Earlier Investigations Research Articles

Two-year Outcomes of Ultra-low-dose Radiotherapy in the Treatment of Ocular Adnexal B-cell Lymphomas.

This study focuses on the efficacy and 2-year outcomes of ultra-low-dose radiotherapy (RT) in treating primary and secondary ocular adnexal lymphoma (OAL). A retrospective analysis was conducted on patients with OAL between 2017 and 2022, treated with 4 Gy of RT. The primary and secondary outcomes assessed were response rate, progression-free survival, and lymphoma-related death. Twenty-one patients with primary and secondary OAL of diverse, presentations, subtypes, and stages were included. The orbital tumors had an average size of 17 × 16 × 16 mm. Of the 14 primary OAL cases, 3 (14%) had T1N0M0 disease, 8 (38%) T2N0M0, and 3 (14%) T3N0M0 (AJCC 8th edition staging); of the 7 secondary OALs, 4 (19%) were stage IE, 2 (10%) stage IIE, and 1 (5%) stage IIIE (Ann Arbor staging). Ultra-low-dose RT yielded a 95% complete response rate and 100% progression-free survival rates, both locally and systemically at 2 years. Mild dry eyes were reported in 14% of patients as a late treatment toxicity. Ultra-low-dose RT emerges as an effective and well-tolerated treatment approach for OAL. Our findings support the use of 4 Gy, showcasing high complete response rates (95%) and durable disease control without significant local relapses over an average follow up of 27 months. Our results align with earlier investigations, validating the curative potential of ultra-low-dose RT and reinforcing the concept of achieving favorable outcomes with minimal intervention. This approach may potentially alleviate the burden of long-term ocular side effects associated with higher radiation doses, enhancing the overall quality of life for OAL patients.

Nitrate and silicate fluxes at the sediment–water interface of the deep North Pacific Ocean illuminated by 226Ra/230Th disequilibria

By taking advantage of recent analytical advances, we herein develop the 226Ra/230Th isotope systematics as a novel tool for quantifying nitrate and dissolved silicate fluxes across the sediment–water interface of the deep-ocean floor. Sediment cores were retrieved from the seabed between 4927 m and 5951 m in the North Pacific Ocean. Downcore profiles of 230Th and both dissolved and total 226Ra were measured using a high-sensitivity inductively coupled plasma mass spectrometer. At all study sites, a marked deficit of total 226Ra with respect to 230Th was observed between 0 and 20 cm, indicating active migration of soluble 226Ra from the sediment into the overlying seawater. By constructing the mass balance of 226Ra in the sediment column, the flux of dissolved 226Ra across the sediment–water interface was estimated to range from 461 to 1320 dpm m−2 yr−1. When coupled to a diffusive transport model as developed by early investigators, these flux values of 226Ra enabled us to calculate the flux of any dissolved constituent of interest by measuring their bottom water concentrations and pore water “saturation” concentrations. Based on the 226Ra/230Th disequilibrium approach, the derived fluxes vary between 4.1 and 10.5 mmol m−2 yr−1 for nitrate and between 11 and 49 mmol m−2 yr−1 for dissolved silicate. A compilation of nitrate and silicate fluxes from the seabed in the deep Pacific Ocean shows that these values are consistent with historical flux measurements based on the conventional core incubation method in the same study region. In addition, both nitrate and silicate fluxes exhibit a clear depth-dependent trend. Overall, our results suggest that sedimentary diagenetic alterations at the North Pacific Ocean floor below ∼ 5000 m are efficient so that only < 2 % of the particulate organic carbon and < 12 % of the biogenic opal raining to the seafloor are ultimately preserved in the sediment.

Finite element method numerical modeling of the crack's impact on the free vibration of 2D functionally graded beams on the Pasternak-Winkler elastic foundation

The study's contribution is to examine, while taking into account pinned-pinned boundary conditions, the free vibration response of multi-cracks Euler-Bernoulli perfect FG beams structure on Pasternak-Winkler elastic foundations. The finite element approach is used to discretize the equations. The material properties are taken into account using a power-law form, and they differ in the thickness and width directions of the beam structure. The 2D FG beam's reduced cross section is used to calculate the stiffness of the cracked structure. On the other hand, the Pasternak-Winkler type foundation has a longitudinal distribution and makes the system stiffer. For convergence research, the numerical results are compared with the outcomes of earlier investigations in terms of dimensionless fundamental frequencies. Case studies were carried out to examine the effects on the natural frequencies of the beams structure of the power law index, multi-cracks, depths, location, and Pasternak-Winkler-elastic foundation. These studies demonstrate the benefits of the two-dimensional FG beam in the presence of cracks over the unidirectional FG and pure metallic beams.

A nearly complete treatment of the effect of non-adiabaticity on rovibrational energies of H3+ (Part III).

In this article, significant contributions of non-adiabaticity for the rovibrational bound states up to 25 000 cm-1 and total angular momentum J = 0-20 of H3+ are investigated. A coupled-perturbed full configuration interaction (CP-FCI) treatment is applied to calculate all couplings between electronic states caused by the nuclear motion. These derivative couplings were evaluated up to the second order by means of a perturbation treatment and include all nuclear Cartesian first and second derivatives of the electronic wavefunctions. In particular, the coupling of special derivatives with respect to r and R in the Jacobi coordinate representation is more significant than thought. The perturbation approach is especially optimal for the treatment of weak non-adiabaticity in case of rovibrational energies in H3+ and had not been available before for H3+ or other triatomics. Using exclusively Gaussian basis functions for CP-FCI appears to be sufficient, because explicit correlated wavefunctions are already used for all other potential energy contributions. Our work is an extension of earlier non-adiabatic investigations based on first derivative couplings of electronic states that led to the concept of geometry-dependent effective nuclear masses and which needs only a single potential energy surface for the dynamics. The implementation allows us to include all non-adiabatic effects up to the order of O(μ-2), μ being the reduced nuclear mass. Our treatment works for any isotopologue and for the whole potential energy curve or surface. By this treatment, a further reduction in deviations to experimental data for most rovibrational levels to less than 0.1 cm-1 is possible. For the related transition frequencies, 1366 of 1720 known rovibrational transitions in H3+ have deviations less than 0.1 cm-1 without using any empirically adjustable parameters or optimizing the nuclear mass for a specific transition. For many questionable assignments (deviations >0.3 cm-1) of observed transitions in H3+, a new labeling is proposed.

How do cultural values affect economic growth? An empirical evidence from world values survey (1994–2021)

PurposeThis study utilizes cultural values from the World Values Survey (WVS) to investigate the cultural hypothesis regarding economic growth. Following Granato et al.'s (1996) theory, this paper describes a systematic method for developing analytical models that clarify the effect of cultural values on economic growth by using seemingly unrelated regression (SUR).Design/methodology/approachThe results are sustained through regression analysis using ordinary least squares (OLS) and SUR. The sample size covers all WVS countries from the third wave in 1994 to the seventh wave in 2021, due to the limited sample size in the first and second surveys, which is insufficient for estimation.FindingsResults highlight culture as a crucial factor for economic growth. Although the study found a positive effect of autonomy, life satisfaction, and post-materialism on economic growth, trust has been found to have a negative impact.Originality/valueAlthough the literature has theoretically proven the impact of cultural values on economic growth, there is a significant disparity in the empirical studies, owing to a lack of applied studies. This study deepens the cultural analysis compared to earlier empirical investigations. To the best of the authors' knowledge, this is the first attempt to assess the combined effect of the selected four cultural values on economic growth during 1994 and 2021. Furthermore, SUR analysis allows for the estimation of the variables' effects throughout the five waves.

Mapping wrist motion: 3D CT analysis after scapholunate ligament transection.

The injury of the scapholunate (SL) ligament is common in wrist traumas leading to pain and reduced wrist function. The wrist's unique joint design and possible underlying theories as the carpal row theory were subject to earlier investigations studying wrist kinematics. Nevertheless, a comprehensive understanding of how SL ligament injuries affect wrist biomechanics is still lacking. Through a quantitative analysis of carpal bone motion patterns, we evaluated the impact on wrist kinematics occurring after SL ligament injury. We conducted a study using computer tomography imaging to analyse wrist kinematics after SL ligament transection in 21 fresh-frozen anatomical specimens. The collected data were then transformed into 3D models, employing both standardized global and object coordinate systems. The study encompassed the evaluation of rotation and translation for each individual carpal bone, as well as the ulna, and all metacarpal bones in reference to the radius. The study showed a significant increase in rotation towards palmar (p < 0.01), particularly notable for the scaphoid, following transection of the SL ligament during palmar flexion. Ulnar deviation did not significantly affect rotation or translation, and radial deviation also showed no significant changes in rotation or translation. The study highlights the significance of the SL ligament in wrist kinematics, revealing that SL ligament tears lead to changes in wrist motion. While we observed significant rotational changes for the scaphoid, other carpal bones showed less pronounced alterations, emphasizing the complexity of wrist biomechanics.

Prenatal air pollution and children's autism traits score: Examination of joint associations with maternal intake of vitamin D, methyl donors, and polyunsaturated fatty acids using mixture methods.

Maternal nutrient intake may moderate associations between environmental exposures and children's neurodevelopmental outcomes, but few studies have assessed joint effects. We aimed to evaluate whether prenatal nutrient intake influences the association between air pollutants and autism-related trait scores. We included 126 participants from the EARLI (Early Autism Risk Longitudinal Investigation, 2009-2012) cohort, which followed US pregnant mothers who previously had a child with autism. Bayesian kernel machine regression and traditional regression models were used to examine joint associations of prenatal nutrient intake (vitamins D, B12, and B6; folate, choline, and betaine; and total omega 3 and 6 polyunsaturated fatty acids, reported via food frequency questionnaire), air pollutant exposure (particulate matter <2.5 μm [PM2.5], nitrogen dioxide [NO2], and ozone [O3], estimated at the address level), and children's autism-related traits (measured by the Social Responsiveness Scale [SRS] at 36 months). Most participants had nutrient intakes and air pollutant exposures that met US standards. Bayesian kernel machine regression mixture models and traditional regression models provided little evidence of individual or joint associations of nutrients and air pollutants with SRS scores or of an association between the overall mixture and SRS scores. In this cohort with a high familial likelihood of autism, we did not observe evidence of joint associations between air pollution exposures and nutrient intake with autism-related traits. Future work should examine the use of these methods in larger, more diverse samples, as our results may have been influenced by familial liability and/or relatively high nutrient intakes and low air pollutant exposures.

Laboratory Benchmark of n ≥ 4 Dielectronic Recombination Satellites of Fe xvii

We calculated cross sections for the dielectronic recombination (DR) satellite lines of Fe xvii and benchmarked our predictions with experimental cross sections of Fe xvii resonances that were monoenergetically excited in an electron-beam ion trap. We extend the benchmark to all resolved DR and direct electron-impact excitation (DE) channels in the experimental data set, specifically the n ≥ 4 DR resonances of Fe xvii, complementing earlier investigations of n = 3 channels. Our predictions for the DR and DE absolute cross sections for the higher n complexes disagree considerably with experimental results when using the same methods as in previous works. However, we achieve agreement within ∼10% of the experimental results by an approach whereby we doubly convolve the predicted cross sections with both the spread of the electron-beam energy and the photon energy resolution of our experiment. We then calculated rate coefficients from the experimental and theoretical cross sections, finding general agreement within 2σ with the rates found in the OPEN-ADAS atomic database.

Evaluating the role of 7-Tesla magnetic resonance imaging in neurosurgery: Trends in literature since clinical approval.

After approval for clinical use in 2017, early investigations of ultra-high-field abdominal magnetic resonance imaging (MRI) have demonstrated its feasibility as well as diagnostic capabilities in neuroimaging. However, there are no to few systematic reviews covering the entirety of its neurosurgical applications as well as the trends in the literature with regard to the aforementioned application. To assess the impact of 7-Tesla MRI (7T MRI) on neurosurgery, focusing on its applications in diagnosis, treatment planning, and postoperative assessment, and to systematically analyze and identify patterns and trends in the existing literature related to the utilization of 7T MRI in neurosurgical contexts. A systematic search of PubMed was conducted for studies published between January 1, 2017, and December 31, 2023, using MeSH terms related to 7T MRI and neurosurgery. The inclusion criteria were: Studies involving patients of all ages, meta-analyses, systematic reviews, and original research. The exclusion criteria were: Pre-prints, studies with insufficient data (e.g., case reports and letters), non-English publications, and studies involving animal subjects. Data synthesis involved standardized extraction forms, and a narrative synthesis was performed. We identified 219 records from PubMed within our defined period, with no duplicates or exclusions before screening. After screening, 125 articles were excluded for not meeting inclusion criteria, leaving 94 reports. Of these, 2 were irrelevant to neurosurgery and 7 were animal studies, resulting in 85 studies included in our systematic review. Data were categorized by neurosurgical procedures and diseases treated using 7T MRI. We also analyzed publications by country and the number of 7T MRI facilities per country was also presented. Experimental studies were classified into comparison and non-comparison studies based on whether 7T MRI was compared to lower field strengths. 7T MRI holds great potential in improving the characterization and understanding of various neurological and psychiatric conditions that may be neurosurgically treated. These include epilepsy, pituitary adenoma, Parkinson's disease, cerebrovascular diseases, trigeminal neuralgia, traumatic head injury, multiple sclerosis, glioma, and psychiatric disorders. Superiority of 7T MRI over lower field strengths was demonstrated in terms of image quality, lesion detection, and tissue characterization. Findings suggest the need for accelerated global distribution of 7T magnetic resonance systems and increased training for radiologists to ensure safe and effective integration into routine clinical practice.

Association Between Dynapenia, Central Obesity, and Physical Function in Young Adults: A Cross-Sectional Study.

Muscle strength is recognized as a key indicator of overall health and can help identify the risk of cardiometabolic disease. This study explores the relationship between low muscle strength, central obesity, and physical function among young adults. We conducted a cross-sectional study from a convenience sample of 513 adults aged 18-25. Participants' anthropometric measures such as height, weight, and circumferences of both waist and hip were measured, and body mass index (BMI) was calculated. Subjects were tested for hand grip strength (HGS) using hand dynamometry. Relative hand grip strength (RHGS) was derived by dividing maximum HGS by BMI. Physical function was assessed using a six-minute walk test. The International Physical Activity Questionnaire (IPAQ) was administered. Overweight and obesity were present in 313 (61%) of the study population. Central obesity was observed in 194 (37.8%) of the population. RHGS showed a positive association with physical function and physical activity, and a negative association was observed with BMI and waist circumference. Low RHGS was categorized as < 25th percentile by gender. The non-dynapenic non-central obese group had higher physical function (644± 124.2) than others. There was no difference in the dynapenic and central obese groups. The dynapenic central obese group had significantly lesser physical function (424.9±69.1) than all other groups in both genders. Our study supports the importance of early investigation of dynapenia, which can increase the risk of chronic disease and accelerate the development of physical limitations. Understanding how dynapenia and central obesity relate to low physical function is of growing importance in young adults, and it can play an important role in overall health.

Semaglutide Attenuates Anxious and Depressive-Like Behaviors and Reverses the Cognitive Impairment in a Type 2 Diabetes Mellitus Mouse Model Via the Microbiota-Gut-Brain Axis.

Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1β and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.

Sensitivity analysis of a Martian atmospheric column model with data from the Mars Science Laboratory

Abstract. An extensive sensitivity analysis was performed for a horizontally homogeneous and hydrostatic 1-D column model at the Mars Science Laboratory (MSL) location. Model experiments were compared with observations from the Curiosity Rover Environmental Monitoring Station humidity (REMS-H) device and ChemCam. Based on our earlier column model investigations, model surface temperature and pressure, dust optical depth (τ), and column precipitable water content (PWC) were the parameters that we investigated with our sensitivity analysis. Our analysis suggests that the most sensitive parameters for the column model temperature profile are τ and surface temperature. The initial value of PWC does not affect the temperature profile of the model, but it is the most important parameter for the humidity profile. The fixed value of τ also seems to have some effect on the humidity profile of the model. Based on our analysis, variations in surface pressure initialization are negligible for the model's temperature and almost negligible for the model's humidity predictions. The model simulations are generally in good agreement with the observations. Our additional model experiments with a different shape of the model's initial humidity profile yielded better results compared to the well-mixed assumption in the predicted water vapor volume mixing ratios at 1.6 m.

A simple method to prepare and characterize ZnO/V2O5 nanostructure thin films for photoelectrochemical and photocatalytic uses in visible light

In this research, we investigated the enhancement of the photocatalytic efficiency of ZnO nanorods by incorporating vanadium pentoxide (V2O5). Zinc oxide (ZnO) nanorods were initially prepared by the chemical bath deposition (CBD) method. Subsequently, vanadium pentoxide (V2O5) nanoparticles, produced by laser ablation, were deposited onto the ZnO nanorods via drop casting. Scanning electron microscopy (SEM) images verified that ZnO grew in the morphology of nanorods and nanotubes, while V2O5 exhibited the structure of tree leaves and nanoparticles. The XRD technique was used to investigate the crystalline structure of the produced ZnO/ V2O5 nanostructure. The high band gap in ZnO limits the efficiency of photocatalysis under visible light. Building a core–shell structure with materials such as V2O5 can boost their performance in such conditions. The prepared samples appeared photodegradation rate of the MB dye reached 39% after 9 h of exposure to visible light. The photoelectrochemical cell measurement of the prepared ZnO/ V2O5 nanostructures demonstrated a positive response to light and achieved a relatively high photoconversion efficiency of 0.084% at 0.35 V, surpassing the results of earlier investigations. The M-S analysis revealed that the ZnO/ V2O5 nanostructure thin films exhibited n-type conductivity, characterized by a negative flat band potential VFB.

Early, typical, and late talkers: an exploratory study on predictors of language development in the first two years of life.

The consensus in scientific literature is that each child undergoes a unique linguistic development path, albeit with shared developmental stages. Some children excel or lag behind their peers in language skills. Consequently, a key challenge in language acquisition research is pinpointing factors influencing individual differences in language development. We observed children longitudinally from 3 to 24 months of life to explore early predictors of vocabulary size. Based on the productive vocabulary size of children at 24 months, 30 children met our sample selection criteria: 10 late talkers and 10 early talkers, and we compared them with 10 typical talkers. We evaluated interactive behaviors at 3, 6, 9 and 12 months, considering vocal production, gaze at mother's face, and gestural production during mother-child interactions, and we considered mothers' report of children's actions and gestures and receptive-vocabulary size at 15 and 18 months. Results indicated early precursors of language outcome at 24 months identifiable as early as 3 months in vocal productions, 6 months for gaze at mother's face and 12 months for gestural productions. Our research highlights both theoretical and practical implications. Theoretically, identifying the early indicators of belonging to the group of late or early talkers underscores the significant role of this developmental period for future studies. On a practical note, our findings emphasize the crucial need for early investigations to identify predictors of vocabulary development before the typical age at which lexical delay is identified.

HISTOMONAS MELEAGRIDIS INFECTIONS IN TURKEYS IN THE USA: A CENTURY OF PROGRESS, RESURGENCE, AND TRIBUTE TO ITS EARLY INVESTIGATORS, THEOBALD SMITH, ERNST TYZZER, AND EVERETT LUND.

Histomoniasis, caused by the protozoan, Histomonas meleagridis, is an economically important disease of turkeys, and it also affects several other species of domesticated and wild Galliformes, including chickens. Under natural conditions, the parasite is transmitted through eggs of a nematode, Heterakis gallinarum, that shares its hosts with Hi. meleagridis. The protozoan infects tissues of both male and female He. gallinarum and eventually is carried within the worm egg. Histomonas meleagridis more readily infects and develops in chickens, and the proximity of chicken farms is a major risk factor for outbreaks in turkeys. Chemoprophylaxis had controlled Hi. meleagridis in turkeys very successfully, but histomoniasis has recently reemerged in turkeys because anti-histomonal drugs are no longer permitted by the United States Food and Drug Administration because of the concerns for residual toxins in poultry meat. Horizontal transmission of the protozoan in the absence of worm eggs remains a mystery because the flagellate trophozoite excreted in the feces of turkeys is not viable for any length of time. A proposed resistant stage of the protozoan has not yet been conclusively demonstrated. Here we review the discovery of the protozoan and the current status of the disease and its control.

EAF2 Downregulation Recruits Tumor-associated Macrophages in Prostate Cancer through Upregulation of MIF

BackgroundThe role of tumor inflammatory microenvironment in the advancement of cancer, particularly prostate cancer, is widely acknowledged. ELL-associated factor 2 (EAF2), a tumor suppressor that has been identified in the prostate, is often downregulated in prostate cancer. Earlier investigations have shown that mice with EAF2 gene knockout exhibited a substantial infiltration of inflammatory cells into the prostatic stroma.MethodsA cohort comprising 38 patients who had been diagnosed with prostate cancer and subsequently undergone radical prostatectomy (RP) was selected. These patients were pathologically graded according to the Gleason scoring system and divided into two groups. The purpose of this selection was to investigate the potential correlation between EAF2 and CD163 using immunohistochemistry (IHC) staining. Additionally, in vitro experimentation was conducted to verify the relationship between EAF2 expression, macrophage migration and polarization.ResultsOur study demonstrated that in specimens of human prostate cancer, the expression of EAF2 was notably downregulated, and this decrease was inversely associated with the number of CD163-positive macrophages that infiltrated the cancerous tissue. Cell co-culture experiments revealed that the chemotactic effect of tumor cells towards macrophages was intensified and that macrophages differentiated into tumor-associated macrophages (TAMs) when EAF2 was knocked out. Additionally, the application of cytokine protein microarray showed that the expression of chemokine macrophage migration inhibitory factor (MIF) increased after EAF2 knockout.ConclusionsOur findings suggested that EAF2 was involved in the infiltration of CD163-positive macrophages in prostate cancer via MIF.Graphical abstract

Exposure to heavy metals in utero and autism spectrum disorder at age 3: a meta-analysis of two longitudinal cohorts of siblings of children with autism

BackgroundAutism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized.MethodsIn Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts.ResultsIn EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD.A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD.ConclusionExposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

Conformational Alterations of the Cell Surface of Monomeric and Dimeric β2m-Free HLA-I (Proto-HLA) May Enable Novel Immune Functions in Health and Disease.

Human leukocyte antigens (HLAs) are polymorphic glycoproteins expressed on the cell surface of nucleated cells and consist of two classes, HLA class I and HLA class II. In contrast, in mice, these molecules, known as H-2, are expressed on both nucleated cells and erythrocytes. HLA-I molecules (Face-1) are heterodimers consisting of a polypeptide heavy chain (HC) and a light chain, B2-microglobulin (B2m). The heterodimers bind to antigenic peptides and present them to the T-cell receptors of CD8+ cytotoxic T lymphocytes. The HCs can also independently emerge on the cell surface as B2m-free HC monomers without peptides (Face-2). Early investigators suggested that the occurrence of B2m-free HCs on the cell surface resulted from the dissociation of B2m from Face-1. However, others documented the independent emergence of B2m-free HCs (Face-2) from the endoplasmic reticulum (ER) to the cell surface. The clustering of such HC molecules on either the cell surface or on exosomes resulted in the dimerization of B2m-free HCs to form homodimers (if the same allele, designated as Face-3) or heterodimers (if different alleles, designated as Face-4). Face-2 occurs at low levels on the cell surface of several normal cells but is upregulated on immune cells upon activation by proinflammatory cytokines and other agents such as anti-CD3 antibodies, phytohemagglutinin, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain activated. After activation-induced upregulation, Face-2 molecules undergo homo- and heterodimerization (Face-3 and Face-4). Observations made on the structural patterns of HCs and their dimerization in sharks, fishes, and tetrapod species suggest that the formation of B2m-free HC monomers and dimers is a recapitalization of a phylogenetically conserved event, befitting the term Proto-HLA for the B2m-free HCs. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/+ mice. Anti-HC-specific monoclonal antibodies (mAbs) delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The conformational alterations that occur in the B2m-free HCs enable them to interact with several inhibitory and activating receptors of cellular components of the innate (natural killer (NK) cells) and adaptive (T and B cells) immune systems. The NK cells express killer immunoglobulin-like receptors (KIRs), whereas leukocytes (T and B lymphocytes, monocytes/macrophages, and dendritic cells) express leukocyte immunoglobulin-like receptors (LILRs). The KIRs and LILRs include activating and inhibitory members within their respective groups. This review focuses on the interaction of KIRs and LILRs with B2m-free HC monomers and dimers in patients with spondylarthritis. Several investigations reveal that the conformational alterations occurring in the alpha-1 and alpha-2 domains of B2m-free HCs may facilitate immunomodulation by their interaction with KIR and LILR receptors. This opens new avenues to immunotherapy of autoimmune diseases and even human cancers that express B2m-free HCs.

P-805 Sperm and embryo genome editing by CRISPR-Cas9 in a mouse model

Abstract Study question We wonder whether it is possible to edit a specific gene in individual mammalian spermatozoa as well as embryo by using CRISPR-Cas9? Summary answer We were able to successfully edit the coat pigment gene on individual spermatozoa as well as embryos by injecting CRISPR-Cas9 during Piezo-ICSI. What is known already Earlier investigations into embryo genome editing with CRISPR-Cas9 were conducted during the S-phase or zygote stage, encountering obstacles such as mosaicism and loss of heterozygosity. To overcome these challenges, performing genome editing at the gamete level is considered more favorable. While it may be achievable in oocytes, sperm genome editing can be ambitious due to the tightly supercoiled DNA around the protamine cores. In initial attempts, simple permeabilization of the sperm membrane allowed CRISPR-Cas9 penetration into the cell; however, the attempts at genomic editing proved to be unsuccessful. Study design, size, duration In the past several months, oocytes were divided into two groups: half of them were used to perform embryo genome editing, whilst the other half was used to edit exclusively the sperm genome through oocyte-mediated sperm decondensation (OMSD), where a single spermatozoon was injected into an enucleated oocyte and used the ooplasmic machinery for DNA decondensation and editing. In both models, CRISPR-Cas9 was used to knock out Tyr gene to create an albino phenotype. Participants/materials, setting, methods B6D2F1 mice were used to retrieve oocytes and spermatozoa. A cohort of oocytes used for the OSMD approach were enucleated, whilst the others were maintained with an intact nucleus. All oocytes, enucleated or not, were injected with a single spermatozoon with Tyr-sgRNA and Cas9 protein. Embryos were cultured until the 8-cell stage and processed for T7E1 cleavage analysis. Genome editing efficiency was calculated following the manufacturer protocol. Main results and the role of chance Of the 40 oocytes used for the study, 20 intact oocytes were used to perform embryo genome editing in the standard fashion, while 20 were enucleated for OMSD experiments. After undergoing Piezo-ICSI with CRISPR-Cas9 solution, 90.0% (18/20) of intact oocytes fertilized. After 48 hours in culture, diploid embryos reached the 8-cell stage at 88.9% (16/18). The 584-bp region of the target site of extracted DNA was amplified and gene modification of the edited diploid embryo cohort was confirmed in 87.5% (14/16). Compared to the OMSD cohort, enucleated oocytes fertilized at 85.0% (17/20) while cleavage rate was lower at 64.7% (11/17) and sperm genome modification at 81.8% (9/11). Both diploid embryos and haploid androgenetic embryos evidence an editing efficiency of 36.8%. Therefore, we verified that genome editing on embryos and sperm achieved the same editing yield. Limitations, reasons for caution While the experimental observations are still limited, it is important to note that these results in the embryo model may be underestimated by the T7E1 cleavage assay that only recognize heterozygous modification. The technique needs further refinement to optimize targeting and editing efficiency. Wider implications of the findings Sperm genome decondensation through an OMSD approach allows CRISPR-Cas9 to edit the sperm genome in order to correct eventual pathogenic mutations present in the gamete. Moreover, these would be the only method to absolutely ensure uniform generation of resulting embryos. Trial registration number not applicable

1011 A Rare Case of Left Sided Hemiparesis Following a Pneumatic Gun-Shot Injury to Left Anterior Chest Wall in a 13-Year-Old Boy

Abstract Introduction Even though pneumatic weapons rarely cause severe direct trauma, pellet embolisation can lead to unexpected, catastrophic events. Case Report A 13-year-old, previously healthy boy was injured by an accidentally fired pneumatic gun, while playing with his twin brother. He sustained a penetrating wound to left anterior chest wall and resultant bleeding was self-limiting. He was hospitalised within 15minutes. On admission, he was hemodynamically stable with normal Respiratory, Cardiovascular and Neurological system findings. Entry wound measuring 5*5 mm was present at 5th intercostal space just left to the sternum. No exit wound was detected. Initial chest radiograph and ultra-sound abdomen and chest were normal. 2D echocardiogram revealed only a very thin layer(3mm) of pericardial effusion. Four hours later, He developed a focal seizure followed by left sided hemiparesis. Urgent NCCT brain and carotid artery duplex showed a high dense pellet in right internal carotid artery at the level of petrous temporal bone and hypo-dense Middle Cerebral Artery (MCA) suggestive of right MCA thrombosis. He was transferred to a tertiary care centre. Interventional radiological and endo-vascular attempts of pellet retrieval have been failed. Ischemic stroke pursued with worsening cerebral oedema; thus decompression craniotomy was performed on day 3. He is currently being rehabilitated in a specialised centre. Conclusions High degree of suspicion should be maintained on the possibility of projectile embolisation, in pneumatic gun-shot injuries, especially in the absence of an exit wound. Extensive early investigations should be performed to localise the projectile and retrieval should be planned.