Parkinson's Disease Associated with G2019S LRRK2 Mutations without Lewy Body Pathology.

BACKGROUND: The G2019S leucine-rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology. OBJECTIVE: Describe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies. METHOD: We present an 89-year-old man with a 10-year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease. RESULTS: Neuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau-immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging-related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found. CONCLUSION: This case illustrates that levodopa-responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies.

The Growth of Complex Syntax in School-Age African American Children Who Speak African American English.

PURPOSE: Syntax provides critical support for both academic success and linguistic growth, yet it has not been a focus of language research in school-age African American children. This study examines complex syntax performance of African American children in second through fifth grades. METHOD: The current study explores the syntactic performances of African American children (N = 513) in Grades 2-5 on the Test of Language Development-Intermediate who speak African American English. Multilevel modeling was used to evaluate the growth and associated changes between dialect density and syntax. Analyzed data were compared both to the normative sample and within the recruited sample. RESULTS: The results suggest that dialect density exerted its impact early but did not continue to influence syntactic growth over time. Additionally, it was not until dialect density was accounted for in growth models that African American children's syntactic growth resembled normative expectations of a standardized language instrument. CONCLUSION: The current study suggests that failure to consider cultural language differences obscures our understanding of African American students' linguistic competence on standardized language assessments.

SVPath: A Deep Learning Tool for Analysis of Stria Vascularis from Histology Slides.

INTRODUCTION: The stria vascularis (SV) may have a significant role in various otologic pathologies. Currently, researchers manually segment and analyze the stria vascularis to measure structural atrophy. Our group developed a tool, SVPath, that uses deep learning to extract and analyze the stria vascularis and its associated capillary bed from whole temporal bone histopathology slides (TBS). METHODS: This study used an internal dataset of 203 digitized hematoxylin and eosin-stained sections from a normal macaque ear and a separate external validation set of 10 sections from another normal macaque ear. SVPath employed deep learning methods YOLOv8 and nnUnet to detect and segment the SV features from TBS, respectively. The results from this process were analyzed with the SV Analysis Tool (SVAT) to measure SV capillaries and features related to SV morphology, including width, area, and cell count. Once the model was developed, both YOLOv8 and nnUnet were validated on external and internal datasets. RESULTS: YOLOv8 implementation achieved over 90% accuracy for cochlea and SV detection. nnUnet SV segmentation achieved a DICE score of 0.84-0.95; the capillary bed DICE score was 0.75-0.88. SVAT was applied to compare both the ears used in the study. There was no statistical difference in SV width, SV area, and average area of capillary between the two ears. There was a statistical difference between the two ears for the cell count per SV. CONCLUSION: The proposed method accurately and efficiently analyzes the SV from temporal histopathology bone slides, creating a platform for researchers to understand the function of the SV further.

Phase I Trial of SPECT-Guided Liver-Directed Radiotherapy for Patients with Low Functional Liver Volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose limiting toxicities (DLTs) were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All twelve patients had colorectal liver metastases and received prior hepatotoxic chemotherapy. Eight patients underwent prior liver resection. Median computed tomography (CT) anatomical non-tumor liver volume was 1,584 cc (range 764-2,699 cc). Median SPECT functional liver volume was 1,117 cc (range 570-1,928cc). Median non-target CT and SPECT liver volumes below the volumetric dose constraint were 997 cc (range 544-1,576 cc) and 684 cc (range 429-1,244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No DLTs were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

Active Direction: A new observational measure of African American parenting.

A new observational measure of a culturally salient, supportive African American parenting style, Active Direction, was developed. Ratings were compared to standard qualitative ratings and across two ethnic groups. Active Direction represents the provision of structure to interactions in the form of corrective direction with clear and concise feedback that is assessed for supportiveness rather than simple content or tone. The 7-point rating item was examined in observations of African American (n = 172) and Hispanic American (n = 196) mother-child interactions collected at age 2.5 years in families from low-income households. Ratings were compared and associations to previously reported ratings of the interactions were examined. Active Direction was often observed among the African American mothers (81%) but rarely observed among the Hispanic mothers (16%), with a large effect size difference, supporting the hypothesis that Active Direction may represent a culturally specific approach to parenting for African American parents. Maternal behavior correlations of Active Direction with cognitive stimulation, intrusiveness, scaffolding, and calm authority and with child affiliative obedience and dyadic routines and rituals were significantly higher and detachment significantly lower in the African American compared to the Hispanic sample. The new measure of Active Direction, centered around culturally salient values and differences in both historical and lived experiences, addresses characteristics of parenting in African American families that are supportive of their children's development and provides a fruitful direction for future research.

Drivers and implications of alternative routes to fuels decarbonization in net-zero energy systems.

Energy transition scenarios are characterized by increasing electrification and improving efficiency of energy end uses, rapid decarbonization of the electric power sector, and deployment of carbon dioxide removal (CDR) technologies to offset remaining emissions. Although hydrocarbon fuels typically decline in such scenarios, significant volumes remain in many scenarios even at the time of net-zero emissions. While scenarios rely on different approaches for decarbonizing remaining fuels, the underlying drivers for these differences are unclear. Here we develop several illustrative net-zero systems in a simple structural energy model and show that, for a given set of final energy demands, assumptions about the use of biomass and CO2 sequestration drive key differences in how emissions from remaining fuels are mitigated. Limiting one resource may increase reliance on another, implying that decisions about using or restricting resources in pursuit of net-zero objectives could have significant tradeoffs that will need to be evaluated and managed.

A Deep Learning Framework for Analysis of the Eustachian Tube and the Internal Carotid Artery.

OBJECTIVE: Obtaining automated, objective 3-dimensional (3D) models of the Eustachian tube (ET) and the internal carotid artery (ICA) from computed tomography (CT) scans could provide useful navigational and diagnostic information for ET pathologies and interventions. We aim to develop a deep learning (DL) pipeline to automatically segment the ET and ICA and use these segmentations to compute distances between these structures. STUDY DESIGN: Retrospective cohort. SETTING: Tertiary referral center. METHODS: From a database of 30 CT scans, 60 ET and ICA pairs were manually segmented and used to train an nnU-Net model, a DL segmentation framework. These segmentations were also used to develop a quantitative tool to capture the magnitude and location of the minimum distance point (MDP) between ET and ICA. Performance metrics for the nnU-Net automated segmentations were calculated via the average Hausdorff distance (AHD) and dice similarity coefficient (DSC). RESULTS: The AHD for the ET and ICA were 0.922 and 0.246 mm, respectively. Similarly, the DSC values for the ET and ICA were 0.578 and 0.884. The mean MDP from ET to ICA in the cartilaginous region was 2.6 mm (0.7-5.3 mm) and was located on average 1.9 mm caudal from the bony cartilaginous junction. CONCLUSION: This study describes the first end-to-end DL pipeline for automated ET and ICA segmentation and analyzes distances between these structures. In addition to helping to ensure the safe selection of patients for ET dilation, this method can facilitate large-scale studies exploring the relationship between ET pathologies and the 3D shape of the ET.

Putting theory to the test: An integrated computational/experimental chemostat model of the tragedy of the commons.

Cooperation via shared public goods is ubiquitous in nature, however, noncontributing social cheaters can exploit the public goods provided by cooperating individuals to gain a fitness advantage. Theory predicts that this dynamic can cause a Tragedy of the Commons, and in particular, a 'Collapsing' Tragedy defined as the extinction of the entire population if the public good is essential. However, there is little empirical evidence of the Collapsing Tragedy in evolutionary biology. Here, we experimentally demonstrate this outcome in a microbial model system, the public good-producing bacterium Pseudomonas aeruginosa grown in a continuous-culture chemostat. In a growth medium that requires extracellular protein digestion, we find that P. aeruginosa populations maintain a high density when entirely composed of cooperating, protease-producing cells but completely collapse when non-producing cheater cells are introduced. We formulate a mechanistic mathematical model that recapitulates experimental observations and suggests key parameters, such as the dilution rate and the cost of public good production, that define the stability of cooperative behavior. We combine model prediction with experimental validation to explain striking differences in the long-term cheater trajectories of replicate cocultures through mutational events that increase cheater fitness. Taken together, our integrated empirical and theoretical approach validates and parametrizes the Collapsing Tragedy in a microbial population, and provides a quantitative, mechanistic framework for generating testable predictions of social behavior.

Bench Press Range-of-Motion and Velocity-based Repetition Control: Effects on Ballistic Push-up Performance in Males.

The purpose of this study was to investigate whether the ballistic push-up (BPU) is responsive to post-activation performance enhancement (PAPE) after a bench press conditioning exercise using velocity-based repetition control. Additionally, we aimed to evaluate the effects of range of motion (ROM) conditions on subsequent BPU performance. In a randomized crossover design, 18 males performed two conditions (full ROM and self-selected partial ROM) of bench press at 80% of their 1RM until mean concentric velocity dropped 10%. Each participant performed two pre- and six post-test BPUs to assess the PAPE effect. Paired sample t-tests assessed bench press performance measures. Multiple two-way repeated measures ANOVAs assessed differences in flight time, impulse, and peak power for the pre- and post-test BPUs. No significant differences existed between ROM conditions for total repetitions, volume load, or peak velocity. Compared to partial ROM, full ROM showed greater displacement (0.42 ± 0.05 vs. 0.34 ± 0.05 m), work (331.99 ± 67.72 vs. 270.92 ± 61.42 J), and mean velocity (0.46 ± 0.09 vs. 0.44 ± 0.08 m/s). Neither bench press ROM condition enhanced the BPU and were detrimental in some cases. Several time points showed partial ROM (flight time: 2 min post, impulse: 12 min post, peak power: 12 min post) significantly greater than full ROM, possibly indicating less fatigue accumulation. The BPU may require a different stimulus or may not be practical for PAPE effects in college-aged males. Partial ROM can be an alternative that achieves similar peak velocities while requiring less overall work.

Race/Ethnicity and Social Determinants of Health and Their Impact on Receiving Appropriate Chemotherapy for Colon Cancer.

INTRODUCTION: Despite the heightened understanding and improved treatment for colorectal cancer in the United States, social determinants of health (SDH) play a significant role in the colorectal cancer outcomes. We sought to investigate the relationship between SDH and appropriate utilization of adjuvant chemotherapy in stage III colon cancer. METHODS: For this retrospective study, we utilized data from the National Cancer Data Base (NCDB). Descriptive statistics are reported, including means and 95% confidence intervals for continuous variables and frequency and proportions for categorical variables. Univariate hypothesis testing to identify categorical level factors associated with treatment used Wilcoxon rank sum or Kruskal-Wallis tests, with multivariate analyses performed using regression analysis. RESULTS: Significant differences were as follows: Metro-non-Hispanic White patients received treatment less frequently (69.7%) when compared to Metro-non-Hispanic Black patients (73.4%) (P < .001). Increasing age was a negative predictor of likelihood to receive with those over 65 years old having an 83% decrease in likelihood to receive chemotherapy when compared to those under 65 (P < .001). Medicaid patients were 47% less likely and Medicare patients were 40% less likely to receive chemotherapy when compared to those with private insurance (P < .001). Rural patients were statistically more likely to receive chemotherapy (OR 1.42, 1.32-2.52, P < .001) as were urban patients, (OR 1.26, 1.20-1.31, P < .001) when compared to patients residing in metro areas. CONCLUSION: Age, living in a Metro area, and government insurance status at diagnosis are negatively correlated with the likelihood of receiving chemotherapy. Race was not associated with differences in receiving chemotherapy.

Trade-offs in land-based carbon removal measures under 1.5 °C and 2 °C futures.

Land-based carbon removals, specifically afforestation/reforestation and bioenergy with carbon capture and storage (BECCS), vary widely in 1.5 °C and 2 °C scenarios generated by integrated assessment models. Because underlying drivers are difficult to assess, we use a well-known integrated assessment model, GCAM, to demonstrate that land-based carbon removals are sensitive to the strength and scope of land-based mitigation policies. We find that while cumulative afforestation/reforestation and BECCS deployment are inversely related, they are both typically part of cost-effective mitigation pathways, with forestry options deployed earlier. While the CO2 removal intensity (removal per unit land) of BECCS is typically higher than afforestation/reforestation over long time horizons, the BECCS removal intensity is sensitive to feedstock and technology choices whereas the afforestation/reforestation removal intensity is sensitive to land policy choices. Finally, we find a generally positive relationship between agricultural prices and removal effectiveness of land-based mitigation, suggesting that some trade-offs may be difficult to avoid.

Effects of a multispecies direct-fed microbial on gastrointestinal permeability during feed restriction in a growing heifer model.

The objectives were to evaluate the effects of a 4-strain direct-fed microbial (DFM) on gastrointestinal tract (GIT) permeability and inflammation during feed restriction (FR) in heifers. Holstein heifers (n = 32; mean ± standard deviation; 295 ± 25 kg body weight; 287 ± 17 d of age) were used in an experiment conducted in 2 replicates (16/replicate). Heifers were randomly assigned to 1 of 2 top-dressed dietary treatments: (1) control (CON; 10 g/d dried lactose; n = 16) or (2) DFM containing a commercial blend of Lactobacillus animalis, Propionibacterium freudenreichii, Bacillus licheniformis, and Bacillus subtilis at 11.8 × 109 cfu/d (PRO; 10 g/d 4-strain DFM; n = 16). The trial consisted of 2 experimental periods (P): P1 (14 d) served as baseline for P2 (5 d), when all heifers were restricted to 40% of their P1 dry matter intake (DMI). On P1 d 12 and P2 d 2 and 5, GIT permeability was evaluated using oral chromium (Cr)-EDTA. By design, FR decreased DMI (60%) and body weight (∼18 kg) in all heifers. Regardless of treatment, during FR, all heifers had decreased circulating glucose, ß-hydroxybutyrate, insulin, and l-lactate (4, 14, 45, and 19%, respectively), but increased nonesterified fatty acids, serum amyloid A, and haptoglobin (3.0-, 1.7-, and 5.0-fold, respectively). Circulating white blood cells, neutrophils, lymphocytes, and basophils decreased (4, 7, 5, and 6%, respectively), whereas eosinophils increased (41%) during P2 irrespective of dietary treatment. Circulating IFN-γ inducible protein-10 increased (23%) during FR compared with P1 regardless of treatment. Plasma Cr area under the curve increased in all heifers on d 2 and 5 (10 and 14%, respectively) of P2 relative to P1, but this was unaltered by dietary treatment. In summary, FR compromised GIT barrier function and stimulated an inflammatory response, but this did not appear to be ameliorated by PRO.

Race/Ethnicity and Social Determinants of Health and Their Impact on the Timely Receipt of Appropriate Operative Treatment of Colon Cancer.

INTRODUCTION: Rates of appropriate surgical treatment of colon cancer are historically worse in traditionally marginalized populations. We sought to examine which social determinants of health may be associated with longer time to appropriate operative intervention. METHODS: The National Cancer Databank was queried for this retrospective study. Adult patients (18 to 90 years of age) diagnosed between 2004 and 2018 with single or primary, stage III colon cancer were included. Patient demographic variables included age at diagnosis, sex, ethnicity (Hispanic or non-Hispanic), comorbidity score, median household income, education status, rural/urban status, treatment facility type and location, and insurance status. Disease characteristics include stage (stage 3), primary site, surgical margins, tumor size, and number of nodes resected. Reported descriptive statistics include means and 95% confidence intervals for continuous variables and frequency and proportions for categorical variables. Univariate and multivariate analyses were performed. RESULTS: A total of 134,601 individuals diagnosed with stage 3 colon cancer were included. Time to surgery in all cases had a mean of 26.4 ± 19.0 days. Multivariate analysis of time to surgery indicated that receiving surgery at a Community Cancer Program, Charlson-Deyo Score of 0, younger age, and non-Hispanic-White race/ethnicity are associated with decreased time to surgery (P < .001). CONCLUSION: Patients who receive surgery at a Community Cancer Program, have fewer comorbidities, have lower household income, are younger, and receive surgery within 50 miles of their primary residence are more likely to have timely surgery.

Alternative mRNA splicing events and regulators in epidermal differentiation.

Alternative splicing (AS) of messenger RNAs occurs in ∼95% of multi-exon human genes and generates diverse RNA and protein isoforms. We investigated AS events associated with human epidermal differentiation, a process crucial for skin function. We identified 6,413 AS events, primarily involving cassette exons. We also predicted 34 RNA-binding proteins (RBPs) regulating epidermal AS, including 19 previously undescribed candidate regulators. From these results, we identified FUS as an RBP that regulates the balance between keratinocyte proliferation and differentiation. Additionally, we characterized the function of a cassette exon AS event in MAP3K7, which encodes a kinase involved in cell signaling. We found that a switch from the short to long isoform of MAP3K7, triggered during differentiation, enforces the demarcation between proliferating basal progenitors and overlying differentiated strata. Our findings indicate that AS occurs extensively in the human epidermis and has critical roles in skin homeostasis.

Patterns of Signal Intensity in CISS MRI of the Inner Ear and Eye.

BACKGROUND: Constructive interference in steady state (CISS) is a gradient echo magnetic resonance imaging (MRI) pulse sequence that provides excellent contrast between cerebrospinal fluid and adjacent structures but is prone to banding artifacts due to magnetic field inhomogeneities. We aimed to characterize artifacts in the inner ear and eye. METHODS: In 30 patients (60 ears/eyes) undergoing CISS sequence MRI, nine low-signal intensity regions were identified in the inner ear and compared to temporal bone histopathology. The number and angle of bands across the eye were examined. RESULTS: In the cochlea, all ears had regions of low signal corresponding to anatomy (modiolus (all), spiral lamina (n = 59, 98.3%), and interscalar septa (n = 50, 83.3%)). In the labyrinth, the lateral semicircular canal crista (n = 42, 70%) and utricular macula (n = 47, 78.3%) were seen. Areas of low signal in the vestibule seen in all ears may represent the walls of the membranous utricle. Zero to three banding artifacts were seen in both eyes (right: 96.7%, mean 1.5; left: 93.3%, mean 1.3). CONCLUSION: Low signal regions in the inner ear on CISS sequences are common and have consistent patterns; most in the inner ear represent anatomy, appearing blurred due to partial volume averaging. Banding artifacts in the eye are more variable.

Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Background: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH) are common causes of hypercalcaemia. Patients are mostly asymptomatic in the case of FHH and often so in the case of PHPT. In addition, biochemical parameters show considerable overlap, making differential diagnosis difficult. Genetic screening for inactivating variants in the calcium-sensing receptor (CASR) gene that are causative of FHH assists with the diagnosis since such variants are not generally associated with PHPT. However, novel CASR variants must undergo functional assessment before they can be definitively assigned a causative role in FHH. Case Presentations. We describe a 73-year-old female (patient A) who presented with mild parathyroid hormone (PTH)-dependent hypercalcaemia and a history of osteoporosis. Family history revealed that her sister (patient B) had presented a decade earlier with symptoms of PHPT including a history of mild hypercalcaemia and multiple renal calculi, prompting parathyroid surgery. However, a subtotal parathyroidectomy did not resolve her hypercalcaemia long term. On this basis, genetic screening was performed on patient A. This identified a heterozygous variant in the CASR, NM_000388.4:c.T101C: p.Leu34Pro (L34P). Functional analysis showed that the L34P variant was unable to produce mature, dimerized receptor and did not respond to Ca++ ions. Adopting American College of Medical Genetics-based guidelines, the variant was classified as 'Pathogenic (II)'. Patient B was subsequently found to carry the L34P variant heterozygously, confirming a diagnosis of FHH, not PHPT. Conclusion: This study shows the importance of examining patient's family history in providing clues to the diagnosis in isolated cases of hypercalcaemia. In this case, history of a sister's unsuccessful parathyroidectomy prompted genetic screening in a patient who might otherwise have undergone inappropriate parathyroid surgery. Screening detected an inactivating CASR variant, firming up a diagnosis of FHH. These studies reaffirm the requirement for functionally assessing novel CASR variants prior to assigning causality to FHH.

Effects of Voice Pitch on Social Perceptions Vary With Relational Mobility and Homicide Rate.

Fundamental frequency ( fo) is the most perceptually salient vocal acoustic parameter, yet little is known about how its perceptual influence varies across societies. We examined how fo affects key social perceptions and how socioecological variables modulate these effects in 2,647 adult listeners sampled from 44 locations across 22 nations. Low male fo increased men's perceptions of formidability and prestige, especially in societies with higher homicide rates and greater relational mobility in which male intrasexual competition may be more intense and rapid identification of high-status competitors may be exigent. High female fo increased women's perceptions of flirtatiousness where relational mobility was lower and threats to mating relationships may be greater. These results indicate that the influence of fo on social perceptions depends on socioecological variables, including those related to competition for status and mates.