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Metacognition is an important skill required for improving students’ reading comprehension ability. Studies have reported effectiveness of metacognitive reading strategies to increase reading comprehension and information retention. However, there is limited research utilizing eye-tracking technology to explore the effectiveness of metacognitive reading strategies. This experimental study utilized eye-tracking technology on 40 undergraduate students to investigate the effectiveness of a metacognitive strategy on reading comprehension outcomes. The Survey, Question, Read, Respond, Recite, Record, and Review (SQ5R) strategy was used as the metacognitive reading strategy intervention. Participants’ eye movements were recorded during the reading process. Reading comprehension was assessed before and after watching the SQ5R intervention. This study revealed that participants adopted the SQ5R when reading scientific text, which enabled the students to better comprehend and retain more information. Results suggests that agricultural educators should incorporate the SQ5R metacognitive reading strategy into the design of agriscience reading materials to improve students’ reading skills and their ability to comprehensively understand complex and controversial issues in agriculture.

This research adds to the knowledge of extension education by revealing the quality of climate-smart agricultural (CSA) advice offered by private and public extension sectors. The study was aimed at addressing the paucity of empirical data that exists relating to the quality of CSA advice. Using a semi-structured questionnaire, the descriptive and correlational study gathered data from a systematic sample of 115 farmers. There was a moderate positive correlation between extension effectiveness and adoption of CSA. There were significant differences between public, private, and both sectors in relation to the quality of information disseminated. The quality of private sector’s advice was significantly lower than that of public sector and both sectors. There was no significant difference in quality of advice between public sector and both sectors. The quality of CSA advice was generally fair, however, heightened dissemination of CSA practices by both sectors of extension would yield better quality advice thus improve the adoption of the practices among farmers.

Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy (cryo-EM) studies showed that a C-terminal fragment (CTF) of TMEM106B (AA120-254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal aging brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical (IHC) analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and IHC in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications.

Purpose Inpatient diabetes management involves frequent assessment of glucose levels for treatment decisions. Here we describe a program for inpatient real-time continuous glucose monitoring (rtCGM) at a community hospital and the accuracy of rtCGM-based glucose estimates. Methods Adult inpatients with preexisting diabetes managed with intensive insulin therapy and a diagnosis of coronavirus disease 2019 (COVID-19) were monitored via rtCGM for safety. An rtCGM system transmitted glucose concentration and trending information at 5-minute intervals to nearby smartphones, which relayed the data to a centralized monitoring station. Hypoglycemia alerts were triggered by rtCGM values of ≤85 mg/dL, but rtCGM data were otherwise not used in management decisions; insulin dosing adjustments were based on blood glucose values measured via fingerstick blood sampling. Accuracy was evaluated retrospectively by comparing rtCGM values to contemporaneous point-of-care (POC) blood glucose values. Results A total of 238 pairs of rtCGM and POC data points from 10 patients showed an overall mean absolute relative difference (MARD) of 10.3%. Clarke error grid analysis showed 99.2% of points in the clinically acceptable range, and surveillance error grid analysis showed 89.1% of points in the lowest risk category. It was determined that for 25% of the rtCGM values, discordances in rtCGM and POC values would likely have resulted in different insulin doses. Insulin dose recommendations based on rtCGM values differed by 1 to 3 units from POC-based recommendations. Conclusion rtCGM for inpatient diabetes monitoring is feasible. Evaluation of individual rtCGM-POC paired values suggested that using rtCGM data for management decisions poses minimal risks to patients. Further studies to establish the safety and cost implications of using rtCGM data for inpatient diabetes management decisions are warranted.

Parkinson’s disease (PD) is a severe neurodegenerative disease characterized by classic motor features associated with the loss of dopaminergic neurons and appearance of Lewy bodies in the substantia nigra. Due to the complexity of PD, a definitive diagnosis in the early stages and effective management of symptoms in later stages are difficult to achieve in clinical practice. Previous research has shown that colocalization of A2A receptors (A2AR) and dopamine D2 receptors (D2R) may induce an antagonistic interaction between adenosine and dopamine. Clinical trials have found that the A2AR antagonist istradefylline decreases dyskinesia in PD and could be used as an adjuvant to levodopa treatment. Meanwhile, the incretin hormone glucagon-like peptide 1 (GLP1) mainly facilitates glucose homeostasis and insulin signaling. Preclinical experiments and clinical trials of GLP1 receptor (GLP1R) agonists show that they may be effective in alleviating neuroinflammation and sustaining cellular functions in the central nervous system of patients with PD. In this review, we summarize up-to-date findings on the usefulness of A2AR antagonists and GLP1R agonists in PD management. We explain the molecular mechanisms of these medications and their interactions with other neurotransmitter receptors. Furthermore, we discuss the efficacy and limitations of A2AR antagonists and GLP1R agonists in clinical practice.

Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population.

Reliance on point-of-care (POC) blood glucose measurements for inpatient diabetes management can result in long between-measurement intervals, which contribute to undetected and untreated dysglycemia. The G6 real-time continuous glucose monitoring (RT-CGM) system (Dexcom) allows for remote monitoring. In the hospital, this may reduce the need for close interactions and infectious disease transmission between patients and hospital staff. A man in his mid-60s was admitted to a non-intensive care unit in an acute care facility with a diagnosis of COVID-19. His preadmission type 2 diabetes was managed with twice-daily intermediate-acting insulin and prandial rapid-acting insulin; steroids and POC glucose testing (prandial and bedtime with a FreeStyle Precision Pro meter [Abbott]) were added to this regimen. A G6 was placed on the abdomen and was set to alert the staff to glucose values ≤85 mg/dL or predicted to be 100 mg/dL, respectively. Inpatient RT-CGM use can detect existing or impending hypoglycemia and assist in diabetes management. Disclosure M.Baker: Other Relationship; Dexcom, Inc. J.Welsh: Employee; Dexcom, Inc. Funding Dexcom, Inc.

The importance of assessing critical thinking has been emphasized extensively by numerous administrators and educators in higher education worldwide. In a contemporary agricultural sustainable development environment, agricultural students need to develop critical thinking to manage complex situations and to deal with controversial issues in international agriculture settings. From psychological points of view, thinking varies cross-culturally. In other words, people from different cultures think differently. With the increasing number of Chinese students studying in the U.S., educators need to be aware of the importance of supporting these Chinese students within the intercultural classroom environment. Thus, it is necessary to explore and understand the way Chinese students think to help them more easily adapt to a culturally diverse educational environment. The purpose of this study was to evaluate the validity and reliability of a Chinese version of the University of Florida Critical Thinking Inventory (UFCTI). The UFCTI measures critical thinking styles using two constructs: engagement and seeking information. Confirmatory Factor Analysis (CFA) was applied to examine the hypothesized measurement model based on the theoretical foundations of the original UFCTI (English version). The CFA findings indicated the UFCTI measurement model between the two versions is equivalent. Specifically, the results confirmed the two-factor measurement of critical thinking style: engagement and seeking information. The findings also indicated adequate validity and reliability for the UFCTI Chinese version

To examine the length of a hexanucleotide expansion in C9orf72, which represents the most frequent genetic cause of frontotemporal lobar degeneration and motor neuron disease, we employed a targeted amplification-free long-read sequencing technology: No-Amp sequencing. In our cross-sectional study, we assessed cerebellar tissue from 28 well-characterized C9orf72 expansion carriers. We obtained 3507 on-target circular consensus sequencing reads, of which 814 bridged the C9orf72 repeat expansion (23%). Importantly, we observed a significant correlation between expansion sizes obtained using No-Amp sequencing and Southern blotting (P = 5.0 × 10−4). Interestingly, we also detected a significant survival advantage for individuals with smaller expansions (P = 0.004). Additionally, we uncovered that smaller expansions were significantly associated with higher levels of C9orf72 transcripts containing intron 1b (P = 0.003), poly(GP) proteins (P = 1.3 × 10− 5), and poly(GA) proteins (P = 0.005). Thorough examination of the composition of the expansion revealed that its GC content was extremely high (median: 100%) and that it was mainly composed of GGGGCC repeats (median: 96%), suggesting that expanded C9orf72 repeats are quite pure. Taken together, our findings demonstrate that No-Amp sequencing is a powerful tool that enables the discovery of relevant clinicopathological associations, highlighting the important role played by the cerebellar size of the expanded repeat in C9orf72-linked diseases., DeJesus-Hernandez et al. employ an innovative long-read sequencing method to examine the length of the expanded C9orf72 repeat that represents the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. Smaller expansion size confers a survival benefit for patients.

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson’s disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P –5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.

Background Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment.

Purpose: Recent studies suggest a large percentage of post-surgical opioid prescriptions are not utilized. This surplus of opioids provides supply for diversion or entry into the waste cycle. Recommendations are available for general surgery procedures which may optimize prescribed quantity while maintaining patient satisfaction which this work was initiated to investigate. Methods: This retrospective patient survey was conducted with Institutional Review Committee approval following adjustments to discharge opioid prescription quantities in an individual General Surgeon practice. Patients were contacted via phone to assess the impact of the reduced opioid quantities. Patients were categorized based on whether they utilized the entire prescription or opioid remained. Data collected include baseline demographics, inpatient stay characteristics, opioid use patterns, and satisfaction with overall pain control. The primary endpoint was to determine if patients were satisfied with their pain control based on response. Secondary endpoints included if patient characteristics could be identified that signal larger opioid quantity use, and whether unused opioids were disposed. Results: Thirty patients utilized all opioid prescribed, 60 had some quantity remaining. Baseline data appear similar aside from age with younger patients using more opioid. Patients were satisfied with their overall pain control in 93% of respondents. A total of 960 opioid tablets (11.4 ± 4.8 tabs/patient) were not prescribed, 8% required refill. Opioid disposal yet to occur in 85% of patients. Conclusion: An evidence-based reduction in opioid discharge prescriptions following general surgery procedures resulted in nearly 1000 opioid tablets not being dispensed without having a negative impact on patient satisfaction.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

The complexities of food, agriculture, natural resources, and human sciences (FANH) programs and projects require faculty to write and secure funding in addition to mastering skills such as evaluation competencies that integrate abilities in quantitative and qualitative research methods and evaluation theory and practice. The EVAL Framework was developed to advance skill development among FANH graduates to include these competencies and increase the pipeline of students who have the essential skills needed to advance FANH initiatives and priorities. The EVAL Framework includes four primary constructs: (a) Evaluation, (b) Value, (c) Active and Experiential Learning, and (d) Leadership. The purpose of EVAL is to build relationships with untapped FANH fields to develop a pipeline for graduates to become evaluation leaders for advancing food and agricultural sciences. This experiential learning and development model focuses on foundational and enrichment experiences, through formal coursework, project-based learning, and contextually rich environments. Mentoring, individualized development plans, scholarly learning communities, collaboration, transferable skills, and career planning and guidance activities are integrated into the EVAL framework to enhance skill development among EVAL scholars.

Background The host-tumour interaction is fundamental to brain tumour biology, orchestration of which is mediated in part by cytokines. We reasoned that detection of a tumour-specific cytokine profile in patient serum could contribute to early diagnosis strategies, and permit prediction of tumour subtypes before histological diagnosis. METHOD Patient serum blood samples (300ul) were collected prospectively from patients with radiological evidence of a new brain tumour diagnosis pre-treatment, and from symptom-matched patients without radiological evidence of a tumour (controls). Our in-house cytokine assay incorporates antibodies captured onto a nitrocellulose slide. 64 capture antibodies are printed per slide, with 4 replicates per antibody. Fluorescence is measured from a biotin secondary antibody, the signal compared to a standard curve, and the averaged relative intensity across 4 replicates determined. We used a hierarchical clustering strategy to examine the relative expression of all 64 biomarkers for each patient class, and for cancer versus non-cancer. We refined this to identify the most discriminatory biomarkers. We made a univariate examination of the association of each antibody with brain tumour type. RESULTS Cytokine profiles were collected from 83 patients (42 glioblastoma, 8 meningioma, 12 metastatic cancer, 6 grade III gliomas, 3 grade II gliomas, 2 other brain tumours, 10 non-cancer patients). The top 4 biomarkers with greatest separation for brain cancer versus non-cancer were osteopontin, MMP3, MMP9 and TIMP-1. A principal component analysis demonstrated clear separation between clusters for these biomarkers. Univariate analysis evidenced discrimination of tumour subtypes, for example MMP9 and oligodendrogliomas. CONCLUSION Cytokine signals can be identified in small volumes of patient serum and used to identify brain cancer ‘risk.’ This could support prioritization for brain imaging, and prediction of tumour subtype to guide pre-operative management decision-making. Combination with other liquid biopsy strategies such as serum spectroscopy may improve spectroscopy test performance and utility.

The majority of the clinico-pathological variability observed in patients harboring a repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) remains unexplained. This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of C9orf72 expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases. To further elucidate the mechanisms underlying C9orf72-related diseases and to identify potential disease modifiers, we performed an extensive RNA sequencing study. We included individuals for whom frontal cortex tissue was available: FTLD and FTLD/MND patients with (n = 34) or without (n = 44) an expanded C9orf72 repeat as well as control subjects (n = 24). In total, 6706 genes were differentially expressed between these groups (false discovery rate [FDR] C9orf72 (FDR = 1.41E-14), which was roughly two-fold lower in C9orf72 expansion carriers than in (disease) controls. Co-expression analysis revealed groups of correlated genes (modules) that were enriched for processes such as protein folding, RNA splicing, synaptic signaling, metabolism, and Golgi vesicle transport. Within our cohort of C9orf72 expansion carriers, machine learning uncovered interesting candidates associated with clinico-pathological features, including age at onset (vascular endothelial growth factor A [VEGFA]), C9orf72 expansion size (cyclin dependent kinase like 1 [CDKL1]), DPR protein levels (eukaryotic elongation factor 2 kinase [EEF2K]), and survival after onset (small G protein signaling modulator 3 [SGSM3]). Given the fact that we detected a module involved in vesicular transport in addition to a GTPase activator (SGSM3) as a potential modifier, our findings seem to suggest that the presence of a C9orf72 repeat expansion might hamper vesicular transport and that genes affecting this process may modify the phenotype of C9orf72-linked diseases.

Objective To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72). Methods We performed quantitative neuropathologic comparison of 17 FTLD-C9ORF72 and 15 FTLD-GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD-GRN and 13 FTLD-C9ORF72). Neuropathological analyses were limited to TDP-43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD-GRN and 11 FTLD-C9ORF72). FTLD cases were also compared to age- and sex-matched normal controls. Immunohistochemistry was performed for pTDP-43, IBA-1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information. Results FTLD-GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD-C9ORF72 had greater hippocampal tau pathology and more TDP-43 neuronal cytoplasmic inclusions. FTLD-GRN had more neocortical microvacuolation, as well as more IBA-1-positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD-GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD-GRN and FTLD-C9ORF72 differed from controls. Interpretation Our findings underscore differences in microglial response in FTLD-C9ORF72 and FTLD-GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD-GRN and FTLD-C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

The transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein involved in RNA splicing. Abnormally deposited TDP-43 is found in the brains of patients with frontotemporal lobar degeneration (FTLD). Different morphological characteristics of TDP-43 immunoreactive inclusions define the different variants of FTLD-TDP. Little is known about the relationships between TDP-43 specie (phosphorylated TDP-43, C-terminal fragments and full length TDP-43) and lesion types. Using novel antibodies that recognize phosphorylated TDP-43 (pTDP-43), a neoepitope in the C-terminal fragment of TDP-43 (cTDP-43) and the N-terminal, i.e. full length (nTDP-43) we assess the relative burden of pTDP-43, cTDP-43 and nTDP-43 in 8 different lesion types across FTLD-TDP type A-C. These include neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions, fine neurites of the hippocampus, peri-vascular inclusions, Pick body-like inclusions, long thick dystrophic neurites and granular pre-inclusions. We also assess for associations with progranulin (GRN) and C9ORF72 genetic mutations. For all eight lesion types, the highest burden was observed for pTDP-43. In six of the eight lesions studied, cTDP-43 burden was greater than nTDP-43 burden. However, we observed a higher burden of nTDP-43 to cTDP-43 for pre-inclusions. We also noted an equal-to-slightly higher burden of nTDP-43 to cTDP-43 for peri-vascular inclusions. There was not strong evidence for associations to be driven by mutation status although for neuronal cytoplasmic inclusions and dystrophic neurites GRN+ cases had higher burden of pTDP-43, cTDP-43 and nTDP-43 compared to GRN- cases, with nTDP-43 inclusions only observed in GRN+ cases. In addition, for pre-inclusions, cTDP-43 and nTDP-43 burden tended to be higher in C9ORF72- cases compared to C9ORF72+ cases, although this was not the case for pTDP-43. There is clear evidence that phosphorylation and C terminal fragments play an important role in lesion formation in FTLD-TDP. However, for some inclusions, particularly pre-inclusions, full-length TDP-43 appears to be playing a role.

Mutations in the TANK binding kinase 1 gene (TBK1) are associated with amyotrophic lateral sclerosis and/or frontotemporal dementia; however, the range of clinical phenotypes and neuropathological changes associated with these mutations have not yet been completely elucidated. We present the detailed clinical, neuroimaging, and neuropathological features of two brothers carrying the TBK1 p.Gly272_Thr331del mutation. Both presented with very similar and unusual clinical features including primary progressive aphasia and asymmetric-onset primary lateral sclerosis (PLS). Repeated electrophysiological studies failed to reveal any lower motor neuron involvement. Neuropathological evaluation of both cases revealed frontotemporal lobar degeneration with TDP-43 proteinopathy type B and selective involvement of upper motor neurons with TDP-43 inclusions. The stereotypical clinical presentation and neuropathological findings in these cases widen the phenotypic spectrum of TBK1 mutations and provide insights into the pathogenesis of PLS.

Progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) has been reported as a rare clinical subtype, but the underlying pathology of its cerebellar ataxia remains unclear. Here, we report a patient with the coexistence of PSP with pontocerebellar atrophy and myotonic dystrophy type 1 (DM1). A 73-year-old man who was an asymptomatic carrier of DM1 (66 CTG repeats) started developing ataxic gait with multiple falls, visual blurring, double vision, and word finding difficulty at age 62 and was initially diagnosed with multiple system atrophy (MSA). Subsequently, the diagnosis was changed to PSP due to hypometric downward gaze, reduced blink frequency, symmetric bradykinesia, rigidity, and the absence of autonomic dysfunction. He eventually developed delayed grip opening with percussion myotonia at age 72. At autopsy, severe neuronal degeneration and astrogliosis in the pontocerebellar structures suggested MSA, but immunohistochemistry for α-synuclein did not reveal neuronal or glial cytoplasmic inclusions. Immunohistochemistry for phospho-tau and 4-repeat tau confirmed a neuropathological diagnosis of PSP with exceptionally numerous coiled bodies and threads in the pontine base and cerebellar white matter. This unusual distribution of 4-repeat tau pathology and neuronal degeneration with astrogliosis is a plausible clinicopathological substrate of PSP-C.

TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0–VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with “typical” TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP-43 immunoreactivity was adjacent to/associated with NFTs in the same neuron (TDP type-β). We compared pathological, genetic (APOE4, TMEM106B and GRN variants), neuroimaging and clinical data between types, as well as compared neuroimaging between types and a group of TDP-43 negative cases (n = 309). Two-hundred forty-one cases were classified as TDP type-α (n = 131, 54%) or TDP type-β (n = 110, 46%). Type-α cases were older than type-β at death (median 89 years vs. 87 years; p = 0.02). Hippocampal sclerosis was present in 78 (60%) type-α cases and 16 (15%) type-β cases (p

The purpose of the study was to determine the topics and courses of a graduate certificate focusing on Global Food Security (GFS) for Latin America and the Caribbean (LAC) through critical action inquiry. GFS is a major issue worldwide that will continue to expand in years to come. Almost 795 million people are estimated to have suffered from chronic hunger globally in 2014-2016. Studies have shown the strong relationship between education and food security and we do not argue for causation, merely association. For this reason, curricula focused on teaching GFS to graduate students will enable professionals in international settings to manage the complexities of food security more effectively. For this critical action inquiry study, identification of the content was the result of a three-round Delphi study performed with experts from LAC and its comparison with the result of the Texas Tech University (TTU) professors survey to determine the topics and courses. Of the 91-originally-idenified topics, 40 reached experts’ consensus. The topics were then grouped into 23 courses. Faculty from TTU also ranked the courses. In the end, seven courses emerged from the research. The curriculum was approved and directed toward professionals in Latin America and the Caribbean. The courses for the online and face-to-face delivery of this multidisciplinary graduate certificate comprise the four pillars of food security and cross-cutting topics.

This study adds to the knowledge base of Entrepreneurial Education (EE) in selected technical training institutes in Kenya. Using qualitative research inquiry, semi-structured interviews were conducted with a question guidebook and follow-up questioning. Data were collected from students, instructors, and administrators selected through purposive sampling. Open and axial coding was used to categorize the transcribed interview responses. Peer review was used to ensure credibility and confirmability. The results reveals that the learning institutions prepared students as entrepreneurs through coursework, mandatory field internships, internal projects, participation in agricultural and business fairs, and providing startup capital for cooperative shops. EE delivery faces numerous constraints including inadequate start-up capital, inadequate access to land, and output and input market resulting from poor infrastructure, competition, lack of marketing skills, and exam-oriented curricula. Dairy, horticulture, poultry, and apiculture enterprises were identified as the most promising and viable enterprises for graduates of middlelevel tertiary institutions. In conclusion, EE was being offered in these institutions as certificate courses or integrated as a topic in their existing curricula. In order to improve upon the delivery of the programs, the institutions needed to upgrade learning facilities, incorporating ICT in the curricula, enhance practical learning, conduct rigorous follow-up evaluations of graduates, and establish business incubators for providing start-up capital to graduates.

AIMS To assess the burden of transactive response DNA-binding protein of 43 kDa (TDP-43) inclusions in a unique cohort of old-age patients with genetic frontotemporal lobar degeneration (gFTLD-TDP) and compare these patients with sporadic old-age individuals with TDP-43, either in the presence of Alzheimer's disease (AD-TDP) or in isolation (pure-TDP). METHODS The brain bank at Mayo Clinic-Jacksonville was searched for cases ≥75 years old at death with TDP-43 extending into middle frontal cortex. Cases were split into the following groups: (1) gFTLD-TDP (n = 15) with progranulin (GRN)/C9ORF72 mutations; (2) AD-TDP (n = 10)-cases with median Braak neurofibrillary tangle (NFT) stage VI, Thal phase V; (3) pure-TDP (n = 10)-cases with median Braak NFT stage I, Thal phase I. Clinical data were abstracted; TDP-43 burden was calculated using digital pathology. RESULTS Amnestic Alzheimer's dementia was the clinical diagnosis in ≥50% patients in each group. The distribution of TDP-43 burden in gFTLD-TDP and AD-TDP, but not pure-TDP, was limbic-predominant targeting CA1 and subiculum. Patients with gFTLD-TDP had higher burden in entorhinal cortex compared to AD-TDP. TDP-43 burden in middle frontal cortex did not differ between the three groups. CONCLUSIONS In old age it is challenging to clinically and pathologically differentiate gFTLD-TDP from AD-TDP and pure-TDP-43 based on burden. Like AD-TDP, old age gFTLD-TDP have a limbic predominant TDP-43 distribution. The finding that amnestic Alzheimer's dementia was the most common clinical diagnosis regardless of group suggests that TDP-43 directly and indirectly targets limbic regions.

We report two cases from the frontotemporal lobar degeneration (FTLD) spectrum with a remarkably slow progression. The first case demonstrated insidious-onset behavioral symptoms and personality changes resembling behavioral variant of frontotemporal dementia, followed by a benign course of over 26 years, and his brain autopsy revealed the diffuse form of argyrophilic grain disease. The second case presented with slowly progressive cognitive and motor deficits, reminiscent of the corticobasal syndrome, deteriorated very slowly over 22 years and his brain autopsy revealed FTLD-TDP with C9ORF72 pathology. These two cases confirm the notion of slowly progressive frontotemporal lobar degeneration caused by an underlying FTLD pathology, rather than a phenocopy.

Genetic variants in TMEM106B are a major risk factor for several neurodegenerative diseases including frontotemporal degeneration, limbic-predominant age-related TDP-43 encephalopathy, Parkinson's disease, late-onset-Alzheimer's disease and constitute a genetic determinant of differential aging. TMEM106B encodes an integral lysosomal membrane protein but its precise physiological function in the central nervous system remains enigmatic. Presently, we aimed to increase understanding of TMEM106B contribution to general brain function and aging. We analyzed an aged cohort of Tmem106b knockout-, heterozygote and wild-type mice in a behavioral test battery including assessments of motor function as well as, social, emotional and cognitive function. Aged Tmem106b knockout (KO) mice displayed diverse behavioral deficits including motor impairment, gait defects and reduced startle reactivity. In contrast, no prominent deficits were observed in social, emotional or cognitive behaviors. Histologically, we observed late-onset loss of Purkinje cells followed by reactive gliosis in the cerebellum, which likely contributed to progressive decline in motor function and gait defects in particular. Reactive gliosis was not restricted to the cerebellum but observed in different areas of the brain including the brain stem and parts of the cerebral cortex. Surviving Purkinje cells showed vacuolated lysosomes in the axon initial segment, implicating TMEM106B-dependent lysosomal trafficking defects as the underlying cause of axonal and more general neuronal dysfunction contributing to behavioral impairments. Our experiments help to elucidate how TMEM106B affects spatial neuronal homeostasis and exemplifies a critical role of TMEM106B in neuronal cells for survival.

Introduction: Semantic dementia (SD) is characterized by fluent speech, anomia, and loss of word and object knowledge with varying degrees of right and left anterior-medial temporal lobe hypometabolism on [18F] fluorodeoxyglucose (FDG)-PET. We assessed neurobehavioral features in SD patients across 3 FDG-PET-defined metabolic patterns and investigated progression over time. Methods: Thirty-four patients with SD who completed FDG-PET were classified into a left- and right-dominant group based on the degree of hypometabolism in each temporal lobe. The left-dominant group was further subdivided depending on whether hypometabolism in the right temporal lobe was more or less than 2 standard deviations from controls (left+ group). Neurobehavioral characteristics determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) were compared across groups. Progression of NPI-Q scores and FDG-PET hypometabolism was assessed in 14 patients with longitudinal follow-up. Results: The right-dominant group performed worse on the NPI-Q and had a greater frequency of abnormal behaviors and more severe disinhibition compared to the left-dominant group. Performance on the NPI-Q and severity of disinhibition correlated with right medial and lateral, but not left, temporal lobe hypometabolism. Severity of abnormal behaviors worsened over time in most left-dominant and left+ patients but appeared to improve in the 2 right-dominant patients with longitudinal follow-up. All groups showed progressive worsening of metabolism in both temporal lobes over time, with hypometabolism spreading from anteromedial to posterior temporal regions. However, the degree of temporal lobe asymmetry remained relatively constant over time. Conclusion: In SD, neurobehavioral features, especially disinhibition, are associated with right medial and lateral temporal lobe hypometabolism and commonly develop over time even in patients that present with left-dominant patterns of hypometabolism.

Highlights • FDG-PET can detect cerebral glucose hypometabolism in presymptomatic C9orf72 carriers. • Metabolic changes are seen in cingulate gyrus, frontal and temporal cortices and thalami. • Glucose metabolic changes are detectable up to 10 years prior to symptom onset. • Glucose metabolic changes are detectable prior to changes in gray matter volume., Objective Our aim is to investigate patterns of brain glucose metabolism using fluorodeoxyglucose positron emission tomography (FDG-PET) in presymptomatic carriers of the C9orf72 repeat expansion to better understand the early preclinical stages of frontotemporal dementia (FTD). Methods Structural MRI and FDG-PET were performed on clinically asymptomatic members of families with FTD caused by the C9orf72 repeat expansion (15 presymptomatic mutation carriers, C9orf72+; 20 non-carriers, C9orf72-). Regional glucose metabolism in cerebral and cerebellar gray matter was compared between groups. Results The mean age of the C9orf72+ and C9orf72- groups were 45.3 ± 10.6 and 56.0 ± 11.0 years respectively, and the mean age of FTD onset in their families was 56 ± 7 years. Compared to non-carrier controls, the C9orf72+ group exhibited regional hypometabolism, primarily involving the cingulate gyrus, frontal and temporal neocortices (left > right) and bilateral thalami. Conclusions The C9orf72 repeat expansion is associated with changes in brain glucose metabolism that are demonstrable up to 10 years prior to symptom onset and before changes in gray matter volume become significant. These findings indicate that FDG-PET may be a particularly sensitive and useful method for investigating and monitoring the earliest stages of FTD in individuals with this underlying genetic basis.

Background: The etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach. Methods: FUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold. Results: We identified 73 significant gene–tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed. Conclusions: We identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Introduction: Up to 30% of patients with Guillain-Barre syndrome (GBS) develop respiratory failure requiring intensive care unit (ICU) admission and mechanical ventilation. Progressive weakness of the respiratory muscles is the leading cause of acute respiratory distress and respiratory failure with hypoxia and/or hypercarbia. Bulbar weakness may compromise airway patency and predispose patients to aspiration pneumonia. Areas covered: Clinical questions related to the use of mechanical ventilation include but are not limited to: When to start? Invasive or noninvasive? When to wean from mechanical ventilation? When to perform tracheostomy? How to manage complications of GBS in the ICU including nosocomial infection, ventilator-associated pneumonia, and ICU-acquired weakness? In this narrative review, the authors summarize the up-to-date knowledge of the incidence, pathophysiology, evaluation, and general management of respiratory failure in GBS. Expert opinion: Respiratory failure in GBS merits more attention from caregivers. Emergency intubation may lead to life-threatening complications. Appropriate methods and time point of intubation and weaning, an early tracheostomy, and predictive prophylaxis of complications benefit patients' long-term prognosis.

Objective The objective of this study was to describe clinical features, [18 F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB). Methods This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD). Results All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE e4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD. Interpretation Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe. ANN NEUROL 2021;89:520-533.