Normative data for executive function tests in an Ecuadorian Waranka minority population.

Objective: To generate normative data (ND) for executive functions tests in the Waranka minority population of Ecuador. Method: Four-hundred participants aged 6-17 completed the Symbol-Digit Modalities Test (SDMT), Trail-Making Test (TMT), Modified-Wisconsin Card Sorting Test (M-WCST), and Test of Colors-Words (STROOP). Scores were normed using multiple linear regressions, including age, age2, natural logarithm of mean parent education (MPE), sex, bilingualism, and two-way interactions as predictors. Results: Age by MPE and Age2 by MPE interactions arose for SDMT, so that children with illiterate parents scored lower than those with literate parents. Girls scored higher in SDMT. All TMT and M-WCST scores were influenced by age2. Age by MPE interaction was found for TMT-A, so that children with higher MPE went faster; and age by bilingualism interaction for TMT-B, so that more bilingual children needed less time. Stroop-Word and Color were influenced by age2 by MPE interaction, so that children, while older, scored higher, especially those with higher MPE. Also, age2 by sex interaction arose, so that girls increased scores curvilinearly while boys linearly. Word-Color was influenced by age, while Stroop-interference by age2. Age by MPE interaction was found for MCST-Categories and Perseveration, so that perseverations decreased to then increased, especially in those with illiterate parents. M-WCST-Category scores increased to then decrease later on age in children with illiterate parents. Z-scores calculated through indigenous ND were significantly lower than generated through non-indigenous norms. Conclusions: ND for minority populations are critical since Waranka sample performed worse when using non-indigenous norms for z-score calculation.

Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Phylogenomics recovers multiple origins of portable case making in caddisflies (Insecta: Trichoptera), nature's underwater architects.

Caddisflies (Trichoptera) are among the most diverse groups of freshwater animals with more than 16 000 described species. They play a fundamental role in freshwater ecology and environmental engineering in streams, rivers and lakes. Because of this, they are frequently used as indicator organisms in biomonitoring programmes. Despite their importance, key questions concerning the evolutionary history of caddisflies, such as the timing and origin of larval case making, remain unanswered owing to the lack of a well-resolved phylogeny. Here, we estimated a phylogenetic tree using a combination of transcriptomes and targeted enrichment data for 207 species, representing 48 of 52 extant families and 174 genera. We calibrated and dated the tree with 33 carefully selected fossils. The first caddisflies originated approximately 295 million years ago in the Permian, and major suborders began to diversify in the Triassic. Furthermore, we show that portable case making evolved in three separate lineages, and shifts in diversification occurred in concert with key evolutionary innovations beyond case making.

De-novo long-read genome assembly and annotation of the luna moth (Actias luna) fully resolves repeat-rich silk genes.

We present the first long-read de-novo -assembly and annotation of the luna moth (Actias luna) and provide the full characterization of heavy chain fibroin (h-fibroin)--, a long and highly repetitive gene (>20 Kbp) essential in silk fiber production. There are more than 160,000 described species of moths and butterflies (Lepidoptera), but only within the last five years have we begun to recover high-quality annotated whole genomes across the order which capture h-fibroin. Using PacBio HiFi reads, we produce the first high-quality long-read reference genome for this species. The assembled genome has a length of 532 Mbp, a contig N50 of 16.8 Mbp, an L50 of 14 contigs, and 99.4% completeness (BUSCO). Our annotation using Bombyx mori protein and A.luna RNAseq evidence captured a total of 20,866 genes at 98.9% completeness with 10,267 functionally annotated proteins and a full-length h-fibroin annotation of 2,679 amino acid residues.

Prevalence of Self-Reported COVID-19 Infection in Persons with Complicated Mild to Severe Traumatic Brain Injury (TBI): A TBI Model Systems Study.

OBJECTIVE: To describe the incidence of self-reported COVID-19 history in a longitudinal cohort of individuals with complicated mild to severe traumatic brain injury (TBI) and describe demographic, injury and functional differences based on history of COVID-19 infection. DESIGN: Individuals with complicated mild to severe TBI aged 16 or older at time of injury who were enrolled in the TBI Model Systems longitudinal cohort study, completed a baseline or follow-up interview between October 1, 2021-March 31, 2023, and provided information about COVID-19 history and timing of COVID-19 infection was collected. RESULTS: Of the 3,627 individuals included in the analysis, 29.5% reported a history of COVID-19 infection. Those with reported COVID-19 history tended to be younger, not of a racial/ethnic minority background, and greater functional status at follow up based on the Glasgow Outcome Scale-Extended scale compared to those with no reported COVID-19 history (p < 0.05). Among those with COVID-19 history, 61.8% did not receive medical care, 27.6% received medical care but no hospitalization, and 10.5% were hospitalized. Of those hospitalized, 21.4% required ventilator use. CONCLUSION: Incidence of COVID-19 diagnosis and related hospitalization characteristics in persons with complicated mild to severe TBI was similar to national incidence between March 2020-2023. Secondary effects of the COVID-19 pandemic on persons with TBI require investigation.

The search for blood biomarkers that indicate risk of adverse neurodevelopmental outcomes in fetal growth restriction.

Fetal growth restriction (FGR) impacts 5%-10% of pregnancies and is associated with increased risk of mortality and morbidity. Although adverse neurodevelopmental outcomes are observed in up to 50% of FGR infants, a diagnosis of FGR does not indicate the level of risk for an individual infant and these infants are not routinely followed up to assess neurodevelopmental outcomes. Identifying FGR infants at increased risk of adverse neurodevelopmental outcomes would greatly assist in providing appropriate support and interventions earlier, resulting in improved outcomes. However, current methods to detect brain injury around the time of birth lack the sensitivity required to detect the more subtle alterations associated with FGR. Blood biomarkers have this potential. This systematic review assessed the current literature on blood biomarkers for identifying FGR infants at increased risk of adverse neurodevelopmental outcomes at >12 months after birth. Four databases were searched from inception to 22 February 2024. Articles were assessed for meeting the inclusion criteria by two reviewers. The quality of the included article was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. A summary of findings is presented as insufficient articles were identified for meta-analysis. Excluding duplicates, 1,368 records were screened with only 9 articles considered for full text review. Only one article met all the inclusion criteria. Quality assessment indicated low risk of bias. Both blood biomarkers investigated in this study, neuron specific enolase and S100B, demonstrated inverse relationships with neurodevelopmental assessments at 2 years. Four studies did not meet all the inclusion criteria yet identified promising findings for metabolites and cytokines which are discussed here. These findings support the need for further research and highlight the potential for blood biomarkers to predict adverse outcomes. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=369242, Identifier CRD42022369242.

National Cancer Institute-funded grants focused on synchronous telehealth cancer care delivery: a portfolio analysis.

BACKGROUND: Telehealth use increased during the COVID-19 pandemic and remains a complementary source of cancer care delivery. Understanding research funding trends in cancer-related telehealth can highlight developments in this area of science and identify future opportunities. METHODS: Applications funded by the US National Cancer Institute (NCI) between fiscal years 2016 and 2022 and focused on synchronous patient-provider telehealth were analyzed for grant characteristics (eg, funding mechanism), cancer focus (eg, cancer type), and study features (eg, type of telehealth service). Of 106 grants identified initially, 60 were retained for coding after applying exclusion criteria. RESULTS: Almost three-quarters (73%) of telehealth grants were funded during fiscal years 2020-2022. Approximately 67% were funded through R01 or R37 mechanism and implemented as randomized controlled trials (63%). Overall, telehealth grants commonly focused on treatment (30%) and survivorship (43%); breast cancer (12%), hematologic malignancies (10%), and multiple cancer sites (27%); and health disparity populations (ie, minorities, rural residents) (73%). Both audio and video telehealth were common (65%), as well as accompanying mHealth apps (20%). Telehealth services centered on psychosocial care, self-management, and supportive care (88%); interventions were commonly delivered by mental health professionals (30%). CONCLUSION: NCI has observed an increase in funded synchronous patient-provider telehealth grants. Trends indicate an evolution of awards that have expanded across the cancer control continuum, applied rigorous study designs, incorporated additional digital technologies, and focused on populations recognized for disparate cancer outcomes. As telehealth is integrated into routine cancer care delivery, additional research evidence will be needed to inform clinical practice.

Selection for high and low antibody responses to sheep red blood cells influences cytokine and chemokine expression in chicken peripheral blood leukocytes and splenic tissue.

White Leghorn chickens from a common founder population have been divergently selected for high (HAS) or low (LAS) antibody responses to sheep red blood cells (SRBC) for 49 generations resulting in 2 diverse lines for this trait. Much has been studied in these two lines; however, the impact of these selection pressures on cytokine and chemokine expression is not fully understood. The purpose of this study is to determine if selection for antibody response to SRBC impacts cytokine and chemokine expression in peripheral blood leukocytes (PBL) and spleen from HAS and LAS chickens. Total RNA was isolated from PBL and spleen after which mRNA expression of cytokines (IL4, IL6, IL10, TGF-ß4) and chemokines (CXCL8, CCL4) were determined by quantitative real-time RT-PCR (qRT-PCR). The data were analyzed using Student's t test comparing HAS and LAS (P < 0.05) and are reported as corrected 40-CT. PBL and spleen samples were analyzed separately. With respect to PBL, expression of IL6 was higher (P < 0.05) in PBL isolated from LAS chickens compared to those from the HAS line whereas there were no differences (P > 0.05) in IL4, IL10, CXCL8, CCL4, or TGF-ß4. The cytokine and chemokine mRNA expression profiles were different in the spleen between the two lines. IL4 and CXCL8 expression were higher (P < 0.05) in spleen samples from HAS chickens than LAS. The expression of IL6, IL10, CCL4, or TGF-ß4 in the spleens did not differ (P > 0.05) between the lines. The data indicate that selection for specific antibody responses to SRBC impacts the cytokine and chemokine expression profile in PBL and spleens but in different ways in HAS and LAS. These studies provide insight into the influence that selection pressures for antibody responses have on different immune response components, specifically cytokines and chemokines typically involved in the innate response.

Recent discoveries on the historical foundations of cancer risk assessment: Shedding light on the limits of LNT.

Within the past three years there has been a spate of historical discoveries by our research team on various different facets of the historical foundations of cancer risk assessment. This series of discoveries was stimulated by the creation of a 22-episode documentary of the historical foundations of cancer risk assessment by the US Health Physics Society and the need to provide documentation. This process yielded nearly two dozen distinct historical findings which have been published in numerous papers in the peer-reviewed literature. These discoveries are itemized and summarized in the present paper, along with the significance of each discovery within the historical context of ionizing radiation research and cancer risk assessment.

Key role of plankton species and nutrients on biomagnification of PAHs in the micro-food chain: A case study in plateau reservoirs of Guizhou, China.

There is considerable inconsistency in results pertaining to the biomagnification of PAHs in aquatic systems. Zooplankton specifically play an important role controlling the fate and distribution of organic contaminants up the food chain, particularly in large plateau reservoirs. However, it remains largely unknown how secondary factors affect the magnification of organic compounds in zooplankton. The present study assessed plankton species and nutrients affecting the trophic transfer of PAHs through the micro-food chain in plateau reservoirs, Guizhou Province China. Results show soluble ∑PAHs range from 99.9 - 147.3 ng L-1, and concentrations of ∑PAHs in zooplankton range from 1003.2 - 22441.3, with a mean of 4460.7 ng g-1 dw. Trophic magnification factors (TMFs) > 1 show biomagnifications of PAHs from phytoplankton to zooplankton. The main mechanisms for trophic magnification > 1 are 1) small Copepoda, Cladocera and Rotifera are prey for larger N. schmackeri and P. tunguidus, and 2) the δ15N and TLs of zooplankton are increasing with the increasing nutrients TN, NO3- and CODMn. As a result, log PAHs concentrations in zooplankton are positively correlated with the trophic levels (TLs) of zooplankton, and log BAFs of the PAHs in zooplankton are increasing with increasing TLs and log Kow. Temperature further enhances TMFs and biomagnifications of PAHs as noted by temperature related reductions in δ15N. There are also available soluble PAHs in the water column which are assimilated with increasing phytoplankton biomass within the taxa groups, diatoms, dinoflagellates and chlorophytes. Notable TMFs of PAHs in zooplankton in Guizhou plateau reservoirs are not significantly affected by phytoplankton and zooplankton biomass dilutions. The present study demonstrates the important roles of species selection, nutrients and temperature in the environmental fate of PAHs in freshwaters.

Diet-induced changes in the jejunal microbiota of developing broilers reduce the abundance of Enterococcus hirae and Enterococcus faecium.

Modern broiler breeds allow for high feed efficiency and rapid growth, which come at a cost of increased susceptibility to pathogens and disease. Broiler growth rate, feed efficiency, and health are affected by the composition of the gut microbiota, which in turn is influenced by diet. In this study, we therefore assessed how diet composition can affect the broiler jejunal gut microbiota. A total of 96 broiler chickens were divided into four diet groups: control, coated butyrate supplementation, medium-chain fatty acid supplementation, or a high-fibre low-protein content. Diet groups were sub-divided into age groups (4, 12 and 33 days of age) resulting in groups of 8 broilers per diet per age. The jejunum content was used for metagenomic shotgun sequencing to determine the microbiota taxonomic composition at species level. The composed diets resulted in a total of 104 differentially abundant bacterial species. Most notably were the butyrate-induced changes in the jejunal microbiota of broilers 4 days post-hatch, resulting in the reduced relative abundance of mainly Enterococcus faecium (-1.8 l2fc, Padj = 9.9E-05) and the opportunistic pathogen Enterococcus hirae (-2.9 l2fc, Padj = 2.7E-08), when compared to the control diet. This effect takes place during early broiler development, which is critical for broiler health, thus exemplifying the importance of how diet can influence the microbiota composition in relation to broiler health. Future studies should therefore elucidate how diet can be used to promote a beneficial microbiota in the early stages of broiler development.

iPSC-derived hindbrain organoids to evaluate escitalopram oxalate treatment responses targeting neuropsychiatric symptoms in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia, and the gradual deterioration of brain function eventually leads to death. Almost all AD patients suffer from neuropsychiatric symptoms (NPS), the emergence of which correlates with dysfunctional serotonergic systems. Our aim is to generate hindbrain organoids containing serotonergic neurons using human induced Pluripotent Stem Cells (iPSCs). Work presented here is laying the groundwork for the application of hindbrain organoids to evaluate individual differences in disease progression, NPS development, and pharmacological treatment response. Human peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 3), an AD patient without NPS (n = 1), and AD patients with NPS (n = 2) were reprogrammed into iPSCs and subsequently differentiated into hindbrain organoids. The presence of serotonergic neurons was confirmed by quantitative reverse transcription PCR, flow cytometry, immunocytochemistry, and detection of released serotonin (5-HT). We successfully reprogrammed PBMCs into 6 iPSC lines, and subsequently generated hindbrain organoids from 6 individuals to study inter-patient variability using a precision medicine approach. To assess patient-specific treatment effects, organoids were treated with different concentrations of escitalopram oxalate, commonly prescribed for NPS. Changes in 5-HT levels before and after treatment with escitalopram were dose-dependent and variable across patients. Organoids from different people responded differently to the application of escitalopram in vitro. We propose that this 3D platform might be effectively used for drug screening purposes to predict patients with NPS most likely to respond to treatment in vivo and to understand the heterogeneity of treatment responses.

A predominately pulmonary activation of complement in a mouse model of severe COVID-19.

Evidence from in vitro studies and observational human disease data suggest the complement system plays a significant role in SARS-CoV-2 pathogenesis, although how complement dysregulation develops in patients with severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501YMA30) and a mouse model of severe COVID-19, we identify significant serologic and pulmonary complement activation following infection. We observed C3 activation in airway and alveolar epithelia, and in pulmonary vascular endothelia. Our evidence suggests that while the alternative pathway is the primary route of complement activation, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia in response to cytokine exposure. This locally generated complement response appears to precede and subsequently drive lung injury and inflammation. Results from this mouse model recapitulate findings in humans, which suggest sex-specific variance in complement activation, with predilection for increased C3 activity in males, a finding that may correlate with more severe disease. Our findings indicate that complement activation is a defining feature of severe COVID-19 in mice and lay the foundation for further investigation into the role of complement in COVID-19.

Newly discovered letter: why Muller failed to cite the negative mouse mutation findings of Snell, preserving his chances to receive the Nobel Prize.

A recently acquired letter between Hermann Muller and his wife (March 21, 1933) reveals that Muller had learned that he had been nominated for the Nobel Prize in 1932 with about 1/3 of the total votes being supportive. Muller was hopeful that over time sufficient votes would lead to receiving the award. The knowledge of Muller on this matter and its timing provide a likely explanation why Muller never cited the negative mouse mutation findings of George Snell, performed under Muller's direction during that time period. This action of Muller, along with the failure of Snell to promote his discovery, greatly reduced the chances that those findings would complicate his attempt to garner support for his LNT single-hit model and its application to hereditary and cancer risk assessment. It also helped Muller achieve the Nobel Prize, allowing him the necessary international visibility to promote his ideologically driven ionizing radiation-related LNT-based paradigm.

First report of X-ray induced somatic mutation by Muller's department chair fails to support Muller's linearity hypothesis.

This paper reevaluates the first report of X-ray-induced somatic gene mutations. It was undertaken by John Patterson, Department Chair of Hermann Muller, using the same biological model, methods and equipment of Muller. Patterson reported X-ray induced mutation frequencies for X-chromosome-linked (sex-linked) recessive gene mutations in somatic cells of Drosophila melanogaster that resulted in color changes in the ommatidia of the eyes. Results were based on color changes detected in both male and female offspring irradiated while in egg, larval or pupal stages and for unirradiated controls. Patterson claimed that the observed dose response displayed linearity, with a clear implication that the linear response extended to background exposure levels of unirradiated controls. This reanalysis disputes Patterson's interpretation, showing that the dose response in the low-dose zone strongly supported a threshold model. The doses in the experiment, which were not clearly presented, were so high that it would preclude the assumption that the experiment provided any information of relevance to radiation exposures of humans at low doses, or even at high doses delivered at low-dose rates. Induced phenotypical changes that occurred at the higher doses, especially in female offspring, overwhelmingly resulted from X-ray-induced chromosome breaks instead of point mutations as initially expected by Patterson. The Patterson findings and linearity interpretations were an important contributory factor in the acceptance of the linear non-threshold (LNT) model during the formative time of concept consolidation. It is rather shocking now to see that the actual data provided no support for the LNT model.

"The dream is that there's one place you go": a qualitative study of women's experiences seeking care from Long COVID clinics in the USA.

BACKGROUND: Seeking and obtaining effective health care for Long COVID remains a challenge in the USA. Women have particularly been impacted, as they are both at higher risk of developing Long COVID and of facing gendered barriers to having symptoms acknowledged. Long COVID clinics, which provide multidisciplinary and coordinated care, have emerged as a potential solution. To date, however, there has been little examination of U.S. patient experiences with Long COVID clinics and how patients may or may not have come to access care at a Long COVID clinic. METHODS: We conducted semi-structured interviews with 30 U.S. women aged 18 or older who had experienced Long COVID symptoms for at least 3 months, who had not been hospitalized for acute COVID-19, and who had seen at least one medical provider about their symptoms. Participants were asked about experiences seeking medical care for Long COVID. Long COVID clinic-related responses were analyzed using qualitative framework analysis to identify key themes in experiences with Long COVID clinics. RESULTS: Of the 30 women, 43.3% (n = 13) had been seen at a Long COVID clinic or by a provider affiliated with a Long COVID clinic and 30.0% (n = 9) had explored or attempted to see a Long COVID clinic but had not been seen at time of interview. Participants expressed five key themes concerning their experiences with seeking care from Long COVID clinics: (1) Access to clinics remains an issue, (2) Clinics are not a one stop shop, (3) Not all clinic providers have sufficient Long COVID knowledge, (4) Clinics can offer validation and care, and (5) Treatment options are critical and urgent. CONCLUSIONS: While the potential for Long COVID clinics is significant, findings indicate that ongoing barriers to care and challenges related to quality and coordination of care hamper that potential and contribute to distress among women seeking Long COVID care. Since Long COVID clinics are uniquely positioned and framed as being the place to go to manage complex symptoms, it is critical to patient wellbeing that they be properly resourced to provide a level of care that complies with emerging best practices.

BET activity plays an essential role in control of stem cell attributes in Xenopus.

Neural crest cells are a stem cell population unique to vertebrate embryos that retains broad multi-germ layer developmental potential through neurulation. Much remains to be learned about the genetic and epigenetic mechanisms that control the potency of neural crest cells. Here, we examine the role that epigenetic readers of the BET (bromodomain and extra terminal) family play in controlling the potential of pluripotent blastula and neural crest cells. We find that inhibiting BET activity leads to loss of pluripotency at blastula stages and a loss of neural crest at neurula stages. We compare the effects of HDAC (an eraser of acetylation marks) and BET (a reader of acetylation) inhibition and find that they lead to similar cellular outcomes through distinct effects on the transcriptome. Interestingly, loss of BET activity in cells undergoing lineage restriction is coupled to increased expression of genes linked to pluripotency and prolongs the competence of initially pluripotent cells to transit to a neural progenitor state. Together these findings advance our understanding of the epigenetic control of pluripotency and the formation of the vertebrate neural crest.