Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Delineation of genes for a major QTL governing heat stress tolerance in chickpea.

Chickpea (Cicer arietinum) is a cool season grain legume experiencing severe yield loss during heat stress due to the intensifying climate changes and its associated gradual increase of mean temperature. Hence, understanding the genetic architecture regulating heat stress tolerance has emerged as an important trait to be addressed for enhancing yield and productivity of chickpea under heat stress. The present study is intended to identify the major genomic region(s) governing heat stress tolerance in chickpea. For this, an integrated genomics-assisted breeding strategy involving NGS-based high-resolution QTL-seq assay, QTL region-specific association analysis and molecular haplotyping was deployed in a population of 206 mapping individuals and a diversity panel of 217 germplasm accessions of chickpea. This combinatorial strategy delineated a major 156.8 kb QTL genomic region, which was subsequently narrowed-down to a functional candidate gene CaHSFA5 and its natural alleles associated strongly with heat stress tolerance in chickpea. Superior natural alleles and haplotypes delineated from the CaHSFA5 gene have functional significance in regulating heat stress tolerance in chickpea. Histochemical staining, interaction studies along with differential expression profiling of CaHSFA5 and ROS scavenging genes suggest a cross talk between CaHSFA5 with ROS homeostasis pertaining to heat stress tolerance in chickpea. Heterologous gene expression followed by heat stress screening further validated the functional significance of CaHSFA5 for heat stress tolerance. The salient outcomes obtained here can have potential to accelerate multiple translational genomic analysis including marker-assisted breeding and gene editing in order to develop high-yielding heat stress tolerant chickpea varieties.

Cytological, transcriptome and miRNome temporal landscapes decode enhancement of rice grain size.

BACKGROUND: Rice grain size (GS) is an essential agronomic trait. Though several genes and miRNA modules influencing GS are known and seed development transcriptomes analyzed, a comprehensive compendium connecting all possible players is lacking. This study utilizes two contrasting GS indica rice genotypes (small-grained SN and large-grained LGR). Rice seed development involves five stages (S1-S5). Comparative transcriptome and miRNome atlases, substantiated with morphological and cytological studies, from S1-S5 stages and flag leaf have been analyzed to identify GS proponents. RESULTS: Histology shows prolonged endosperm development and cell enlargement in LGR. Stand-alone and comparative RNAseq analyses manifest S3 (5-10 days after pollination) stage as crucial for GS enhancement, coherently with cell cycle, endoreduplication, and programmed cell death participating genes. Seed storage protein and carbohydrate accumulation, cytologically and by RNAseq, is shown to be delayed in LGR. Fourteen transcription factor families influence GS. Pathway genes for four phytohormones display opposite patterns of higher expression. A total of 186 genes generated from the transcriptome analyses are located within GS trait-related QTLs deciphered by a cross between SN and LGR. Fourteen miRNA families express specifically in SN or LGR seeds. Eight miRNA-target modules display contrasting expressions amongst SN and LGR, while 26 (SN) and 43 (LGR) modules are differentially expressed in all stages. CONCLUSIONS: Integration of all analyses concludes in a "Domino effect" model for GS regulation highlighting chronology and fruition of each event. This study delineates the essence of GS regulation, providing scope for future exploits. The rice grain development database (RGDD) ( www.nipgr.ac.in/RGDD/index.php ; https://doi.org/10.5281/zenodo.7762870 ) has been developed for easy access of data generated in this paper.

A Novel Trial of Mirabegron and Behavioral Modification Including Pelvic Floor Exercise for Overactive Bladder in Parkinson's Disease (MAESTRO).

Overactive bladder (OAB) is experienced by more than half of patients with untreated Parkinson's disease. Treatment of overactive bladder in these patients has included antimuscarinic anticholinergics, raising concerns about the possibility of exacerbating cognitive impairment or constipation. Mirabegron (Myrbetriq), a ß3-receptor agonist, provides relief of OAB without increasing cognitive impairment. While prior studies have examined the effect of mirabegron on OAB in a variety of patient populations, this study is the first controlled, prospective study investigating the effect of mirabegron on overactive bladder in patients with Parkinson's disease. By studying effective treatments for overactive bladder, this trial emphasizes the importance of antimicrobial stewardship so that lower urinary tract symptoms are not treated as lower urinary tract infections with antimicrobials and instead overactive bladder can be treated appropriately with medication. The MAESTRO study compared the effect of adding mirabegron to behavioral modification (including pelvic floor exercises) to behavior modification alone. Results from this novel study show that both the mean absolute change in the volume of micturition (objective measure) and the mean percent change increased significantly between visits two and three in the experimental group using mirabegron. Moreover, improvements in micturition in this study indicate that a larger-scale study of mirabegron with pelvic floor exercises and behavior modification is warranted.

OnabotulinumtoxinA Dosing, Disease Severity, and Treatment Benefit in Patients With Cervical Dystonia: A Cohort Analysis From CD PROBE.

Introduction: The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE) study (ClinicalTrials.gov identifier: NCT00836017), a multicenter, prospective, observational registry, was designed to identify real-world practices and outcomes for patients with cervical dystonia (CD) treated with onabotulinumtoxinA (onabotA). This secondary analysis from CD PROBE aims to determine the impact of presentation subtype on onabotA utilization and CD severity. Materials and Methods: The study cohort includes those who completed all 3 treatments, 4 office visits, and had data recorded for all assessments. Patient outcomes were assessed with the Cervical Dystonia Impact Profile (CDIP-58), Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and determination of CD severity. Treatment interval, dose, and adverse events (AEs) were also recorded. Data were stratified according to prior exposure to botulinum toxins (BoNTs) and analyzed with descriptive statistics. Results: Torticollis was the most common presentation subtype in the study cohort (N = 350); the proportion of patients with torticollis was highest in those with severe disease. At each treatment, between 40.7 and 65.2% of those categorized as severe shifted to moderate or mild severity after treatment. Sustained improvements in CDIP-58 and TWSTRS were observed regardless of prior exposure to BoNTs. Dosing of onabotA generally increased from injection 1 to injection 3 and tended to be lower for patients naïve to BoNT. Median time interval between injections for the study cohort was 94.0 to 97.5 days. The most common AEs (dysphagia, muscular weakness) and injection intervals were similar between naïve vs. non-naïve patients; there were no serious treatment-related AEs. Conclusions: This secondary cohort analysis from CD PROBE demonstrates that three repeat treatments with onabotA at intervals consistent with labeling attenuated disease severity and neck pain, resulting in sustained improvements in physician- and patient-reported outcomes. No new safety signals were identified.

OsCPK29 interacts with MADS68 to regulate pollen development in rice.

Pollen development and its germination are obligatory for the reproductive success of flowering plants. Calcium-dependent protein kinases (CPKs, also known as CDPKs) regulate diverse signaling pathways controlling plant growth and development. Here, we report the functional characterization of a novel OsCPK29 from rice, which is mainly expressed during pollen maturation stages of the anther. OsCPK29 exclusively localizes in the nucleus, and its N-terminal variable domain is responsible for retaining it in the nucleus. OsCPK29 knockdown rice plants exhibit reduced fertility, set fewer seeds, and produce collapsed non-viable pollen grains that do not germinate. Cytological analysis of anther semi-thin sections during different developmental stages suggested that pollen abnormalities appear after the vacuolated pollen stage. Detailed microscopic study of pollen grains further revealed that they were lacking the functional intine layer although exine layer was present. Consistent with that, downregulation of known intine development-related rice genes was also observed in OsCPK29 silenced anthers. Furthermore, it has been demonstrated that OsCPK29 interacts in vitro as well as in vivo with the MADS68 transcription factor which is a known regulator of pollen development. Therefore, phenotypic observations and molecular studies suggest that OsCPK29 is an important regulator of pollen development in rice.

Delirium as a Presenting Symptom of COVID-19.

BACKGROUND: Delirium is a common neurologic manifestation of coronavirus disease 2019 (COVID-19) in older adults who present to the emergency department (ED). OBJECTIVE: To investigate clinical characteristics associated with delirium as a presenting symptom of COVID-19 in older adults and develop a logistic regression to predict the likelihood of delirium. METHOD: We compared clinical characteristics in an age- and gender-matched sample of 68 delirious individuals with 68 nondelirious individuals (Mage = 78) who presented to the ED with COVID-19. RESULTS: The delirious group was more likely to have neurologic, psychiatric, and cardiovascular comorbidities; a prior history of delirium; and deliriogenic medications in their medication list. They were less likely to present with respiratory symptoms and more likely to present with sepsis, hypoxia, higher heart rate, and higher sodium. The delirious group had higher mortality (51%) than the nondelirious group (32%). Delirium developed within an average of 2 days of initial COVID-19 symptom onset, with symptom onset to ED within an average of 4 days and symptom onset to death within an average of 11 days. Logistic regression based on five delirium predictors correctly predicted 80% of those with delirium (75% sensitivity at 86% specificity). CONCLUSION: Our results are largely consistent with prior studies and suggest that delirium is a common, early occurring, and lethal manifestation of COVID-19 in older adults presenting to the ED, in most cases causing acute on chronic neurocognitive dysfunction strongly influenced by inflammatory and hypoxic-ischemic mechanisms.

BID-Net: An Automated System for Bone Invasion Detection Occurring at Stage T4 in Oral Squamous Carcinoma Using Deep Learning.

Detection of the presence and absence of bone invasion by the tumor in oral squamous cell carcinoma (OSCC) patients is very significant for their treatment planning and surgical resection. For bone invasion detection, CT scan imaging is the preferred choice of radiologists because of its high sensitivity and specificity. In the present work, deep learning algorithm based model, BID-Net, has been proposed for the automation of bone invasion detection. BID-Net performs the binary classification of CT scan images as the images with bone invasion and images without bone invasion. The proposed BID-Net model has achieved an outstanding accuracy of 93.62%. The model is also compared with six Transfer Learning models like VGG16, VGG19, ResNet-50, MobileNetV2, DenseNet-121, ResNet-101 and BID-Net outperformed over the other models. As there exists no previous studies on bone invasion detection using Deep Learning models, so the results of the proposed model have been validated from the experts of practitioner radiologists, S.M.S. hospital, Jaipur, India.

Altered mental status in 71 deaths due to COVID-19.

OBJECTIVE: The purpose of this study was to investigate the occurrence of neurologic symptoms with a focus on altered mental status in a sample of deaths due to COVID-19. METHODS: We reviewed neurologic symptoms in 71 deaths due to COVID-19 at the first US hospital with reported cases, of which 66 (93%) had medical comorbidities, 47 (66%) came from assisted living facilities or nursing homes and 35 (49%) had baseline dementia. RESULTS: Sixty-one patients (86%) demonstrated neurologic symptoms at hospital admission. Altered mental status was seen in 47 patients (66%) and represented the most common neurologic symptom. Seven patients (10%) were comatose at hospital admission and 5 (7%) presented with altered mental status without respiratory symptoms. Three patients had seizures and two had strokes. Hypertension (61%), cardiovascular disease (59%), and dementia (49%) were the most common comorbidities associated with death due to COVID-19 in our sample. CONCLUSIONS: Neurologic symptoms, particularly altered mental status, are very common in COVID-19 patients with high risk of mortality. In a small subset of patients, altered mental status is the defining feature of disease presentation. A mental status examination should be incorporated in the medical assessment of COVID-19.

Vision, challenges and opportunities for a Plant Cell Atlas.

With growing populations and pressing environmental problems, future economies will be increasingly plant-based. Now is the time to reimagine plant science as a critical component of fundamental science, agriculture, environmental stewardship, energy, technology and healthcare. This effort requires a conceptual and technological framework to identify and map all cell types, and to comprehensively annotate the localization and organization of molecules at cellular and tissue levels. This framework, called the Plant Cell Atlas (PCA), will be critical for understanding and engineering plant development, physiology and environmental responses. A workshop was convened to discuss the purpose and utility of such an initiative, resulting in a roadmap that acknowledges the current knowledge gaps and technical challenges, and underscores how the PCA initiative can help to overcome them.

Predictors of survival in older adults hospitalized with COVID-19.

OBJECTIVE: This study was designed to investigate clinical characteristics associated with mortality and predictors of survival in older adults hospitalized with COVID-19 with a focus on neurological comorbidities and presenting neurological manifestations. METHODS: We compared clinical characteristics in an age- and gender-matched sample of 75 deceased and 75 recovered patients (MAge = 78) hospitalized with COVID-19 and developed a logistic regression to predict likelihood of survival. RESULTS: Deceased patients were more like to have dementia, altered mental status (AMS), acute respiratory distress syndrome (ARDS), sepsis, mechanical ventilation, and balance difficulties; higher heart rate, respiratory rate, blood urea nitrogen, creatinine, and absolute neutrophils; lower oxygen saturation and absolute lymphocytes; and shorter length of hospitalization. Logistic regression based on three mortality predictors (ARDS, AMS, and length of hospitalization) correctly predicted 87% of the outcome (89% sensitivity at 85% specificity). CONCLUSIONS: Dementia and AMS were strong predictors of death in older adults hospitalized with COVID-19. Our findings add to the rapidly growing neurology of COVID-19 literature and underscore the importance of early recognition and the incorporation of a mental status examination into the medical assessment of COVID-19.

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

BACKGROUND AND PURPOSE: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread. METHODS: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping. RESULTS: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread. CONCLUSIONS: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

A Multi-center Genome-wide Association Study of Cervical Dystonia.

BACKGROUND: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

Uptake of telehealth in Parkinson's disease clinical care and research during the COVID-19 pandemic.

INTRODUCTION: Traditionally, medical care and research in Parkinson's disease (PD) have been conducted with in-person encounters. The recent COVID-19 pandemic has profoundly impacted the delivery of in-person clinical care and clinical research. We conducted an online survey of active clinician members of the Parkinson Study Group (PSG) to evaluate the adoption of various non-face-to-face methods in clinical practice and research in PD during the COVID-19 pandemic. METHODS: We conducted a survey using the open-access online SurveyMonkey tool (http://www.surveymonkey.com). The survey had 27 items and was designed to elucidate clinical/research care before and during the COVID-19 pandemic. The survey was sent to 414 active PSG members with weekly reminders and it remained accessible for 30 days from May 2020. RESULTS: We received 142 responses, of which 133 (93.7%) provided demographic data. The clinical use of virtual visits via synchronous video conferencing increased from 39.5% pre-COVID-19 to 94.6% during the COVID-19 pandemic. Lack of access for patients (68.2%) and patient resistance (51.4%) were the top barriers for its use. Approximately 70% respondents stated that 75-100% of their research activities were suspended during the COVID-19 pandemic. Many sites had to fill out protocol deviations (38.2%), protocol exceptions (25.5%) or change their research profile due to layoffs (16.8%). The overall use of video conferencing increased from 30.3% to 64.1%. CONCLUSION: The current results suggest a need for flexibility in conducting office visits and clinical trials in PD patients. Technology has the potential to enhance patient care and convenience, when in-person visits can be challenging.

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

OBJECTIVE: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia. METHODS: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition. RESULTS: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics. CONCLUSION: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.

SUPER STARCHY1/ONAC025 participates in rice grain filling.

NAC transcription factors (TFs) are known for their role in development and stress. This article attempts to functionally validate the role of rice SS1/ ONAC025 (LOC_Os11g31330) during seed development. The gene is seed-specific and its promoter directs reporter expression in the developing endosperm and embryo in rice transgenic plants. Furthermore, rice transgenic plants ectopically expressing SS1/ ONAC025 have a plantlet lethal phenotype with hampered vegetative growth, but increased tillers and an altered shoot apical meristem structure. The vegetative cells of these plantlets are filled with distinct starch granules. RNAseq analysis of two independent plantlets reveals the differential expression of reproductive and photosynthetic genes. A comparison with seed development transcriptome indicates differential regulation of many seed-related genes by SS1/ ONAC025. Genes involved in starch biosynthesis, especially amylopectin and those encoding seed storage proteins, and regulating seed size are also differentially expressed. In conjunction, SS1/ ONAC025 shows highest expression in japonica rice. As a TF, SS1/ ONAC025 is a transcriptional repressor localized to endoplasmic reticulum and nucleus. The article shows that SS1/ ONAC025 is a seed-specific gene promoting grain filling in rice, and negatively affecting vegetative growth.