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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting approximately 45% of male and 16% of female carriers of the FMR1 premutation over the age of 50 years. Currently, no effective treatment is available. We performed an open-label intervention study to assess whether allopregnanolone, a neurosteroid promoting regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. Six patients underwent weekly intravenous infusions of allopregnanolone (2-6 mg over 30 min) for 12 weeks. All patients completed baseline and follow-up studies, though MRI scans were not collected from 1 patient because of MRI contraindications. The MRI scans from previous visits, along with scans from 8 age-matched male controls, were also included to establish patients' baseline condition as a reference. Functional outcomes included quantitative measurements of tremor and ataxia and neuropsychological evaluations. Brain activity consisted of event-related potential N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, and microstructural integrity of the corpus callosum. The results of the study showed that allopregnanolone infusions were well tolerated in all subjects. Before treatment, the patients disclosed impairment in executive function, verbal fluency and learning, and progressive deterioration of all MRI measurements. After treatment, the patients demonstrated improvement in executive functioning, episodic memory and learning, and increased N400 repetition effect amplitude. Although MRI changes were not significant as a group, both improved and deteriorated MRI measurements occurred in individual patients in contrast to uniform deterioration before the treatment. Significant correlations between baseline MRI measurements and changes in neuropsychological test scores indicated the effects of allopregnanolone on improving executive function, learning, and memory for patients with relatively preserved hippocampus and corpus callosum, while reducing psychological symptoms for patients with small hippocampi and amygdalae. The findings show the promise of allopregnanolone in improving cognitive functioning in patients with FXTAS and in partially alleviating some aspects of neurodegeneration. Further studies are needed to verify the efficacy of allopregnanolone for treating FXTAS.

ObjectiveClinical observations and a limited number of research studies provide evidence that the fragile X premutation may confer risk for autism, executive dysfunction, and psychopathology. The link to autism spectrum symptoms and social cognition deficits with the premutation remains uncertain, and thus was the focus of the present investigation.MethodOur sample included 131 individuals, 42 men/22 women with the FMR1 premutation (mean age = 31.83 ± 8.59 years) with a normal neurological exam, and 48 men/19 women healthy age-matched controls (mean age = 29.48 ± 7.29 years). Individuals completed a comprehensive neuropsychological battery with additional assessments for social cognition, broad autism spectrum, and obsessive-compulsive (OC) symptoms.ResultsPremutation carriers self-reported higher rates of autism-related symptoms (Autism Quotient; p = .001). Among males only, premutation carriers showed more atypical social interaction (p

Fragile X premutation carriers (fXPC) are characterized by 55-200 CGG trinucleotide repeats in the 5′ untranslated region on the Xq27.3 site of the X chromosome. Clinically, they are associated with the fragile X-Associated Tremor/Ataxia Syndrome, a late-onset neurodegenerative disorder with diffuse white matter neuropathology. Here, we conducted first-ever graph theoretical network analyses in fXPCs using 30-direction diffusion-weighted magnetic resonance images acquired from 42 healthy controls aged 18-44 years (HC; 22 male and 20 female) and 46 fXPCs (16 male and 30 female). Globally, we found no differences between the fXPCs and HCs within each gender for all global graph theoretical measures. In male fXPCs, global efficiency was significantly negatively associated with the number of CGG repeats. For nodal measures, significant group differences were found between male fXPCs and male HCs in the right fusiform and the right ventral diencephalon (for nodal efficiency), and in the left hippocampus [for nodal clustering coefficient (CC)]. In female fXPCs, CC in the left superior parietal cortex correlated with counting performance in an enumeration task. © 2014 Wiley Periodicals, Inc.

Lay Abstract: What is already known about the topic? Some people support the neurodiversity movement and other people criticize it. They often disagree about what the neurodiversity movement means. Confusion about what the neurodiversity movement is makes it hard for people to agree about how best to support autistic or disabled people. What does this article add? We studied autistic and autism community members' views on the neurodiversity movement and autism interventions. Most participants supported the neurodiversity movement. Support for the neurodiversity movement was related to wanting to change society and make places more comfortable for autistic people. Neurodiversity supporters felt autistic children should choose their own intervention goals and that autistic adults should help children choose goals. Neurodiversity supporters did not think autistic people should be taught to act less autistic. Both those agreeing and disagreeing with the neurodiversity movement said that it is important to help autistic people be well. Many participants said that society causes all the difficulties disabled people experience. Yet they were somewhat open to helping people grow by teaching them useful skills and trying to cure depression and epilepsy. Implications for practice, research or policy . To better help autistic people, we should listen to participants in this study. They called for improving society, building more spaces where autistic people feel comfortable and helping autistic people lead change. They warned against teaching autistic people to hide their autism. Critics of the neurodiversity movement should read this article to better understand what neurodiversity movement supporters believe. By taking time to learn from one another, we can work together to better support autistic people., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Controversy regarding the neurodiversity movement (NDM), the social and medical models of disability, autism intervention goals, and causal attributions of disability contributes to divides in the autistic and autism communities. The present study investigates the views of autistic and non-autistic autistic and autism community members on these topics. We explored whether these views are shaped by having close relationships to autistic people with intellectual disabilities (ID) and nonspeaking autistic (NSA) people., Methods: A total of 504 autistic and autism community members (278 autistic, 226 non-autistic) completed an online survey about theoretical models and intervention goals. Participants reported whether they had one or more close relationships with NSA people, autistic people with ID, neither, or both., Results: Overall, there was considerable consensus regarding desired intervention goals: normalization goals were generally opposed, while participants generally supported well-being, societal reform, supportive environment, and adaptive skill goals. While autistic participants reported less support for normalization and adaptive skills goals than non-autistic participants, they expressed somewhat more enthusiasm for societal reform and supportive environments than non-autistic people. Autistic people supported the NDM more and the medical model less than non-autistic people. Those close to autistic people with ID gave higher ratings to adaptive skill goals. On average, participants not close to autistic people with ID saw the challenges of those without ID as being slightly more due to environmental/social factors than the challenges of those with ID; there was no such statistical difference among those close to autistic people with ID., Conclusion: Further research investigating community views, with the inclusion of more autistic people with ID and NSA people themselves, is needed, but the results of this study suggest that the broader autistic and autism communities see NDM-consistent intervention goals as appropriate for all autistic people, including NSA people and those with ID. As autism interventions have often pursued unpopular normalization goals, this suggests directions for reform., (Copyright 2024, Mary Ann Liebert, Inc., publishers.)

Ethnopharmacological Relevance: In traditional Persian medicine (TPM), people often use herbal infusions as a dosage form to treat diseases related to hyperglycemia, known as 'dam-kardeh'. Traditionally, herbal preparations of Eryngium bungei Boiss. (E. b), Tragopogon buphthalmoides (DC.) Boiss. (T. b), Salvia hydrangea DC. ex Benth. (S. h), and Juniperus polycarpos K. Koch. (J. p) are used to manage diabetes in Iran. However, there is no evidence of their effectiveness in controlling glucose levels and their mechanisms remain unclear., Aim of the Study: This study aimed to investigate whether traditional doses of plant infusions can have hypoglycemic and/or anti-hyperglycemic effects during fasting and/or postprandial states and establish the basis for future research on their potential mechanisms of action., Materials and Methods: The effects of traditional doses of herbal extracts on blood glucose levels in STZ-NA-induced hyperglycemic rats were investigated in 2-h acute tests during fasting and postprandial states (with a glucose load). In addition, the potential inhibitory effect in vitro of enzymes involved in relevant pathways, such as gluconeogenesis (fructose-1,6-bisphosphatase, FBPase and glucose-6-phosphatase, G6Pase), carbohydrate breakdown (intestinal α-glucosidases), and insulin sensitivity (protein tyrosine phosphatase 1B, PTP-1B) was evaluated. Acute toxicity tests were carried out and HPLC-SQ-TOF was used to analyze the chemical profiles of the plant extracts., Results: In the fasting state, T. b, S. h, and E. b were as effective as glibenclamide in lowering blood glucose levels in hyperglycemic rats. Moreover, all three suppressed G6Pase and FBPase enzymatic activity by 90-97% and 80-91%, respectively. On the other hand, significant postprandial hypoglycemic efficacy was observed for E. b, S. h, and T. b. Based on the AUC values, T. b caused a reduction comparable to the therapeutic efficacy of repaglinide. When investigating the possible mechanisms of action involved in this activity, E. b, S. h, and T. b showed significant inhibition of PTP-1B in vitro (>70%). Finally, all plant extracts showed no signs of acute toxicity. Several compounds that may contribute to biological activities were identified, including phenolic acids and flavonoid glycosides., Conclusions: The present study supports the traditional use of T. b, E. b and S. h for the control of diabetes in the fasting and postprandial state. Moreover, these plants were found to be rich in bioactive compounds with hypoglycemic and antihyperglycemic activities. On the other hand, J. p, showed a modest effect only in the fasting state and after 90 min. Further studies are needed to expand these results by analyzing the chemical composition and using complementary experimental models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The autistic-developed monotropism account suggests that atypical, domain-general attentional hyper-focus on interests is a central aspect of autism, but domain-general attention differences in autism can manifest differently. Prior research suggests autistic children are often slow to disengage attention from stimuli-a pattern often called "sticky attention"-and that they can show reduced novelty preference. These attentional patterns could influence sensory experiences and learning. We used eye-tracking to investigate novelty preference and "sticky attention" in young autistic children; we also examined whether attentional patterns were related to cognitive abilities and caregiver-reported sensory responsiveness. A total of 46 autistic and 28 nonautistic participants, aged between 2 and 4 years, provided usable data. We found no evidence that autistic children exhibited greater "sticky attention" than nonautistics, but "sticky attention" in autism was associated with more caregiver-reported sensory hyper-responsiveness, seeking/interests, and enhanced perception. Autistic children also nonsignificantly trended toward exhibiting reduced novelty preference. Unexpectedly, the time-course of this trending novelty preference difference implied it was not driven by reduced orienting to novelty, but increased returning to already-familiarized stimuli: what we call "springy attention." Exploratory analyses of data from the attentional disengagement task suggest autistic participants may have exhibited greater "springy attention," though further research with paradigms optimized for measuring this construct should confirm this. Importantly, "springy attention" was robustly related to reduced cognitive abilities and greater caregiver-reported hypo-responsiveness. Thus, this study illuminates two distinct domain-general attentional patterns, each with distinct correlates in young autistic children, which could have important implications for understanding autistic children's learning, development, and experiences., (© 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO ( ε2-ε3-ε4 ) and KLOTHO variant ( KL-VS ) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele ( p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4 .

FMR1 premutation carriers (55-200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1-10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology., Competing Interests: Declaration of competing interest R.J.H. has received funding from Zynerba,Tetra Pharma and the Azrieli Foundation to carry out treatment studies in fragile X syndrome and has also consulted with Zynerba regarding treatment studies in fragile X syndrome. D.H. has received funding from the following, all of which are directed to the UC Davis, in support of fragile X treatment programs, and he receives no personal funds and has no relevant financial interest in any of the commercial entities listed: Autifony, Ovid, Tetra/Shionogi, Healx, and Zynerba pharmaceutical companies to consult on outcome measures and clinical trial design. F.T. has received funding from Zynerba and the Azrieli Foundation to carry out molecular studies in fragile X syndrome. The remaining 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. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum., Methods: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls., Results: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity., Interpretation: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: The clinical significance of newly available platforms for specific IgE measurement must be evaluated. However, data are lacking for NOVEOS (Hycor), especially for food allergens., Objective: We compared the technical and clinical performance of two platforms (ImmunoCAP and NOVEOS) to measure specific IgE to 10 food allergens., Methods: Sera from 289 clinically characterized patients were tested for IgE specific for six food allergen extracts (egg white, cow's milk, peanut, hazelnut, fish, and shrimp) and four molecular allergens (Gal d 1, Bos d 8, Ara h 2, and Cor a 14). Specific IgE measurements were carried out using ImmunoCAP and NOVEOS methods. Food allergy diagnoses were established according to international guidelines., Results: A strong correlation (ρ > 0.9) was present between the two platforms whereas specific IgE concentrations measured with NOVEOS were consistently lower (mean, -15%) than with ImmunoCAP. NOVEOS and ImmunoCAP provided similar overall odds ratios and relative risks for food allergy diagnosis with both allergen extracts and molecular allergens. When all 10 allergens were considered, NOVEOS provided better receiver operating characteristic curves (P = .04). Finally, we found that the most discordant results were observed with hazelnut and peanut extracts and were related to cross-reactive carbohydrate determinants for these two with ImmunoCAP., Conclusions: Specific IgE determination by either ImmunoCAP or NOVEOS (odds ratios of allergy, 25.1 or 33.0, respectively) is highly informative regarding the risk of allergy in the selected population. The NOVEOS platform presents the advantage of being less affected by unwanted reactivity owing to carbohydrate determinant-specific IgE while requiring a 10-fold lower test sample volume., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cancer immunotherapies have demonstrated remarkable success; however, the majority of patients do not respond or develop resistance. Here, we conduct epigenetic gene-targeted CRISPR-Cas9 screens to identify epigenomic factors that limit CD8 + T cell-mediated anti-tumor immunity. We identify that PRMT1 suppresses interferon gamma (Ifnγ)-induced MHC-I expression, thus dampening CD8 + T cell-mediated killing. Indeed, PRMT1 knockout or pharmacological targeting of type I PRMT with the clinical inhibitor GSK3368715 enhances Ifnγ-induced MHC-I expression through elevated STAT1 expression and activation, while re-introduction of PRMT1 in PRMT1-deficient cells reverses this effect. Importantly, loss of PRMT1 enhances the efficacy of anti-PD-1 immunotherapy, and The Cancer Genome Atlas analysis reveals that PRMT1 expression in human melanoma is inversely correlated with expression of human leukocyte antigen molecules, infiltration of CD8 + T cells, and overall survival. Taken together, we identify PRMT1 as a negative regulator of anti-tumor immunity, unveiling clinical type I PRMT inhibitors as immunotherapeutic agents or as adjuncts to existing immunotherapies., Competing Interests: Declaration of interests S.J.H. is an employee of AbbVie and holds stock in the company. R.W.J. receives research support from Roche, BMS, Astra-Zeneca, Pfizer, and MecRx and is a scientific consultant and shareholder in MecRx., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Adaptive radiations are bursts in biodiversity that generate new evolutionary lineages and phenotypes. However, because they typically occur over millions of years, it is unclear how their macroevolutionary dynamics vary through time and among groups of organisms. Phyllostomid bats radiated extensively for diverse diets-from insects to vertebrates, fruit, nectar, and blood-and we use their molars as a model system to examine the dynamics of adaptive radiations. Three-dimensional shape analyses of lower molars of Noctilionoidea (Phyllostomidae and close relatives) indicate that different diet groups exhibit distinct morphotypes. Comparative analyses further reveal that phyllostomids are a striking example of a hierarchical radiation; phyllostomids' initial, higher-level diversification involved an "early burst" in molar morphological disparity as lineages invaded new diet-affiliated adaptive zones, followed by subsequent lower-level diversifications within adaptive zones involving less dramatic morphological changes. We posit that strong selective pressures related to initial shifts to derived diets may have freed molars from morpho-functional constraints associated with the ancestral molar morphotype. Then, lineages with derived diets (frugivores and nectarivores) diversified within broad adaptive zones, likely reflecting finer-scale niche partitioning. Importantly, the observed early burst pattern is only evident when examining molar traits that are strongly linked to diet, highlighting the value of ecomorphological traits in comparative studies. Our results support the hypothesis that adaptive radiations are commonly hierarchical and involve different tempos and modes at different phylogenetic levels, with early bursts being more common at higher levels., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies has made it difficult to address this hypothesis., Objective: To determine whether executive function deterioration experienced by premutation carriers (PC) in daily life precedes and predicts FXTAS., Methods: This study included 66 FMR1 PC ranging from 40 to 78 years (mean, 59.5) and 31 well-matched healthy controls (HC) ages 40 to 75 (mean, 57.7) at baseline. Eighty-four participants returned for 2 to 5 follow up visits over a duration of 1 to 9 years (mean, 4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit., Results: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, increased self-report executive function problems at baseline significantly predicted later development of FXTAS., Conclusions: Executive function changes experienced by male PC represent a prodrome of the later movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Elevated "neural noise" has been advanced as an explanation of autism and autistic sensory experiences. However, functional neuroimaging measures of neural noise may be vulnerable to contamination by recording noise. This study explored variability of electrophysiological responses to tones of different intensities in 127 autistic and 79 typically-developing children aged 2-5 years old. A rigorous data processing pipeline, including advanced visualizations of different signal sources that were maximally independent across different time lags, was used to identify and eliminate putative recording noise. Inter-trial variability was measured using median absolute deviations (MADs) of EEG amplitudes across trials and inter-trial phase coherence (ITPC). ITPC was elevated in autism in the 50 and 60 dB intensity conditions, suggesting diminished (rather than elevated) neural noise in autism, although reduced ITPC to soft 50 dB sounds was associated with increased loudness discomfort. Autistic and non-autistic participants did not differ in MADs, and indeed, the vast majority of the statistical tests examined in this study yielded no significant effects. These results appear inconsistent with the neural noise account., (© 2022. The Author(s).)

Autistic individuals often exhibit motor atypicalities, which may relate to difficulties in social communication. This study utilized a smart tablet activity to computationally characterize motor control by testing adherence to the two-thirds power law (2/3 PL), which captures a systematic covariation between velocity and curvature in motor execution and governs many forms of human movement. Children aged 4-8 years old participated in this study, including 24 autistic children and 33 typically developing children. Participants drew and traced ellipses on an iPad. We extracted data from finger movements on the screen, and computed adherence to the 2/3 PL and other kinematic metrics. Measures of cognitive and motor functioning were also collected. In comparison to the typically developing group, the autistic group demonstrated greater velocity modulation between curved and straight sections of movement, increased levels of acceleration and jerk, and greater intra- and inter-individual variability across several kinematic variables. Further, significant motor control development was observed in typically developing children, but not in those with autism. This study is the first to examine motor control adherence to the 2/3 PL in autistic children, revealing overall diminished motor control. Less smooth, more varied movement and an indication of developmental stasis in autistic children were observed. This study offers a novel tool for computational characterization of the autism motor signature in children's development, demonstrating how smart tablet technology enables accessible assessment of children's motor performance in an objective, quantifiable and scalable manner., (© 2024. The Author(s).)

Prior studies suggest that habituation of sensory responses is reduced in autism and that diminished habituation could be related to atypical autistic sensory experiences, for example, by causing brain responses to aversive stimuli to remain strong over time instead of being suppressed. While many prior studies exploring habituation in autism have repeatedly presented identical stimuli, other studies suggest group differences can still be observed in habituation to intermittent stimuli. The present study explored habituation of electrophysiological responses to auditory complex tones of varying intensities (50-80 dB SPL), presented passively in an interleaved manner, in a well-characterized sample of 127 autistic (M DQ  = 65.41, SD = 20.54) and 79 typically developing (M DQ  = 106.02, SD = 11.50) children between 2 and 5 years old. Habituation was quantified as changes in the amplitudes of single-trial responses to tones of each intensity over the course of the experiment. Habituation of the auditory N2 response was substantially reduced in autistic participants as compared to typically developing controls, although diagnostic groups did not clearly differ in habituation of the P1 response. Interestingly, the P1 habituated less to loud 80 dB sounds than softer sounds, whereas the N2 habituated less to soft 50 dB sounds than louder sounds. No associations were found between electrophysiological habituation and cognitive ability or participants' caregiver-reported sound tolerance (Sensory Profile Hyperacusis Index). The results present study results extend prior research suggesting habituation of certain sensory responses is reduced in autism; however, they also suggest that habituation differences observed using this study's paradigm might not be a primary driver of autistic participants' real-world sound intolerance., (© 2023 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.)

The premutation of the fragile X messenger ribonucleoprotein 1 ( FMR1 ) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Breast cancer is currently the most commonly diagnosed cancer, with 287,850 new cases estimated for 2022 as reported by the American Cancer Society. Therefore, finding an effective treatment for this disease is imperative. Chalcones are α,β-unsaturated systems found in nature. These compounds have shown a wide array of biological activities, making them popular synthetic targets. Chalcones consist of two aromatic substituents connected by an enone bridge; this arrangement allows for a large number of derivatives. Given the biological relevance of these compounds, novel ferrocene-heterocycle-containing chalcones were synthesized and characterized based on a hybrid drug design approach. These heterocycles included thiophene, pyrimidine, thiazolyl, and indole groups. Fourteen novel heterocyclic ferrocenyl chalcones were synthesized and characterized. Herein, we also report their cytotoxicity against triple-negative breast cancer cell lines MDA-MB-231 and 4T1 and the noncancer lung cell line MRC-5. System 3 ferrocenyl chalcones displayed superior anticancer properties compared to their system 1 analogues. System 3 chalcones bearing five-membered heterocyclic substituents (thiophene, pyrazole, pyrrole, and pyrimidine) were the most active toward the MDA-MB-231 cancer cell line with IC 50 values from 6.59 to 12.51 μM. Cytotoxicity of the evaluated compounds in the 4T1 cell line exhibited IC 50 values from 13.23 to 213.7 μM. System 3 pyrazole chalcone had consistent toxicity toward both cell lines (IC 50 ∼ 13 μM) as well as promising selectivity relative to the noncancer MRC-5 control. Antioxidant activity was also evaluated, where, contrary to anticancer capabilities, system 1 ferrocenyl chalcones were superior to their system 3 analogues. Antioxidant activity comparable to that of ascorbic acid was observed for thiophene-bearing ferrocenyl chalcone with EC 50 = 31 μM., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

The Centers for Disease Control and Prevention Minority HIV Research Initiative (MARI) funded 8 investigators in 2016 to develop HIV prevention and treatment interventions in highly affected communities. We describe MARI studies who used community-based participatory research methods to inform the development of interventions in Black/African American and Hispanic/Latinx communities focused on sexual minority men (SMM) or heterosexual populations. Each study implemented best practice strategies for engaging with communities, informing recruitment strategies, navigating through the impacts of COVID-19, and disseminating findings. Best practice strategies common to all MARI studies included establishing community advisory boards, engaging community members in all stages of HIV research, and integrating technology to sustain interventions during the COVID-19 pandemic. Implementing community-informed approaches is crucial to intervention uptake and long-term sustainability in communities of color. MARI investigators' research studies provide a framework for developing effective programs tailored to reducing HIV-related racial/ethnic disparities., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Dengue continues to be a global public health problem due to its impact in terms of morbidity and mortality and economic burden on health systems, with severe effects mainly on children. Among the objectives of sustainable development is the control of infectious diseases; therefore, it is necessary to evaluate the impact of existing programs on the prevention and management of infectious diseases. The aim of this study was to analyze the epidemiological, clinical, and geospatial behavior of dengue in children in a region of the Colombian Caribbean. A retrospective cross-sectional study was carried out. The data provided by the Municipal Health Secretariat were taken and the cases of dengue and severe dengue in children aged 0 to 17 years reported in Sincelejo, Colombia, were extracted. The sociodemographic and clinical characteristics presented were analyzed and descriptive statistics were performed with tables and graphs of frequency and accumulated percentages. To locate the areas with the highest incidence of cases during the year, a geospatial location of the cases was carried out with the QGIS v.3.8 program. In 2019, there were 3611 cases of dengue fever in children aged 0 to 17 years. There were 1394 (38.6%) cases with warning signs, and 41 (1.1%) cases of severe dengue fever. Cases of severe dengue fever occurred more frequently in women. The incidence rate found was 3927 and 45.1 cases per 100,000 population, for dengue and severe dengue in children, respectively. The age ranges with the highest number of cases were children aged 4 to 9 years with 1778 cases. The clinical presentation was varied, with the most frequent symptoms, in all groups, being fever in 100% of cases, myalgias ≥71%, and arthralgias ≥64%. Only 9% (n=315) of the cases, corresponded to cases in the rural area. A very high incidence of cases of dengue and dengue with alarm signs in children was evidenced in the Colombian Caribbean region, mainly in the urban area, despite the existence of public health programs and strategies to control the burden of diseases transmitted by arbovirus vectors., Competing Interests: Declaration of conflicting interest The authors declare that there is no conflict of interest.

Phytochemical screening of an ethanol-water extract (EWE) from the bark of Croton guatemalensis led to the isolation and identification of eight compounds, among them: five ent -clerodane diterpenoids [junceic acid ( 1 ), 6( s )-acetoxy-15,16-diepoxy- ent -cleroda-3,13(16),14-trien-20-oic acid (crotoguatenoic acid A) ( 2 ), 6( s )-hydroxyoxy-15,16-diepoxy- ent -cleroda-3,13(16),14-trien-20-oic acid (crotoguatenoic acid B) ( 3 ), formosin F ( 4 ), bartsiifolic acid ( 5 )], and three flavonoids [rutin ( 6 ), epicatechin ( 7 ), and quercetin ( 8 )]. Of these, 2 and 3 are reported here for the first time. Structures were established through conventional spectroscopy methods and their absolute configurations were determined by optical rotation and comparison of experimental electronic circular dichroism (ECD) and theoretical calculated ECD spectra. A suitable high performance liquid chromatography (HPLC) method for quantifying rutin ( 6 ) was developed and validated according to standard protocols. Affinity-directed fractionation was used to identify possible in vitro active compounds on α -glucosidases from Saccharomyces cerevisiae . HPLC-ESI-MS was used to identify the inhibitors as free ligands after being released from the enzymatic complex by denaturing acidic conditions. The affinity studies led to the identification of ent -clerodane diterpenoids as active compounds. In silico analysis allowed us to determine the best conformational rearrangement for the α -glucosidase inhibitors.

Most prior studies of multisensory integration (MSI) in autism have measured MSI in only a single combination of modalities - typically audiovisual integration. The present study used onset reaction times (RTs) and 125-channel electroencephalography (EEG) to examine different forms of bimodal and trimodal MSI based on combinations of auditory (noise burst), somatosensory (finger tap), and visual (flash) stimuli presented in a spatially-aligned manner using a custom desktop apparatus. A total of 36 autistic and 19 non-autistic adolescents between the ages of 11-14 participated. Significant RT multisensory facilitation relative to summed unisensory RT was observed in both groups, as were significant differences between summed unisensory and multisensory ERPs. Although the present study's statistical approach was not intended to test effect latencies, these interactions may have begun as early as ∼45 ms, constituting "early" (<100 ms) MSI. RT and ERP measurements of MSI appeared independent of one another. Groups did not significantly differ in multisensory RT facilitation, but we found exploratory evidence of group differences in the magnitude of audiovisual interactions in ERPs. Future research should make greater efforts to explore MSI in under-represented populations, especially autistic people with intellectual disabilities and nonspeaking/minimally-verbal autistic people., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study uses factor mixture modelling of the Short Sensory Profile (SSP) at two time points to describe subgroups of young autistic and typically-developing children. This approach allows separate SSP subscales to influence overall SSP performance differentially across subgroups. Three subgroups were described, one including almost all typically-developing participants plus many autistic participants. SSP performance of a second, largely-autistic subgroup was predominantly shaped by a subscale indexing behaviours of low energy/weakness. Finally, the third subgroup, again largely autistic, contained participants with low (or more "atypical") SSP scores across most subscales. In this subgroup, autistic participants exhibited large P1 amplitudes to loud sounds. Autistic participants in subgroups with more atypical SSP scores had higher anxiety and more sleep disturbances., (© 2021. The Author(s).)

Background: Reconciling results obtained using different types of sensory measures is a challenge for autism sensory research. The present study used questionnaire, psychophysical, and neurophysiological measures to characterize autistic sensory processing in different measurement modalities., Methods: Participants were 46 autistic and 21 typically developing 11- to 14-year-olds. Participants and their caregivers completed questionnaires regarding sensory experiences and behaviors. Auditory and somatosensory event-related potentials (ERPs) were recorded as part of a multisensory ERP task. Auditory detection, tactile static detection, and tactile spatial resolution psychophysical thresholds were measured., Results: Sensory questionnaires strongly differentiated between autistic and typically developing individuals, while little evidence of group differences was observed in psychophysical thresholds. Crucially, the different types of measures (neurophysiological, psychophysical, questionnaire) appeared to be largely independent of one another. However, we unexpectedly found autistic participants with larger auditory Tb ERP amplitudes had reduced hearing acuity, even though all participants had hearing acuity in the non-clinical range., Limitations: The autistic and typically developing groups were not matched on cognitive ability, although this limitation does not affect our main analyses regarding convergence of measures within autism., Conclusion: Overall, based on these results, measures in different sensory modalities appear to capture distinct aspects of sensory processing in autism, with relatively limited convergence between questionnaires and laboratory-based tasks. Generally, this might reflect the reality that laboratory tasks are often carried out in controlled environments without background stimuli to compete for attention, a context which may not closely resemble the busier and more complex environments in which autistic people's atypical sensory experiences commonly occur. Sensory questionnaires and more naturalistic laboratory tasks may be better suited to explore autistic people's real-world sensory challenges. Further research is needed to replicate and investigate the drivers of the unexpected association we observed between auditory Tb ERP amplitudes and hearing acuity, which could represent an important confound for ERP researchers to consider in their studies., 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 Dwyer, Takarae, Zadeh, Rivera and Saron.)

Background: Quantitative measurement of eye movements can reveal subtle progression in neurodegenerative diseases., Objective: To determine if quantitative measurements of eye movements may reveal subtle progression of fragile X-associated tremor and ataxia (FXTAS)., Methods: Prosaccade (PS) and antisaccade (AS) behavior was analyzed in 25 controls, 57 non-FXTAS carriers, and 46 carriers with FXTAS., Results: Symptomatic individuals with FXTAS had longer AS latencies, increased rates of AS errors, and increased AS dysmetria relative to non-FXTAS carriers and controls. These deficits, along with PS latency and velocity, were greater in advanced FXTAS stages., Conclusion: AS deficits differentiated FXTAS from non-FXTAS premutation carriers implicating top-down control and frontostriatal deterioration. However, the absence of group differences between non-FXTAS carriers and controls in AS and PS markers suggests saccade performance may not be a sensitive enough measure for detecting conversion to FXTAS, but instead more helpful as translational biomarkers of FXTAS progression., (© 2022 International Parkinson and Movement Disorder Society.)

One undescribed acylated flavonol glucoside and five known compounds were isolated from the aerial parts of Eryngium cymosum F. Delaroche, a plant that is used in traditional Mexican medicine to treat type 2 diabetes. The chemical structures of the isolated compounds were elucidated using a variety of spectroscopic techniques, including 1D and 2D nuclear magnetic resonance (NMR) and mass spectrometry (MS). Chlorogenic acid ( 1 ), rosmarinic acid ( 2 ), caffeic acid ( 3 ), protocatechuic acid ( 4 ), kaempferol-3- O -(2,6- di - O - trans - ρ -coumaryl)- β -d-glucopyranoside ( 5 ), and the new acylated flavonol glucoside quercetin-3- O -(2,6- di - O - trans - ρ -coumaryl)- β -d-glucopyranoside ( 6 ) were isolated. This is the first report on the natural occurrence of quercetin-3- O -(2,6- di - O - trans - ρ -coumaryl)- β -D-glucopyranoside ( 6 ). In addition, according to the HPLC profile obtained for the water extract (WE), chlorogenic acid ( 1 ) and rosmarinic acid ( 2 ) were identified as the main compounds, while kaempferol-3- O -(2,6- di - O - trans - ρ -coumaryl)- β -d-glucopyranoside ( 5 ) were the main compound in the butanolic extract. We demonstrate the important role of compound 5 over the inhibition of G6Pase and FBPase. The isolated compounds may play an important role in the hypoglycemic effect of the extract and may act in a synergic way, but more experiments are needed to corroborate these findings.

Background: Carriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention., Methods: This was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm "converters," 15 Pm "nonconverters," 15 Nc) that were one-one matched on age, education, and socioeconomic status., Results: Compared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters., Conclusions: Accelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder., (© 2022. The Author(s).)

Background: Fragile X premutation carriers (55-200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle-the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown., Methods: We estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8-86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus., Results: Among participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus., Conclusions: Only the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occurrence of combined MCP and pallidal T2-abnormalities may present a risk for greater cognitive impairment and increased iron variability in the globus pallidus., Competing Interests: Author RH had received funding from Zynerba, Ovid, and the Azrieli Foundation to carry out treatment studies in fragile X syndrome, and had also consulted with Zynerba and Fulcrum regarding treatment studies in fragile X syndrome. Author DH had received funding from Novartis, Roche, Zynerba, and Seaside Therapeutics for consultation regarding treatment studies in fragile X syndrome. Author FT had received funding from Zynerba and the Azrieli Foundation to carry out molecular studies in fragile X syndrome. The remaining 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 Wang, Grigsby, Placido, Wei, Tassone, Kim, Hessl, Rivera and Hagerman.)

One of the most universally accepted facts about autism is that it is heterogenous. Individuals diagnosed with autism spectrum disorder have a wide range of behavioral presentations and a variety of co-occurring medical and mental health conditions. The identification of more homogenous subgroups is likely to lead to a better understanding of etiologies as well as more targeted interventions and treatments. In 2006, we initiated the UC Davis MIND Institute Autism Phenome Project (APP) with the overarching goal of identifying clinically meaningful subtypes of autism. This ongoing longitudinal multidisciplinary study now includes over 400 children and involves comprehensive medical, behavioral, and neuroimaging assessments from early childhood through adolescence (2-19 years of age). We have employed several strategies to identify sub-populations within autistic individuals: subgrouping by neural, biological, behavioral or clinical characteristics as well as by developmental trajectories. In this Mini Review, we summarize findings to date from the APP cohort and describe progress made toward identifying meaningful subgroups of autism., Competing Interests: DGA was on the Scientific Advisory Boards of Stemina Biomarkers Discovery, Inc. and Axial Therapeutics. The remaining 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 Nordahl, Andrews, Dwyer, Waizbard-Bartov, Restrepo, Lee, Heath, Saron, Rivera, Solomon, Ashwood and Amaral.)

Background: HIV prevention interventions which support engagement in care and increased awareness of biomedical options, including pre-exposure prophylaxis (PrEP), are highly desired for disproportionately affected Black/African American, Hispanic/Latinx and gay, bisexual, and other men who have sex with men (GBMSM) populations in the United States (US). However, in almost 40 years of HIV research, few interventions have been developed directly by and for these priority populations in domestic counties most at risk. We submit that interventions developed by early-career scientists who identify with and work directly with affected subgroups, and which include social and structural determinants of health, are vital as culturally tailored HIV prevention and care tools., Methods: We reviewed and summarized interventions developed from 2007 to 2020 by historically underrepresented early-career HIV prevention scientists in a federally funded research mentoring program. We mapped these interventions to determine which were in jurisdictions deemed as high priority (based on HIV burden) by national prevention strategies., Results: We summarized 11 HIV interventions; 10 (91%) of the 11 interventions are in geographic areas where HIV disparities are most concentrated and where new HIV prevention and care activities are focused. Each intervention addresses critical social and structural determinants of health disparities, and successfully reaches priority populations., Conclusion: Focused funding that supports historically underrepresented scientists and their HIV prevention and care intervention research can help facilitate reaching national goals to reduce HIV-related disparities and end the HIV epidemic. Maintaining these funding streams should remain a priority as one of the tools for national HIV prevention., (© 2020. W. Montague Cobb-NMA Health Institute.)

Although prior studies have compared sensory event-related potential (ERP) responses between groups of autistic and typically-developing participants, it is unclear how heterogeneity contributes to the results of these studies. The present study used examined individual differences in these responses. 130 autistic children and 81 typically-developing children, aged between 2 and 5 years, listened to tones at four identity levels while 61-channel electroencephalography was recorded. Hierarchical clustering was used to group participants based on rescaled ERP topographies between 51 and 350 ms. The hierarchical clustering analysis revealed substantial heterogeneity. Some of the seven clusters defined in this analysis were characterized by prolonged fronto-central positivities and/or weak or absent N2 negativities. However, many other participants fell into clusters in which N2 responses were present at varying latencies. Atypical response morphologies such as absent N2 responses and/or prolonged positive-going responses found in some autistic participants may account for prior research findings of attenuated N2 amplitudes in autism. However, there was also considerable overlap between groups, with participants of both groups appearing in all clusters. These results emphasize the utility of using clustering to explore individual differences in brain responses, which can expand on and clarify the results of analyses of group mean differences., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele (55-200 CGG repeats; PM) in the fragile X mental retardation ( FMR1 ) gene. It is currently unknown how the observed brain changes are associated with metabolic signatures in individuals who develop the disorder over time. The primary objective of this study was to investigate the correlation between longitudinal changes in the brain (area of the pons, midbrain, and MCP width) and the changes in the expression level of metabolic biomarkers of early diagnosis and progression of FXTAS in PM who, as part of an ongoing longitudinal study, emerged into two distinct categories. These included those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not meet the criteria of diagnosis (non-converters, NCON) and were compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Magnetic Resonance Imaging (MRIs) acquisition was obtained on a 3T Siemens Trio scanner and metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. Our findings indicate that differential metabolite levels are linked with the area of the pons between healthy control and premutation groups. More specifically, we observed a significant association of ceramides and mannonate metabolites with a decreased area of the pons, both at visit 1 (V1) and visit 2 (V2) only in the CON as compared to the NCON group suggesting their potential role in the development of the disorder. In addition, we found a significant correlation of these metabolic signatures with the FXTAS stage at V2 indicating their contribution to the progression and pathogenesis of FXTAS. Interestingly, these metabolites, as part of lipid and sphingolipid lipids pathways, provide evidence of the role that their dysregulation plays in the development of FXTAS and inform us as potential targets for personalized therapeutic development., Competing Interests: DH has received funding from Novartis, Roche, Seaside Therapeutics LLC and Marinus Pharmaceuticals, Inc. for designing Fragile X clinical Trials. FT has received funding from Azrieli Foundation, Zynerba and Asuragen, Inc. for studies in Fragile X syndrome. The remaining 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 © 2021 Zafarullah, Durbin-Johnson, Fourie, Hessl, Rivera and Tassone.)

We conducted an online survey among adults in Puerto Rico to identify factors associated with the intention to receive vaccination against COVID-19. Sociodemographic variables were analyzed independently for association with intent to receive vaccination. Significant associations were included in the multivariate logistic regression analysis. A total of 1016 responses were available for analysis. In the bivariate analysis, younger age, higher education, pre-COVID-19 employment, male sex, gay/bisexual identity, and single marital status were associated with increased intent to receive the vaccination. In the multivariate logistic regression, younger, male respondents, and those with higher educational attainment reported higher intent to receive the vaccination. Lower-income and living outside the San Juan metro region were associated with lower intent to receive the vaccination. National and international health organizations were identified as the most reliable sources of information, followed by healthcare professionals. These findings highlight the importance of considering sociodemographic characteristics and using trusted sources of information when designing COVID-19 vaccination public messaging.

Limited research has investigated the development of auditory ERPs in young children, and particularly how stimulus intensity may affect these auditory ERPs. Previous research has also yielded inconsistent findings regarding differences in the development of auditory ERPs in autism and typical development. Furthermore, stimulus intensity may be of particular interest in autism insofar as autistic people may have atypical experiences of sound intensity (e.g., hyperacusis). Therefore, the present study examined associations between age and ERPs evoked by tones of differing intensities (50, 60, 70, and 80 dB SPL) in a large sample of young children (2-5 years) with and without an autism diagnosis. Correlations between age and P1 latencies were examined, while cluster-based permutation testing was used to examine associations between age and neural response amplitudes, as well as group differences in amplitude, over all electrode sites in the longer time window of 1-350 ms. Older autistic participants had faster P1 latencies, but these effects only attained significance over the right hemisphere in response to soft 50 dB sounds. Autistic participants had slower P1 responses to 80 dB sounds over the right hemisphere. Over the scalp regions associated with the later N2 response, more negative response amplitudes (that is, larger N2 responses) were observed in typically-developing than autistic participants. Furthermore, continuous associations between response amplitudes and age suggested that older typically-developing participants exhibited stronger N2 responses to all intensities, though this effect may have at least in part reflected the absence of small positive voltage deflections in the N2 latency window. Age was associated with amplitudes of responses to 50 dB through 70 dB sounds in autism, but in contrast to Typical Development (TD), little evidence of relationships between age and amplitudes in the N2 latency window was found in autism in the 80 dB condition. Although caution should be exercised in interpretation due to the cross-sectional nature of this study, these findings suggest that developmental changes in auditory responses may differ across diagnostic groups in a manner that depends on perceived loudness and/or stimulus intensity., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Children with FMR1 gene expansions are known to experience a range of developmental challenges, including fragile X syndrome. However, little is known about early development and symptom onset, information that is critical to guide earlier identification, more accurate prognoses, and improved treatment options., Methods: Data from 8 unique studies that used the Mullen Scales of Early Learning to assess children with an FMR1 gene expansion were combined to create a data set of 1178 observations of >500 young children. Linear mixed modeling was used to explore developmental trajectories, symptom onset, and unique developmental profiles of children <5 years of age., Results: Boys with an FMR1 gene full mutation showed delays in early learning, motor skills, and language development as young as 6 months of age, and both sexes with a full mutation were delayed on all developmental domains by their second birthday. Boys with a full mutation continued to gain skills over early childhood at around half the rate of their typically developing peers; girls with a full mutation showed growth at around three-quarters of the rate of their typically developing peers. Although children with a premutation were mostly typical in their developmental profiles and trajectories, mild but significant delays in fine motor skills by 18 months were detected., Conclusions: Children with the FMR1 gene full mutation demonstrate significant developmental challenges within the first 2 years of life, suggesting that earlier identification is needed to facilitate earlier implementation of interventions and therapeutics to maximize effectiveness., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Objective: Evaluate the appropriateness of acetaminophen dosing by caregivers seeking care for their children/wards at the emergency department of a pediatric hospital., Methods: Design: Cross-sectional descriptive study. Setting: The emergency department of the University Pediatric Hospital in San Juan, Puerto Rico. Participants: Eighty-eight caregivers who had, in the past 24 hours, administered a known quantity of acetaminophen to a pediatric patient under their care and were visiting the emergency room with that patient. Intervention: The caregivers were interviewed by the investigators, using a standardized questionnaire. Main outcome measures: The appropriateness of the acetaminophen doses administered by caregivers. The product's dosage form and strength, measurement device used (if any), and demographic data (of the caregiver and child) were also collected. Doses of 10 to 15 mg/kg of acetaminophen were considered appropriate., Results: Overall, 45% of the caregivers had administered an inappropriate dose. Of these, 70% were subtherapeutic and 30% were supratherapeutic. Although 74% of the caregivers knew their child's/ward's weight, only 50% had used it to determine the dose. Caregivers with previous experience (as caregivers) were most likely to have administered an inappropriate dose (P = 0.03). Physicians were the source most consulted (40%) by caregivers, followed by the product's label (35%). Only 9% of the caregivers consulted a pharmacist for dosing recommendations., Conclusion: Nearly half of all the caregivers administered an incorrect acetaminophen dose, suggesting that there is a need for better caregiver education. Due to their accessibility at the point of sale of OTC medications and pharmacotherapy knowledge, pharmacists could have an active role in promoting the safe and effective use of acetaminophen.

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. It is currently unknown when, and if, individual premutation carriers will develop FXTAS. Thus, with the aim of identifying biomarkers for early diagnosis, development, and progression of FXTAS, we performed global metabolomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct categories: those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not (non-converters, NCON) and we compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. In this study we found 47 metabolites were significantly dysregulated between HC and the premutation groups (PM). Importantly, we identified 24 metabolites that showed significant changes in expression in the CON as compared to the NCON both at V1 and V2, and 70 metabolites in CON as compared to NCON but only at V2. These findings suggest the potential role of the identified metabolites as biomarkers for early diagnosis and for FXTAS disease progression, respectively. Interestingly, the majority of the identified metabolites were lipids, followed by amino acids. To our knowledge, this the first report of longitudinal metabolic profiling and identification of unique biomarkers of FXTAS. The lipid metabolism and specifically the sub pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered in FXTAS., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)