'-dichloro-diphenyl-trichloroethane (p,p'-DDT) is associated with poorer cognitive function in children and adolescents, but the neural mechanisms underlying this association remain unclear., Objective: We investigated associations of prenatal and childhood exposure to p,p'-DDT and its metabolite p,p'-dichloro-diphenyl-dichloroethylene (p,p'-DDE) with cortical activation in adolescents using functional near-infrared spectroscopy (fNIRS)., Methods: We administered fNIRS to 95 adolescents from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) aged 15-17 years. We assessed cortical activity in the frontal, temporal, and parietal brain regions while participants completed tasks of executive function, language comprehension, and social cognition. We measured serum p,p'-DDT and -DDE concentrations at age 9 years and then estimated exposure-outcome associations using linear regression models adjusted for sociodemographic characteristics. In secondary analyses, we back-extrapolated prenatal concentrations using prediction models and examined their association with cortical activation., Results: Median (P25-P75) p,p'-DDT and -DDE concentrations in childhood were 1.4 (1-2.3) and 141.5 (75.0-281.3) ng/g lipid, respectively. We found that childhood exposure to p,p'-DDT and -DDE was associated with altered patterns of brain activation during tasks of cognition and executive functions. For example, we observed increased activity in the left frontal lobe during a language comprehension task (β per 10 ng/g lipid increase of serum p,p'-DDE at age 9 years = 3.4; 95% CI: 0.0, 6.9 in the left inferior frontal lobe; and β = 4.2; 95% CI: 0.9, 7.5 in the left superior frontal lobe). We found no sex differences in the associations of childhood p,p'-DDT and -DDE concentrations with neural activity. Associations between prenatal p,p'-DDT and p,p'-DDE concentrations and brain activity were similar to those observed for child p,p'-DDT and -DDE concentrations., Conclusions: Childhood p,p'-DDT and -DDE exposure may impact cortical brain activation, which could be an underlying mechanism for its previously reported associations with poorer cognitive function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Periodic resurgences of COVID-19 in the coming years can be expected, while public health interventions may be able to reduce their intensity. We used a transmission model to assess how the use of booster doses and non-pharmaceutical interventions (NPIs) amid ongoing pathogen evolution might influence future transmission waves. We find that incidence is likely to increase as NPIs relax, with a second seasonally driven surge expected in autumn 2022. However, booster doses can greatly reduce the intensity of both waves and reduce cumulative deaths by 20% between 7 January 2022 and 7 January 2023. Reintroducing NPIs during the autumn as incidence begins to increase again could also be impactful. Combining boosters and NPIs results in a 30% decrease in cumulative deaths, with potential for greater impacts if variant-adapted boosters are used. Reintroducing these NPIs in autumn 2022 as transmission rates increase provides similar benefits to sustaining NPIs indefinitely (307 000 deaths with indefinite NPIs and boosters compared with 304 000 deaths with transient NPIs and boosters). If novel variants with increased transmissibility or immune escape emerge, deaths will be higher, but vaccination and NPIs are expected to remain effective tools to decrease both cumulative and peak health system burden, providing proportionally similar relative impacts.

On April 21, 2022, CDC issued a health advisory † encouraging U.S. clinicians to report all patients aged <10 years with hepatitis of unknown etiology to public health authorities, after identification of similar cases in both the United States (1) and Europe. § A high proportion of initially reported patients had adenovirus detected in whole blood specimens, thus the health advisory encouraged clinicians to consider requesting adenovirus testing, preferentially on whole blood specimens. For patients meeting the criteria in the health advisory (patients under investigation [PUIs]), jurisdictional public health authorities abstracted medical charts and interviewed patient caregivers. As of June 15, 2022, a total of 296 PUIs with hepatitis onset on or after October 1, 2021, were reported from 42 U.S. jurisdictions. The median age of PUIs was 2 years, 2 months. Most PUIs were hospitalized (89.9%); 18 (6.1%) required a liver transplant, and 11 (3.7%) died. Adenovirus was detected in a respiratory, blood, or stool specimen of 100 (44.6%) of 224 patients. ¶ Current or past infection with SARS-CoV-2 (the virus that causes COVID-19) was reported in 10 of 98 (10.2%) and 32 of 123 (26.0%) patients, respectively. No common exposures (e.g., travel, food, or toxicants) were identified. This nationwide investigation is ongoing. Further clinical data are needed to understand the cause of hepatitis in these patients and to assess the potential association with adenovirus., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Competing Interests: Competing interests: None declared.

In November 2021, CDC was notified of a cluster of previously healthy children with hepatitis of unknown etiology evaluated at a single U.S. hospital (1). On April 21, 2022, following an investigation of this cluster and reports of similar cases in Europe (2,3), a health advisory* was issued requesting U.S. providers to report pediatric cases † of hepatitis of unknown etiology to public health authorities. In the United States and Europe, many of these patients have also received positive adenovirus test results (1,3). Typed specimens have indicated adenovirus type 41, which typically causes gastroenteritis (1,3). Although adenovirus hepatitis has been reported in immunocompromised persons, adenovirus is not a recognized cause of hepatitis in healthy children (4). Because neither acute hepatitis of unknown etiology nor adenovirus type 41 is reportable in the United States, it is unclear whether either has recently increased above historical levels. Data from four sources were analyzed to assess trends in hepatitis-associated emergency department (ED) visits and hospitalizations, liver transplants, and adenovirus stool testing results among children in the United States. Because of potential changes in health care-seeking behavior during 2020-2021, data from October 2021-March 2022 were compared with a pre-COVID-19 pandemic baseline. These data do not suggest an increase in pediatric hepatitis or adenovirus types 40/41 above baseline levels. Pediatric hepatitis is rare, and the relatively low weekly and monthly counts of associated outcomes limit the ability to interpret small changes in incidence. Ongoing assessment of trends, in addition to enhanced epidemiologic investigations, will help contextualize reported cases of acute hepatitis of unknown etiology in U.S. children., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Suzanne E. Dale reports Labcorp contracts with BioMerieux for BioFire equipment and reagents to perform testing, travel funding for a conference presentation from SpeeDx, and stock and stock options from Labcorp as part of employee compensation. No other potential conflicts of interest were disclosed.

Time is of the essence in how neural codes, synchronies, and oscillations might function in encoding, representation, transmission, integration, storage, and retrieval of information in brains. This Hypothesis and Theory article examines observed and possible relations between codes, synchronies, oscillations, and types of neural networks they require. Toward reverse-engineering informational functions in brains, prospective, alternative neural architectures incorporating principles from radio modulation and demodulation, active reverberant circuits, distributed content-addressable memory, signal-signal time-domain correlation and convolution operations, spike-correlation-based holography, and self-organizing, autoencoding anticipatory systems are outlined. Synchronies and oscillations are thought to subserve many possible functions: sensation, perception, action, cognition, motivation, affect, memory, attention, anticipation, and imagination. These include direct involvement in coding attributes of events and objects through phase-locking as well as characteristic patterns of spike latency and oscillatory response. They are thought to be involved in segmentation and binding, working memory, attention, gating and routing of signals, temporal reset mechanisms, inter-regional coordination, time discretization, time-warping transformations, and support for temporal wave-interference based operations. A high level, partial taxonomy of neural codes consists of channel, temporal pattern, and spike latency codes. The functional roles of synchronies and oscillations in candidate neural codes, including oscillatory phase-offset codes, are outlined. Various forms of multiplexing neural signals are considered: time-division, frequency-division, code-division, oscillatory-phase, synchronized channels, oscillatory hierarchies, polychronous ensembles. An expandable, annotative neural spike train framework for encoding low- and high-level attributes of events and objects is proposed. Coding schemes require appropriate neural architectures for their interpretation. Time-delay, oscillatory, wave-interference, synfire chain, polychronous, and neural timing networks are discussed. Some novel concepts for formulating an alternative, more time-centric theory of brain function are discussed. As in radio communication systems, brains can be regarded as networks of dynamic, adaptive transceivers that broadcast and selectively receive multiplexed temporally-patterned pulse signals. These signals enable complex signal interactions that select, reinforce, and bind common subpatterns and create emergent lower dimensional signals that propagate through spreading activation interference networks. If memory traces share the same kind of temporal pattern forms as do active neuronal representations, then distributed, holograph-like content-addressable memories are made possible via temporal pattern resonances., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cariani and Baker.)

In 1995, journalist Gary Taubes published an article in Science titled "Epidemiology faces its limits," which questioned the utility of nonrandomized epidemiologic research and has since been cited more than 1000 times. He highlighted numerous examples of research topics he viewed as having questionable merit. Studies have since accumulated for these associations. We systematically evaluated current evidence of 53 example associations discussed in the article. Approximately one-quarter of those presented as doubtful are now widely viewed as causal based on current evaluations of the public health consensus. They include associations between alcohol consumption and breast cancer, residential radon exposure and lung cancer, and the use of tanning devices and melanoma. This history should inform current debates about the reproducibility of epidemiologic research results.

Background: Vaccines may play a role in controlling the spread of antibiotic resistance. However, it is unknown if rotavirus vaccination affects antibiotic use in the United States (US)., Methods: Using data from the IBM MarketScan Commercial Database, we conducted a retrospective cohort of US children born between 2007 and 2018 who were continuously enrolled for the first 8 months of life (N = 2 136 136). We followed children through 5 years of age and compared children who completed a full rotavirus vaccination series by 8 months of age to children who had not received any doses of rotavirus vaccination. We evaluated antibiotic prescriptions associated with an acute gastroenteritis (AGE) diagnosis and defined the switching of antibiotics as the prescription of a second, different antibiotic within 28 days. Using a stratified Kaplan-Meier approach, we estimated the cumulative incidence for each study group, adjusted for receipt of pneumococcal conjugate vaccine, provider type, and urban/rural status., Results: Overall, 0.8% (n = 17 318) of participants received an antibiotic prescription following an AGE diagnosis. The 5-year adjusted relative cumulative incidence of antibiotic prescription following an AGE diagnosis was 0.793 (95% confidence interval [CI], .761-.827) among children with complete rotavirus vaccination compared to children without rotavirus vaccination. Additionally, children with complete vaccination were less likely to switch antibiotics (0.808 [95% CI, .743-.887]). Rotavirus vaccination has averted an estimated 67 045 (95% CI, 53 729-80 664) antibiotic prescriptions nationally among children born between 2007 and 2018., Conclusions: These results demonstrate that rotavirus vaccines reduce antibiotic prescribing for AGE, which could help reduce the growth of antibiotic resistance., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The microbiome is an important and increasingly-studied mediator of organismal metabolism, although how the microbiome affects metabolism remains incompletely understood. Many investigators use antibiotics to experimentally perturb the microbiome. However, antibiotics have poorly understood yet profound off-target effects on behavior and diet, including food and water aversion, that can confound experiments and limit their applicability. We thus sought to determine the relative influence of microbiome modulation and off-target antibiotic effects on the behavior and metabolic activity of mice., Results: Mice treated with oral antibiotics via drinking water exhibited significant weight loss in fat, liver, and muscle tissue. These mice also exhibited a reduction in water and food consumption, with marked variability across antibiotic regimens. While administration of bitter-tasting but antimicrobially-inert compounds caused a similar reduction in water consumption, this did not cause tissue weight loss or reduced food consumption. Mice administered intraperitoneal antibiotics (bypassing the gastrointestinal tract) exhibited reduced tissue weights and oral intake, comparable to the effects of oral antibiotics. Antibiotic-treated germ-free mice did not have reduced tissue weights, providing further evidence that direct microbiome modulation (rather than behavioral effects) mediates these metabolic changes., Conclusions: While oral antibiotics cause profound effects on food and water consumption, antibiotic effects on organismal metabolism are primarily mediated by microbiome modulation. We demonstrate that tissue-specific weight loss following antibiotic administration is due primarily to microbiome effects rather than food and water aversion, and identify antibiotic regimens that effectively modulate gut microbiota while minimizing off-target behavioral effects., Competing Interests: The authors have declared that no competing interests exist.

Background: As the field of education was adapting to virtual learning during the COVID-19 pandemic, a need quickly emerged for a course to prepare medical students for future clinical practice. This call to action was answered by creating an innovative Fundamentals of COVID-19 course at the Indiana University School of Medicine (IUSM). As a group of medical student leaders at IUSM, we developed this online course in order to support our fellow students and the community., Methods: The study examined the educational effects of completing the Fundamentals of COVID-19 course. In order to examine these effects, the study asked enrolled students to complete both a pre- and post-course self-assessment survey. Students were asked an identical set of questions on each survey about their knowledge, skills, and abilities (KSA) regarding COVID-19. Composite scores were created for each KSA learning domain. Responses were provided using a five-point Likert scale ranging from 1 = strongly disagree to 5 = strongly agree., Results: Out of the 724 students enrolled, 645 students completed both the pre- and post-course assessment surveys. Findings show that there were both meaningful and statistically significant differences in students' responses to the pre- and post-course surveys. Results show 1.) a significant mean increase in the knowledge composite score of 1.01, 95% CI [0.95, 1.06], t(644) = 36.4, p < .001, d = 1.43; 2.) a significant mean increase in the skills composite score of .55, 95% CI [0.50, 0.60], t(644) = 20.70, p < .001, d = 0.81. and 3.) a significant mean increase of the abilities composite score of 1.02, 95% CI [.97, 1.07], t(644) = 36.56, p < .001, d = 1.44., Conclusions: These findings demonstrate that the student-developed, online Fundamentals of COVID-19 course resulted in notable and statistically significant educational effects. The increase in students' self-reported ratings, especially in the knowledge and abilities domains, indicate that meaningful learning occurred within the course. These findings have notable implications for medical student training during healthcare emergencies, such as a pandemic, as well as within modern clerkship environments. Overall, our findings provide evidence that student-led curricular design and virtual delivery of course content can be effective tools in undergraduate medical education., (© 2022. The Author(s).)

The B.1.1.529 (Omicron) variant, first detected in November 2021, was responsible for a surge in U.S. infections with SARS-CoV-2, the virus that causes COVID-19, during December 2021-January 2022 (1). To investigate the effectiveness of prevention strategies in household settings, CDC partnered with four U.S. jurisdictions to describe Omicron household transmission during November 2021-February 2022. Persons with sequence-confirmed Omicron infection and their household contacts were interviewed. Omicron transmission occurred in 124 (67.8%) of 183 households. Among 431 household contacts, 227 were classified as having a case of COVID-19 (attack rate [AR] = 52.7%). † The ARs among household contacts of index patients who had received a COVID-19 booster dose, of fully vaccinated index patients who completed their COVID-19 primary series within the previous 5 months, and of unvaccinated index patients were 42.7% (47 of 110), 43.6% (17 of 39), and 63.9% (69 of 108), respectively. The AR was lower among household contacts of index patients who isolated (41.2%, 99 of 240) compared with those of index patients who did not isolate (67.5%, 112 of 166) (p-value <0.01). Similarly, the AR was lower among household contacts of index patients who ever wore a mask at home during their potentially infectious period (39.5%, 88 of 223) compared with those of index patients who never wore a mask at home (68.9%, 124 of 180) (p-value <0.01). Multicomponent COVID-19 prevention strategies, including up-to-date vaccination, isolation of infected persons, and mask use at home, are critical to reducing Omicron transmission in household settings., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Lynn E. Sosa reports being a past Council of State and Territorial Epidemiologists STD Subcommittee chair. No other potential conflicts of interest were disclosed.

The ability to represent approximate quantities appears to be phylogenetically widespread, but the selective pressures and proximate mechanisms favouring this ability remain unknown. We analysed quantity discrimination data from 672 subjects across 33 bird and mammal species, using a novel Bayesian model that combined phylogenetic regression with a model of number psychophysics and random effect components. This allowed us to combine data from 49 studies and calculate the Weber fraction (a measure of quantity representation precision) for each species. We then examined which cognitive, socioecological and biological factors were related to variance in Weber fraction. We found contributions of phylogeny to quantity discrimination performance across taxa. Of the neural, socioecological and general cognitive factors we tested, cortical neuron density and domain-general cognition were the strongest predictors of Weber fraction, controlling for phylogeny. Our study is a new demonstration of evolutionary constraints on cognition, as well as of a relation between species-specific neuron density and a particular cognitive ability. This article is part of the theme issue 'Systems neuroscience through the lens of evolutionary theory'.

Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD) patients. Iron causes oxidative stress and is a nutrient for pathogenic bacteria. Iron may therefore play an important role in the pathophysiology of COPD. The CD163-haptglobin axis plays a central role in the regulation of iron bioavailability. The aim of this study was to examine dysregulation of the CD163-haptglobin axis in COPD. We measured soluble CD163 (sCD163) and haptoglobin levels in sputum supernatants by enzyme-linked immunosorbent assay (ELISA) and sputum macrophage CD163 and haptoglobin expression by flow cytometry in COPD patients and controls. SCD163 levels were lower in COPD patients compared to controls ( p = 0.02), with a significant correlation to forced expiratory volume in 1 s (FEV1)% predicted (rho = 0.5, p = 0.0007). Sputum macrophage CD163 expression was similar between COPD patients and controls. SCD163 levels and macrophage CD163 expression were lower in COPD current smokers compared to COPD ex-smokers. Haptoglobin levels were not altered in COPD patients but were regulated by genotype. Macrophage CD163 and haptolgobin expression were significantly correlated, supporting the role of CD163 in the cellular uptake of haptoglobin. Our data implicates a dysfunctional CD163-haptoglobin axis in COPD, which may contribute to disease pathophysiology, presumably due to reduced clearance of extracellular iron.

Cerebral Hyperperfusion Syndrome (CHS) is a rare syndrome, commonly described as a prodrome of symptoms including a severe ipsilateral headache, focal neurological deficits, intracerebral hemorrhage, and occasionally includes seizures or encephalopathy. Our case involves a 76-year-old man who underwent a left carotid endarterectomy (CEA) for symptomatic high-grade stenosis of his left carotid artery. Post-operative day one, the patient was seen and examined in the early morning and found to be doing well, with blood pressures well-controlled and at his neurologic baseline. Three hours later, he was reported to have a sudden spike in his blood pressure and was experiencing focal motor seizures involving the right arm and face, both of which were unrelieved by anti-hypertensives and anti-seizure medications. The patient subsequently developed worsening respiratory function requiring intubation for status epilepticus. Repeat head and neck imaging with CT, CT angiography, and MRI demonstrated the known previous subacute infarct with new cerebral edema, patent carotid arteries bilaterally, and no acute infarct or intracerebral hemorrhage. While CHS is a rare syndrome with well-documented symptomatology, we present a unique case in which focal motor status epilepticus was the only presenting symptom in a patient who otherwise meets the criteria of CHS based on radiographic evidence of cerebral edema following an elective CEA., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Edwards et al.)