Lateralization of ERPs to speech and handedness in the early development of Autism Spectrum Disorder

Background: Language is a highly lateralized function, with typically developing individuals showing left hemispheric specialization. Individuals with autism spectrum disorder (ASD) often show reduced or reversed hemispheric lateralization in response to language. However, it is unclear when this difference emerges and whether or not it can serve as an early ASD biomarker. Additionally, atypical language lateralization is not specific to ASD as it is also seen more frequently in individuals with mixed- and left-handedness. Here, we examined early asymmetry patterns measured through neural responses to speech sounds at 12 months and behavioral observations of handedness at 36 months in children with and without ASD. Methods: Three different groups of children participated in the study: low-risk controls (LRC), high risk for ASD (HRA; infants with older sibling with ASD) without ASD, and HRA infants who later receive a diagnosis of ASD (ASD). Event-related potentials (ERPs) to speech sounds were recorded at 12 months. Utilizing a novel observational approach, handedness was measured by hand preference on a variety of behaviors at 36 months. Results: At 12 months, lateralization patterns of ERPs to speech stimuli differed across the groups with the ASD group showing reversed lateralization compared to the LRC group. At 36 months, factor analysis of behavioral observations of hand preferences indicated a one-factor model with medium to high factor loadings. A composite handedness score was derived; no group differences were observed. There was no association between lateralization to speech at 12 months and handedness at 36 months in the LRC and HRA groups. However, children with ASD did show an association such that infants with lateralization patterns more similar to the LRC group at 12 months were stronger right-handers at 36 months. Conclusions: These results highlight early developmental patterns that might be specific to ASD, including a potential early biomarker of reversed lateralization to speech stimuli at 12 months, and a relation between behavioral and neural asymmetries. Future investigations of early asymmetry patterns, especially atypical hemispheric specialization, may be informative in the early identification of ASD

Identification of Lineage-Uncommitted, Long-Lived, Label-Retaining Cells in Healthy Human Esophagus and Stomach, and in Metaplastic Esophagus

Background & Aims The existence of slowly cycling, adult stem cells has been challenged by the identification of actively cycling cells. We investigated the existence of uncommitted, slowly cycling cells by tracking 5-iodo-2'-deoxyuridine (IdU) label-retaining cells (LRCs) in normal esophagus, Barrett's esophagus (BE), esophageal dysplasia, adenocarcinoma, and healthy stomach tissues from patients. Methods Four patients (3 undergoing esophagectomy, 1 undergoing esophageal endoscopic mucosal resection for dysplasia and an esophagectomy for esophageal adenocarcinoma) received intravenous infusion of IdU (200 mg/m2 body surface area; maximum dose, 400 mg) over a 30-minute period; the IdU had a circulation half-life of 8 hours. Tissues were collected at 7, 11, 29, and 67 days after infusion, from regions of healthy esophagus, BE, dysplasia, adenocarcinoma, and healthy stomach; they were analyzed by in situ hybridization, flow cytometry, and immunohistochemical analyses. Results No LRCs were found in dysplasias or adenocarcinomas, but there were significant numbers of LRCs in the base of glands from BE tissue, in the papillae of the basal layer of the esophageal squamous epithelium, and in the neck/isthmus region of healthy stomach. These cells cycled slowly because IdU was retained for at least 67 days and co-labeling with Ki-67 was infrequent. In glands from BE tissues, most cells did not express defensin-5, Muc-2, or chromogranin A, indicating that they were not lineage committed. Some cells labeled for endocrine markers and IdU at 67 days; these cells represented a small population (<0.1%) of epithelial cells at this time point. The epithelial turnover time of the healthy esophageal mucosa was approximately 11 days (twice that of the intestine). Conclusions LRCs of human esophagus and stomach have many features of stem cells (long lived, slow cycling, uncommitted, and multipotent), and can be found in a recognized stem cell niche. Further analyses of these cells, in healthy and metaplastic epithelia, is required

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Obesity in adults: a 2022 adapted clinical practice guideline for Ireland

This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients' lived experiences; move beyond simplistic approaches of "eat less, move more" and address the root drivers of obesity. People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Collider constraints on interactions of dark energy with the Standard Model.

We study models in which a light scalar dark energy particle couples to the gauge fields of the electroweak force, the photon, Z and W bosons. Our analysis applies to a large class of interacting dark energy models, including those in which the dark energy mass can be adjusted to evade fifth-force bounds by the so-called chameleon mechanism. We conclude that--with the usual choice of Higgs sector--electroweak precision observables are screened from the indirect effects of dark energy, making such corrections effectively unobservable at present-day colliders, and limiting the dark energy discovery potential of any future International Linear Collider. We show that a similar screening effect applies to processes mediated by flavour-changing neutral currents, which can be traced to the Glashow-Iliopoulos-Maiani mechanism. However, Higgs boson production at the Large Hadron Collider via weak boson fusion may receive observable corrections.Comment: 39 pages, 8 figures, uses ioplatex.sty and feynmp. v2: Matches version accepted by JHEP; extended discussion of straight corrections, summarized in the text and described in detail in a new Appendix A. Conclusions unchange

Higgs production as a probe of dark energy interactions.

We study Higgs production under the influence of a light, scalar dark energy field with chameleon-like couplings to matter. Our analysis is relevant for hadron colliders, such as the Large Hadron Collider, which are expected to manufacture Higgs particles through weak boson fusion, or associated production with a Z or W. We show that the corrections arising in these models are too small to be observed. This result can be attributed to the gauge invariance of the low energy Lagrangian. As a by-product of our analysis, we provide the first microphysical realization of a dark energy model coupled to the electromagnetic field strength. In models where dark energy couples to all matter species in a uniform manner we are able to give a new, stringent bound on its coupling strength

Identification and characterization of RET fusions in advanced colorectal cancer.

There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC