Probabilistic Refinement of Focused Ultrasound Thalamotomy Targeting for Parkinson's Disease Tremor.

BACKGROUND: There remains high variability in clinical outcomes when the same magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy target is used for both essential tremor (ET) and tremor-dominant Parkinson's disease (TDPD). OBJECTIVE: Our goal is to refine the MRgFUS thalamotomy target for TDPD versus ET. METHODS: We retrospectively performed voxel-wise efficacy and structural connectivity mapping using 3-12-month post-procedure hand tremor scores for a multicenter cohort of 32 TDPD patients and a previously published cohort of 79 ET patients, and 24-hour T1-weighted post-MRgFUS brain images. We validated our findings using Unified Parkinson's Disease Rating Scale part III scores for an independent cohort of nine TDPD patients. RESULTS: The post-MRgFUS clinical improvements were 45.9% ± 35.9%, 55.5% ± 36%, and 46.1% ± 18.6% for ET, multicenter TDPD and validation TDPD cohorts, respectively. The TDPD and ET efficacy maps differed significantly (ppermute < 0.05), with peak TDPD improvement (87%) at x = -13.5; y = -15.0; z = 1.5, ~3.5 mm anterior and 3 mm dorsal to the ET target. Discriminative connectivity projections were to the motor and premotor regions in TDPD, and to the motor and somatosensory regions in ET. The disorder-specific voxel-wise efficacy map could be used to estimate outcome in TDPD patients with high accuracy (R = 0.8; R2 = 0.64; P < 0.0001). The model was validated using the independent cohort of nine TDPD patients (R = 0.73; R2 = 0.53; P = 0.025-voxel analysis). CONCLUSION: We demonstrated that the most effective MRgFUS thalamotomy target in TDPD is in the ventral intermediate nucleus/ventralis oralis posterior border region. This finding offers new insights into the thalamic regions instrumental in tremor control, with pivotal implications for improving treatment outcomes. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Fishers (Pekania pennanti) are forest structure specialists when resting and generalists when moving: behavior influences resource selection in a northern Rocky Mountain fisher population.

BACKGROUND: Studies of animal habitat selection are important to identify and preserve the resources species depend on, yet often little attention is paid to how habitat needs vary depending on behavioral state. Fishers (Pekania pennanti) are known to be dependent on large, mature trees for resting and denning, but less is known about their habitat use when foraging or moving within a home range. METHODS: We used GPS locations collected during the energetically costly pre-denning season from 12 female fishers to determine fisher habitat selection during two critical behavioral activities: foraging (moving) or resting, with a focus on response to forest structure related to past forest management actions since this is a primary driver of fisher habitat configuration. We characterized behavior based on high-resolution GPS and collar accelerometer data and modeled fisher selection for these two behaviors within a home range (third-order selection). Additionally, we investigated whether fisher use of elements of forest structure or other important environmental characteristics changed as their availability changed, i.e., a functional response, for each behavior type. RESULTS: We found that fishers exhibited specialist selection when resting and generalist selection when moving, with resting habitat characterized by riparian drainages with dense canopy cover and moving habitat primarily influenced by the presence of mesic montane mixed conifer forest. Fishers were more tolerant of forest openings and other early succession elements when moving than resting. CONCLUSIONS: Our results emphasize the importance of considering the differing habitat needs of animals based on their movement behavior when performing habitat selection analyses. We found that resting fishers are more specialist in their habitat needs, while foraging fishers are more generalist and will tolerate greater forest heterogeneity from past disturbance.

Multi-generational benefits of genetic rescue.

Genetic rescue-an increase in population fitness following the introduction of new alleles-has been proven to ameliorate inbreeding depression in small, isolated populations, yet is rarely applied as a conservation tool. A lingering question regarding genetic rescue in wildlife conservation is how long beneficial effects persist in admixed populations. Using data collected over 40 years from 1192 endangered Florida panthers (Puma concolor coryi) across nine generations, we show that the experimental genetic rescue implemented in 1995-via the release of eight female pumas from Texas-alleviated morphological, genetic, and demographic correlates of inbreeding depression, subsequently preventing extirpation of the population. We present unequivocal evidence, for the first time in any terrestrial vertebrate, that genetic and phenotypic benefits of genetic rescue remain in this population after five generations of admixture, which helped increase panther abundance (> fivefold) and genetic effective population size (> 20-fold). Additionally, even with extensive admixture, microsatellite allele frequencies in the population continue to support the distinctness of Florida panthers from other North American puma populations, including Texas. Although threats including habitat loss, human-wildlife conflict, and infectious diseases are challenges to many imperiled populations, our results suggest genetic rescue can serve as an effective, multi-generational tool for conservation of small, isolated populations facing extinction from inbreeding.

The effect of thoraco-lumbo-sacral orthosis wear time and clinical risk factors on curve progression for individuals with adolescent idiopathic scoliosis.

BACKGROUND CONTEXT: The effectiveness of bracing with a thoraco-lumbo-sacral orthosis (TLSO) for adolescent idiopathic scoliosis (AIS) has been studied extensively, with a growing body of evidence supporting TLSO use. In this study we examine the effect of wear time and other important causal factors affecting curve progression and develop a risk model that can be applied to individual patients and is based on important casual factors. PURPOSE: Understand the impact of TLSO wear time and other risk factors in order to guide optimal treatment. STUDY DESIGN/SETTING: Prospective, multi-center, cohort study PATIENT SAMPLE: Individuals with a diagnosis of AIS, age of 10 to 16 years, primary Cobb angle of 20 to 45 degrees, Risser 0 to 2, <1 year post menarche if female, who were to be treated with a TLSO OUTCOME MEASURES: (1) Rate of primary curve progression, (2) surgery recommendation during TLSO treatment METHODS: Wear time was monitored with thermochrons. Participants were followed until the end of growth. We examined the causal effects of wear time and baseline skeletal maturity as measured by triradiate cartilage (TRC) status, Cobb angle, and age. We then fit an outcome prediction model (logistic regression) based on important casual factors. RESULTS: Our final cohort consisted of 145 individuals (baseline age 12.1-13.4 years). Wear time was an important cause of response to treatment, including an interaction with TRC status. Baseline Cobb angle and age were also meaningful causes of response. The prediction model was accurate (79%) and had good specificity (81%) and moderate sensitivity (68%) and an area under the receiver operating characteristic curve (AUC) of 0.81. Additionally, we were able to independently confirm previous estimates of treatment efficacy, with an odds ratio around 2.0. CONCLUSIONS: Our study showed the explicit causal effects of wear time, and baseline skeletal maturity, Cobb angle and age. The risk model we developed can be used for counseling patients and their families regarding TLSO wear and expectations for outcome.

Barriers Experienced by First Nations Deaf People in the Justice System.

Anecdotal evidence strongly suggests that members of the First Nations Deaf community experience more barriers when engaging with the criminal justice system than those who are not deaf. Therefore, our purpose for writing this article is to highlight legal and policy issues related to First Nations Deaf people, including perspectives of professionals working with these communities, living in Australia who have difficulty in accessing supports within the criminal justice system. In this article, we present data from semi-structured qualitative interviews focused on four key themes: (a) indefinite detention and unfit to plead, (b) a need for an intersectional approach to justice, (c) applying the maximum extent of the law while minimizing social services-related resources, and (d) the need for language access and qualified sign language interpreters. Through this article and the related larger sustaining project, we seek to center the experiences and needs of First Nations Deaf communities to render supports for fair, just, and equitable access in the Australian criminal justice system to this historically marginalized group.

A Description and Safety Overview of Irreversible Electroporation for Prostate Tissue Ablation in Intermediate-Risk Prostate Cancer Patients: Preliminary Results from the PRESERVE Trial.

The PRESERVE study (NCT04972097) aims to evaluate the safety and effectiveness of the NanoKnife System to ablate prostate tissue in patients with intermediate-risk prostate cancer (PCa). The NanoKnife uses irreversible electroporation (IRE) to deliver high-voltage electrical pulses to change the permeability of cell membranes, leading to cell death. A total of 121 subjects with organ-confined PCa ≤ T2c, prostate-specific antigens (PSAs) ≤ 15 ng/mL, and a Gleason score of 3 + 4 or 4 + 3 underwent focal ablation of the index lesion. The primary endpoints included negative in-field biopsy and adverse event incidence, type, and severity through 12 months. At the time of analysis, the trial had completed accrual with preliminary follow-up available. Demographics, disease characteristics, procedural details, PSA responses, and adverse events (AEs) are presented. The median (IQR) age at screening was 67.0 (61.0-72.0) years and Gleason distribution 3 + 4 (80.2%) and 4 + 3 (19.8%). At 6 months, all patients with available data (n = 74) experienced a median (IQR) percent reduction in PSA of 67.6% (52.3-82.2%). Only ten subjects (8.3%) experienced a Grade 3 adverse event; five were procedure-related. No Grade ≥ 4 AEs were reported. This study supports prior findings that IRE prostate ablation with the NanoKnife System can be performed safely. Final results are required to fully assess oncological, functional, and safety outcomes.

Characterizing the human intestinal chondroitin sulfate glycosaminoglycan sulfation signature in inflammatory bowel disease.

The intestinal extracellular matrix (ECM) helps maintain appropriate tissue barrier function and regulate host-microbial interactions. Chondroitin sulfate- and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) are integral components of the intestinal ECM, and alterations in CS/DS-GAGs have been shown to significantly influence biological functions. Although pathologic ECM remodeling is implicated in inflammatory bowel disease (IBD), it is unknown whether changes in the intestinal CS/DS-GAG composition are also linked to IBD in humans. Our aim was to characterize changes in the intestinal ECM CS/DS-GAG composition in intestinal biopsy samples from patients with IBD using mass spectrometry. We characterized intestinal CS/DS-GAGs in 69 pediatric and young adult patients (n = 13 control, n = 32 active IBD, n = 24 IBD in remission) and 6 adult patients. Here, we report that patients with active IBD exhibit a significant decrease in the relative abundance of CS/DS isomers associated with matrix stability (CS-A and DS) compared to controls, while isomers implicated in matrix instability and inflammation (CS-C and CS-E) were significantly increased. This imbalance of intestinal CS/DS isomers was restored among patients in clinical remission. Moreover, the abundance of pro-stabilizing CS/DS isomers negatively correlated with clinical disease activity scores, whereas both pro-inflammatory CS-C and CS-E content positively correlated with disease activity scores. Thus, pediatric patients with active IBD exhibited increased pro-inflammatory and decreased pro-stabilizing CS/DS isomer composition, and future studies are needed to determine whether changes in the CS/DS-GAG composition play a pathogenic role in IBD.

Demonstrating the utility of Instrumented Gait Analysis in the treatment of children with cerebral palsy.

BACKGROUND: Instrumented gait analysis (IGA) has been around for a long time but has never been shown to be useful for improving patient outcomes. In this study we demonstrate the potential utility of IGA by showing that machine learning models are better able to estimate treatment outcomes when they include both IGA and clinical (CLI) features compared to when they include CLI features alone. DESIGN: We carried out a retrospective analysis of data from ambulatory children diagnosed with cerebral palsy who were seen at least twice at our gait analysis center. Individuals underwent a variety of treatments (including no treatment) between sequential gait analyses. We fit Bayesian Additive Regression Tree (BART) models that estimated outcomes for mean stance foot progression to demonstrate the approach. We built two models: one using CLI features only, and one using CLI and IGA features. We then compared the models' performance in detail. We performed similar, but less detailed, analyses for a number of other outcomes. All results were based on independent test data from a 70%/30% training/testing split. RESULTS: The IGA model was more accurate than the CLI model for mean stance-phase foot progression outcomes (RMSEIGA = 11∘, RMSECLI = 13∘) and explained more than 1.5 × as much of the variance (R2IGA = .45, R2CLI = .28). The IGA model outperformed the CLI model for every level of treatment complexity, as measured by number of simultaneous surgeries. The IGA model also exhibited superior performance for estimating outcomes of mean stance-phase knee flexion, mean stance-phase ankle dorsiflexion, maximum swing-phase knee flexion, gait deviation index (GDI), and dimensionless speed. INTERPRETATION: The results show that IGA has the potential to be useful in the treatment planning process for ambulatory children diagnosed with cerebral palsy. We propose that the results of machine learning outcome estimators-including estimates of uncertainty-become the primary IGA tool utilized in the clinical process, complementing the standard medical practice of conducting a through patient history and physical exam, eliciting patient goals, reviewing relevant imaging data, and so on.

Evolution of chromosome-arm aberrations in breast cancer through genetic network rewiring.

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module we name PGCKA1. Genome-wide pooled overexpression screens using a barcoded library of human open reading frames identify chromosomal regions, including chr4p, that suppress proliferation when overexpressed in a context-dependent manner, implicating network interactions. Together, these results shed light on the early emergence of complex aneuploid karyotypes involving chr4p and adaptive landscapes shaping breast cancer genomes.

Simultaneous species detection and discovery with environmental DNA metabarcoding: A freshwater mollusk case study.

Environmental DNA (eDNA) sampling is a powerful tool for rapidly characterizing biodiversity patterns for specious, cryptic taxa with incomplete taxonomies. One such group that are also of high conservation concern are North American freshwater gastropods. In particular, springsnails of the genus Pyrgulopsis (Family: Hydrobiidae) are prevalent throughout the western United States where >140 species have been described. Many of the described species are narrow endemics known from a single spring or locality, and it is believed that there are likely many additional species which have yet to be described. The distribution of these species across the landscape is of interest because habitat loss and degradation, climate change, groundwater mining, and pollution have resulted in springsnail imperilment rates as high as 92%. Determining distributions with conventional sampling methods is limited by the fact that these snails are often <5 mm in length with few distinguishing morphological characters, making them both difficult to detect and to identify. We developed an eDNA metabarcoding protocol that is both inexpensive and capable of rapid, accurate detection of all known Pyrgulopsis species. When compared with conventional collection techniques, our pipeline consistently resulted in detection at sites previously known to contain Pyrgulopsis springsnails and at a cost per site that is likely to be substantially less than the conventional sampling and individual barcoding that has been done historically. Additionally, because our method uses eDNA extracted from filtered water, it is non-destructive and suitable for the detection of endangered species where "no take" restrictions may be in effect. This effort represents both a tool which is immediately applicable to taxa of high conservation concern across western North America and a case study in the broader application of eDNA sampling for landscape assessments of cryptic taxa of conservation concern.

(Pro)renin receptor signaling in hypothalamic tyrosine hydroxylase neurons is required for obesity-associated glucose metabolic impairment.

Glucose homeostasis is achieved via complex interactions between the endocrine pancreas and other peripheral tissues and glucoregulatory neurocircuits in the brain that remain incompletely defined. Within the brain, neurons in the hypothalamus appear to play a particularly important role. Consistent with this notion, we report evidence that (pro)renin receptor (PRR) signaling within a subset of tyrosine hydroxylase (TH) neurons located in the hypothalamic paraventricular nucleus (PVNTH neurons) is a physiological determinant of the defended blood glucose level. Specifically, we demonstrate that PRR deletion from PVNTH neurons restores normal glucose homeostasis in mice with diet-induced obesity (DIO). Conversely, chemogenetic inhibition of PVNTH neurons mimics the deleterious effect of DIO on glucose. Combined with our finding that PRR activation inhibits PVNTH neurons, these findings suggest that, in mice, (a) PVNTH neurons play a physiological role in glucose homeostasis, (b) PRR activation impairs glucose homeostasis by inhibiting these neurons, and (c) this mechanism plays a causal role in obesity-associated metabolic impairment.

Delayed Diagnosis of Complete Achilles Tendon Rupture in a Teenage Athlete: A Case Report of Nonoperative Treatment.

CASE: A 19-year-old female athlete experienced calf pain during sport. A complete Achilles tendon rupture was diagnosed 4 weeks after injury. Ultrasound revealed discontinuity of the Achilles tendon with 2.0 cm of diastasis, persisting in plantarflexion. Plantarflexion immobilization was initiated, and progressive dorsiflexion was used until 10 weeks from injury. At 1 year from injury, ankle magnetic resonance imaging revealed a contiguous tendon, the patient was pain-free, and had returned to high-level athletics with equivalent sport performance relative to her preoperative status. CONCLUSION: Certain Achilles tendon ruptures in young people may be treated nonoperatively with good clinical outcomes, even if diagnosis and immobilization are delayed and tendon diastasis persists in maximum plantarflexion.

A Survey of Sleep Quality From a Post-COVID Clinic.

OBJECTIVES: To assess the prevalence of sleep disturbance among patients evaluated at a clinic for patients afflicted with Post-acute sequelae of COVID-19 (PASC). METHODS: Sleep disturbance was assessed with the Patient-Reported Outcomes Measurement Information System-Sleep Disturbance (PROMIS-SD) framework among adult patients of the PASC clinic. RESULTS: Among 312 patients, the mean age was 46.2 years, and 70.2% were women. About 41.0% of patients had no sleep disturbance; sleep disturbance was mild to moderate in 51.3% and severe in 7.7%. PROMIS-SD score was negatively correlated with the time from the initial positive COVID-19 test to the initial consultation in the PASC clinic (Pearson r = -.094; r2 = .0088). CONCLUSIONS: The PROMIS-Sleep Disturbance framework can serve as a tool to assess the burden of sleep disturbances in PASC patients.

The unknown unknown: A framework for assessing environmental DNA assay specificity against unsampled taxa.

Taxon-specific quantitative PCR (qPCR) assays are commonly used for environmental DNA sampling-based inference of animal presence. These assays require thorough validation to ensure that amplification truly indicates detection of the target taxon, but a thorough validation is difficult when there are potentially many non-target taxa, some of which may have incomplete taxonomies. Here, we use a previously published, quantitative model of cross-amplification risk to describe a framework for assessing qPCR assay specificity when there is missing information and it is not possible to assess assay specificity for each individual non-target confamilial. In this framework, we predict assay specificity against unsampled taxa (non-target taxa without sequence data available) using the sequence information that is available for other confamilials. We demonstrate this framework using four case study assays for: (1) An endemic, freshwater arthropod (meltwater stonefly; Lednia tumana), (2) a globally distributed, marine ascidian (Didemnum perlucidum), (3) a continentally distributed freshwater crustacean (virile crayfish; Faxonius virilis, deanae and nais species complex) and (4) a globally distributed freshwater teleost (common carp; Cyprinus carpio and its close relative C. rubrofuscus). We tested the robustness of our approach to missing information by simulating application of our framework for all possible subsamples of 20-all non-target taxa. Our results suggest that the modelling framework results in estimates which are largely concordant with observed levels of cross-amplification risk using all available sequence data, even when there are high levels of data missingness. We explore potential limitations and extensions of this approach for assessing assay specificity and provide users with an R Markdown template for generating reproducible reports to support their own assay validation efforts.

Effect of Cobalt-60 Treatment Dose Rate on Arteriovenous Malformation Obliteration After Stereotactic Radiosurgery With Gamma Knife.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) marginal dose is associated with successful obliteration of cerebral arteriovenous malformations (AVM). SRS dose rate-how old the cobalt-60 sources are-is known to influence outcomes for some neurological conditions and benign tumors. The objective of this study was to determine the association between cobalt-60 treatment dose rate and cerebral AVM obliteration in patients treated with SRS. METHODS: We performed a retrospective cohort study of 361 patients undergoing 411 AVM-directed SRS treatments between 2005 and 2019 at a single institution. Lesion characteristics, SRS details, obliteration dates, and post-treatment toxicities were recorded. Univariate and multivariate regression analyses of AVM outcomes regarding SRS dose rate (range 1.3-3.7 Gy, mean = 2.4 Gy, median = 2.5 Gy) were performed. RESULTS: At 10 years post-SRS, 68% of AVMs were obliterated on follow-up imaging. Dose rates >2.9 Gy/min were found to be significantly associated with AVM obliteration compared with those <2.1 Gy/min ( P = .034). AVM size, biologically effective dose, and SRS marginal dose were also associated with obliteration, with obliteration more likely for smaller lesions, higher biologically effective dose, and higher marginal dose. Higher dose rates were not associated with the development of post-SRS radiological or symptomatic edema, although larger AVM volume was associated with both types of edema. CONCLUSION: Patients with cerebral AVMs treated with higher SRS dose rates (from newer cobalt-60 sources) experience higher incidences of obliteration without a significant change in the risk of post-treatment edema.

Comparative neural correlates of DBS and MRgFUS lesioning for tremor control in essential tremor.

BACKGROUND: Given high rates of early complications and non-reversibility, refined targeting is necessitated for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for essential tremor (ET). Selection of lesion location can be informed by considering optimal stimulation area from deep brain stimulation (DBS). METHODS: 118 patients with ET who received DBS (39) or MRgFUS (79) of the ventral intermediate nucleus (VIM) underwent stimulation/lesion mapping, probabilistic mapping of clinical efficacy and normative structural connectivity analysis. The efficacy maps were compared, which depict the relationship between stimulation/lesion location and clinical outcome. RESULTS: Efficacy maps overlap around the VIM ventral border and encompass the dentato-rubro-thalamic tract. While the MRgFUS map extends inferiorly into the posterior subthalamic area, the DBS map spreads inside the VIM antero-superiorly. CONCLUSION: Comparing the efficacy maps of DBS and MRgFUS suggests a potential alternative location for lesioning, more antero-superiorly. This may reduce complications, without sacrificing efficacy, and individualise targeting. TRIAL REGISTRATION NUMBER: NCT02252380.

Impact of Integrated Pharmacology Instruction by Principal Faculty Pharmacists in Two Physician Assistant Programs: A Retrospective Study.

PURPOSE: In recent years, there has been a growing trend toward integrating pharmacology instruction into physician assistant (PA) programs by dedicated PA faculty pharmacists. Pharmacists train to become medication experts. Incorporating pharmacist instruction in a PA program during the didactic year provides PA students with an early opportunity to experience interprofessional education and interdisciplinary synergy through clinical application. METHODS: This article presents a retrospective study that aims to evaluate the impact of integrated pharmacology instruction by principal PA faculty pharmacists on student satisfaction and standardized assessment metrics. Student satisfaction was measured by course evaluations and exit/alumni surveys. Standardized metrics included Physician Assistant Clinical Knowledge Rating and Assessment Tool and Physician Assistant National Certifying Exam assessments. RESULTS: The findings indicate that having a principal faculty member with specialized expertise in pharmacology has improved the overall course satisfaction, knowledge, and competence of PA students and perceptions of the relevance and effectiveness of pharmacology instruction in their clinical practice. CONCLUSION: The results of this study support the value of using pharmacist faculty members in PA programs to enhance the quality of pharmacology instruction and ultimately contribute to the success of PA students in their professional careers.