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Recent insights into the frequency of occurrence and the genetic and mechanistic basis of nervous system disease have demonstrated that neurologic disorders occur as a spectrum across all ages. To meet future needs of patients with neurologic disease of all ages and prepare for increasing implementaton of precision therapies, greater integration of child and adult neurology residency training is needed. ANN NEUROL 2023;94:1005-1007.

Background: Provisional Tic Disorder (PTD) is common in childhood. The received wisdom among clinicians is that PTD is short-lived and mild, with at most a few tics, and rarely includes complex tics, premonitory phenomena or comorbid illnesses. However, such conclusions come from clinical experience, with biased ascertainment and limited follow-up. Methods: Prospective study of 89 children with tics starting 0–9 months ago (median 4 months), fewer than half from clinical sources. Follow-up at 12 (± 24, 36, 48) months after the first tic. Results: At study entry, many children had ADHD (39), an anxiety disorder (27), OCD (9) or enuresis (17). All had at least two current tics, with a mean total since onset of 6.9 motor and 2.0 phonic tics. Forty-one had experienced a complex tic, and 69 could suppress some tics. Tics were clinically meaningful: 64 had tics severe enough for a clinical trial, and 76 families sought medical attention for the tics.At 12 months, 79 returned, and 78 still had tics. Of these, 29 manifested no tics during history and extended examination, but only via audio-visual monitoring when the child was seated alone. Only 12/70 now had plans to see a doctor for tics. Most who returned at 2–4 years still had tics known to the child and family, but medical impact was low. Conclusions: Our results do not contradict previous data, but overturn clinical lore. The data strongly argue against the longstanding but arbitrary tradition of separating tic disorders into recent-onset versus chronic.

Abstract Widespread adoption of mirror-image biological systems presents difficulties in accessing the requisite D-protein substrates. In particular, mirror-image phage display has the potential for high-throughput generation of biologically stable macrocyclic D-peptide binders with potentially unique recognition modes but is hindered by the individualized optimization required for D-protein chemical synthesis. We demonstrate a general mirror-image phage display pipeline that utilizes automated flow peptide synthesis to prepare D-proteins in a single run. With this approach, we prepare and characterize 12 D-proteins – almost one third of all reported D-proteins to date. With access to mirror-image protein targets, we describe the successful discovery of six macrocyclic D-peptide binders: three to the oncoprotein MDM2, and three to the E3 ubiquitin ligase CHIP. Reliable production of mirror-image proteins can unlock the full potential of D-peptide drug discovery and streamline the study of mirror-image biology more broadly.

Diffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain's white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927-1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL's BedpostX [BPX], DSI Studio's Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3's Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed a novel Bayesian Multi-tensor Model-selection (BaMM) method and applied it to the popular ball-and-stick model used in BedpostX within the FSL software package. BaMM was robust to overfitting and showed high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, sufficient data and an overfitting resistant analysis method enhance precision diffusion imaging. For potential clinical applications of diffusion imaging, such as neurosurgical planning and deep brain stimulation (DBS), the quantities of data required to achieve diffusion imaging reliability are lower than those needed for functional MRI.

The natural product himastatin has an unusual homodimeric structure that presents a substantial synthetic challenge. We report the concise total synthesis of himastatin from readily accessible precursors, incorporating a final-stage dimerization strategy that was inspired by a detailed consideration of the compound's biogenesis. Combining this approach with a modular synthesis enabled expedient access to more than a dozen designed derivatives of himastatin, including synthetic probes that provide insight into its antibiotic activity.

Tics manifest as brief, purposeless and unintentional movements or noises that, for many individuals, can be suppressed temporarily with effort. Previous work has hypothesized that the chaotic temporal nature of tics could possess an inherent fractality, that is, have neighbour-to-neighbour correlation at all levels of timescale. However, demonstrating this phenomenon has eluded researchers for more than two decades, primarily because of the challenges associated with estimating the scale-invariant, power law exponent-called the fractal dimension Df-from fractional Brownian noise. Here, we confirm this hypothesis and establish the fractality of tics by examining two tic time series datasets collected 6-12 months apart in children with tics, using random walk models and directional statistics. We find that Df is correlated with tic severity as measured by the YGTTS total tic score, and that Df is a sensitive parameter in examining the effect of several tic suppression conditions on the tic time series. Our findings pave the way for using the fractal nature of tics as a robust quantitative tool for estimating tic severity and treatment effectiveness, as well as a possible marker for differentiating typical from functional tics.

Background: The goal of this study was to estimate the short-term (∼2 years) healthcare costs of failed primary arthroscopic rotator cuff repair (RCR) in the United States. Methods: A review of current literature was performed to estimate the number of RCR performed in the United States in the year 2022 and the rate of progression of these patients to lose repair continuity, reach clinical failure, and progress to nonoperative intervention and revision procedures. A review of the current literature was performed to estimate the costs incurred by these failures over the ensuing 2-year postoperative time period. Results: The direct and indirect healthcare costs of structural and clinical failure of primary RCR performed in 2022 are estimated to reach $438,892,670 in the short-term postoperative period. The majority of the costs come from the estimated $229,390,898 in nonoperative management that these patients undergo after they reach clinical failure. Conclusion: The short-term healthcare costs of failed arthroscopic RCR performed in the United States in 2022 are predicted to be $438,892,670. Although RCR improves quality of life, pain, function, and is cost-effective, there remains great potential for reducing the economic burden of failed RCR repairs on the US society. Investments into research aimed to improve RCR healing rates are warranted. Clinical Relevance: Although RCR improves quality of life, pain, function, and is cost-effective, this study provides evidence that there remains great potential for reducing the economic burden of failed RCR repairs on the US society. Investments into research aimed to improve RCR healing rates are warranted.

Purpose: Pediatric brain tumor patients often experience significant cognitive sequelae. Resting-state functional MRI (rsfMRI) provides a measure of brain network organization, and we hypothesize that pediatric brain tumor patients treated with proton therapy will demonstrate abnormal brain network architecture related to cognitive outcome and radiation dosimetry. Participants and Methods: Pediatric brain tumor patients treated with proton therapy were enrolled on a prospective study of cognitive assessment using the NIH Toolbox Cognitive Domain. rsfMRI was obtained in participants able to complete unsedated MRI. Brain system segregation (BSS), a measure of brain network architecture, was calculated for the whole brain, the high-level cognition association systems, and the sensory-motor systems. Results: Twenty-six participants were enrolled in the study for cognitive assessment, and 18 completed rsfMRI. There were baseline cognitive deficits in attention and inhibition and processing speed prior to radiation with worsening performance over time in multiple domains. Average BSS across the whole brain was significantly decreased in participants compared with healthy controls (1.089 and 1.101, respectively; P = 0.001). Average segregation of association systems was significantly lower in participants than in controls (P

Coho salmon (Oncorhynchus kisutch) are highly sensitive to 6PPD-Quinone (6PPD-Q). Details of the hydrological and biogeochemical processes controlling spatial and temporal dynamics of 6PPD-Q fate and transport from points of deposition to receiving waters (e.g., streams, estuaries) are poorly understood. To understand the fate and transport of 6PPD and mechanisms leading to salmon mortality Visualizing Ecosystem Land Management Assessments (VELMA), an ecohydrological model developed by US Environmental Protection Agency (EPA), was enhanced to better understand and inform stormwater management planning by municipal, state, and federal partners seeking to reduce stormwater contaminant loads in urban streams draining to the Puget Sound National Estuary. This work focuses on the 5.5 km2 Longfellow Creek upper watershed (Seattle, Washington, United States), which has long exhibited high rates of acute urban runoff mortality syndrome in coho salmon. We present VELMA model results to elucidate these processes for the Longfellow Creek watershed across multiple scales–from 5-m grid cells to the entire watershed. Our results highlight hydrological and biogeochemical controls on 6PPD-Q flow paths, and hotspots within the watershed and its stormwater infrastructure, that ultimately impact contaminant transport to Longfellow Creek and Puget Sound. Simulated daily average 6PPD-Q and available observed 6PPD-Q peak in-stream grab sample concentrations (ng/L) corresponds within plus or minus 10 ng/L. Most importantly, VELMA’s high-resolution spatial and temporal analysis of 6PPD-Q hotspots provides a tool for prioritizing the locations, amounts, and types of green infrastructure that can most effectively reduce 6PPD-Q stream concentrations to levels protective of coho salmon and other aquatic species.

Assessing the risk of nontarget attack (NTA) for federally listed threatened and endangered (T&E) plant species confamilial to invasive plants targeted for classical biological control, is one of the most important objectives of pre-release environmental safety assessments in the United States. However, evaluating potential NTA on T&E species is often complicated by restrictive agency requirements for obtaining propagules, or the ability to propagate plants and rear agents to the appropriate phenostages synchronously for testing, or both. Here, we assessed whether plant cues associated with a host recognition can be used for testing the attractiveness of four T&E and one rare single population plant species non-destructively for a candidate biocontrol agent. We used the seed-feeding weevil, Mogulones borraginis, a candidate for the biological control of the invasive plant, Cynoglossum officinale (Boraginaceae) as the study system. We collected olfactory and visual cues in the form of flowering sprigs from T&E plant species confamilial to the invasive plant in a non-destructive manner and used them to measure behavioral responses and searching time of weevils. Female weevils preferred C. officinale to all tested plant species in dual-choice bioassays using either olfactory or visual cues in a modified y-tube device. Furthermore, female weevils were repelled by the combined olfactory and visual cues from all tested T&E plant species in a dual-choice test against controls (e.g., purified air in an empty arm), indicating that it would be extremely unlikely for the weevil to attack any of these species upon release in the United States. Principal component analysis based on 61 volatile organic compounds effectively separated the five confamilial plant species and C. officinale, corroborating the results of behavioral bioassays. We conclude that studies on pre-alighting host selection behavior and the underlying physiological mechanisms of how organisms select host plants they exploit can aid in environmental safety testing of weed biological control agents.

Governments and society increasingly are demanding that industrial projects result in a net positive impact (NPI) on biodiversity. Impacts are commonly measured in terms of losses and gains of area and quality of vegetation, where quality refers to how closely a site matches the condition of native vegetation in its undisturbed state. Existing vegetation quality frameworks share a number of limitations, including little or no replication, uncertain scope of inference, vulnerability to bias, and inability to measure error. Here we present the Vegetation Quality Assessment (VQA) framework, a sampling-based extension of Quality Hectares that measures vegetation quality in terms of overlap between the probability distributions of ecological indicators at a project site and in undisturbed (benchmark) vegetation of the same kind. Distribution overlap incorporates natural variation at the landscape scale and provides an intuitive measure of quality that varies between 0 and 1. Indicators are measured using a stratified-random sampling design that minimizes bias and supports inference at the scale of the project landscape. Confidence limits of quality and quality hectares are determined by bootstrapping; power and minimum sample sizes are estimated by Monte Carlo simulation. Multiple assessments track losses and gains of quality hectares and enable accurate accounting of progress to NPI. The VQA framework can be implemented using a variety of vegetation sampling methods, allowing existing vegetation databases to be leveraged as sources of data. We conclude by demonstrating the application of VQA at several mining operations in the Elk Valley of southeastern British Columbia, Canada.

Current literature emphasizes the necessary and increasing role of the emergency department (ED) psychologist. This perspective paper will illustrate that the recent focus on an ED psychologist is necessary, but insufficient. Equally important, is an understanding of when a patient in a potential crisis does not require an ED admission, but rather an assessment that is made prior to the patient going to the ED. The essential role of an outpatient crisis team is vital in differentiating when an ED admission is indicated for a psychiatric crisis (true positive) and when an ED admission is not indicated for a psychiatric crisis (false positive). Evaluating crises prior to ED admissions accomplishes two critical healthcare objectives in a parallel process: 1) accurately assessing the proper level of care needed when a patient reports they are experiencing acute psychiatric symptoms (which may or may not necessitate emergency department level of care, and 2) reducing burden on an already over-extended ED when emergency care is not indicated. Our findings are uniquely drawn from a highly diverse youth patient population in Northern California, United States.

Salmonella is a global bacterial foodborne pathogen associated with a variety of contaminated food products. Poultry products are a common source of Salmonella-associated foodborne illness, and an estimated 7% of human illnesses in the United States are attributed to turkey products. From November 2017 to March 2019, the Centers for Disease Control and Prevention reported a turkey-associated outbreak of multidrug-resistant (MDR; resistant to ≥3 antimicrobial classes) Salmonella enterica serovar Reading (S. Reading) linked to 358 human infections in 42 US states and Canada. Since S. Reading was seldom linked to human illness prior to this outbreak, the current study compared genomic sequences of S. Reading isolates prior to the outbreak (pre-outbreak) to isolates identified during the outbreak period, focusing on genes that were different between the two groups but common within a group. Following whole-genome sequence analysis of five pre-outbreak and five outbreak-associated turkey/turkey product isolates of S. Reading, 37 genes located within two distinct chromosomal regions were identified only in the pre-outbreak isolates: (1) an ~5 kb region containing four protein-coding genes including uidA which encodes beta-glucuronidase, pgdA encoding peptidoglycan deacetylase, and two hypothetical proteins and (2) an ~28 kb region comprised of 32 phage-like genes and the xerC gene, which encodes tyrosine recombinase (frequently associated with phage genes). The five outbreak isolates also had a deletional event within the cirA gene, introducing a translational frame shift and premature stop codon. The cirA gene encodes a protein with dual receptor functions: a siderophore receptor for transport of dihydroxybenzoylserine as well as a colicin Ia/b receptor. Significant differences for the identified genetic variations were also detected in 75 S. Reading human isolates. Of the 41 S. Reading isolates collected before or in 2017, 81 and 90% of the isolates contained the uidA and pgdA genes, respectively, but only 24% of the isolates collected after 2017 harbored the uidA and pgdA genes. The truncation event within the cirA gene was also significantly higher in isolates collected after 2017 (74%) compared to before or in 2017 (5%). Phenotypic analysis of the S. Reading isolates for colicin and cefiderocol sensitivities (CirA) and β-methyl-D-glucuronic acid utilization (UidA and accessory proteins) supported the genomic data. Overall, a similar genome reduction pattern was generally observed in both the turkey and human isolates of S. Reading during the outbreak period, and the genetic differences were present in genes that could potentially promote pathogen dissemination due to variation in Salmonella colonization, fitness, and/or virulence.

The hippocampus is critically important for a diverse range of cognitive processes, such as episodic memory, prospective memory, affective processing, and spatial navigation. Using individual-specific precision functional mapping of resting-state functional MRI data, we found the anterior hippocampus (head and body) to be preferentially functionally connected to the default mode network (DMN), as expected. The hippocampal tail, however, was strongly preferentially functionally connected to the parietal memory network (PMN), which supports goal-oriented cognition and stimulus recognition. This anterior-posterior dichotomy of resting-state functional connectivity was well-matched by differences in task deactivations and anatomical segmentations of the hippocampus. Task deactivations were localized to the hippocampal head and body (DMN), relatively sparing the tail (PMN). The functional dichotomization of the hippocampus into anterior DMN-connected and posterior PMN-connected parcels suggests parallel but distinct circuits between the hippocampus and medial parietal cortex for self- versus goal-oriented processing.