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Abstract Individual variability exists in parkinsonian motor symptoms despite a similar degree of nigrostriatal dopamine depletion in Parkinson’s disease (PD), called motor reserve. We enrolled 397 patients newly diagnosed with PD who underwent dual-phase 18F-FP-CIT PET upon initial assessment. Individual motor reserve was estimated based on initial parkinsonian motor symptoms and striatal dopamine transporter availability using a residual model. Patients with low motor reserve (the lowest quartile group, n = 100) exhibited decreased uptake in the occipital region compared to those with high motor reserve (the highest quartile group, n = 100) on early-phase 18F-FP-CIT PET images. Patients with high motor reserve had a lower risk of conversion to dementia than the those with low motor reserve, whereas the effect of PD groups on the risk of dementia conversion was not mediated by occipital hypoperfusion. These findings suggest that cerebral hypoperfusion in the occipital region is associated with low motor reserve in patients with PD.

Abstract Pancreatic cancer has a five-year survival rate of only 10%, mostly due to late diagnosis and limited treatment options. In patients with unresectable disease, either FOLFIRINOX, a combination of 5-fluorouracil (5-FU), oxaliplatin and irinotecan, or gemcitabine plus nab-paclitaxel combined with radiation are frontline standard regimens. However, chemo-radiation therapy has shown limited success because patients develop resistance to chemotherapy and/or radiation. In this study, we evaluated the role of pancreatic cancer stem cells (CSC) using OCT4 and SOX2, CSC markers in mouse pancreatic tumor organoids. We treated pancreatic tumor organoids with 4 or 8 Gy of radiation, 10 μM of 5-FU (5-Fluorouracil), and 100 μM 3-Bromopyruvate (3BP), a promising anti-cancer drug, as a single treatment modalities, and in combination with RT. Our results showed significant upregulation of, OCT4, and SOX2 expression in pancreatic tumor organoids treated with 4 and 8 Gy of radiation, and downregulation following 5-FU treatment. The expression of CSC markers with increasing treatment dose exhibited elevated upregulation levels to radiation and downregulation to 5-FU chemotherapy drug. Conversely, when tumor organoids were treated with a combination of 5-FU and radiation, there was a significant inhibition in SOX2 and OCT4 expression, indicating CSC self-renewal inhibition. Noticeably, we also observed that human pancreatic tumor tissues exhibited heterogeneous and aberrant OCT4 and SOX2 expression as compared to normal pancreas, indicating their potential role in pancreatic cancer growth and therapy resistance. In addition, the combination of 5-FU and radiation treatment exhibited significant inhibition of the β-catenin pathway in pancreatic tumor organoids, resulting in sensitization to treatment and organoid death. In conclusion, our study emphasizes the crucial role of CSCs in therapeutic resistance in PC treatment. We recommend using tumor organoids as a model system to explore the impact of CSCs in PC and identify new therapeutic targets.

Abstract We conducted an experimental investigation to examine the immiscible radial displacement flows of air invading three-dimensional foam in a Hele-Shaw cell. Our study successfully identified three distinct flow regimes. In the initial regime, characterized by relatively low fingertip velocities, the foam underwent a slow displacement through plug flow. During this process, the three-phase contact lines slipped at the cell walls. Notably, we discovered that the air injection pressure exhibited a proportional relationship with the power of the fingertip velocity. This relationship demonstrated excellent agreement with a power law, where the exponent was determined to be 2/3. Transitioning to the second regime, we observed relatively high velocities, resulting in the displacement of the foam as a plug within single layers of foam bubbles. The movement of these bubbles near the cell walls was notably slower. Similar to the first regime, the behavior in this regime also adhered to a power law. In the third regime, which manifested at higher air injection pressures, the development of air fingers occurred through narrow channels. These channels had the potential to isolate the air fingers as they underwent a process of "healing." Furthermore, our results unveiled a significant finding that the width of the air fingers exhibited a continuous scaling with the air injection pressure, irrespective of the flow regimes being observed.

Abstract Patients with dementia with Lewy bodies (DLB) show widespread brain metabolic changes. This study investigated whether brain hypo- and hypermetabolism in DLB have differential effects on cognition. We enrolled 55 patients with DLB (15 prodromal DLB [MCI-LB] and 40 probable DLB) and 13 healthy controls who underwent 18F-fluorodeoxyglucose positron emission tomography and detailed neuropsychological tests. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism were calculated as follows: index(-) for hypometabolism [DLB-hypo] and index(+) for hypermetabolism [DLB-hyper]. The effects of DLB-hypo or DLB-hyper on cognitive function were assessed using a multivariate linear regression model. Additionally, a linear mixed model was used to investigate the association between each index and the longitudinal cognitive decline. There was no correlation between DLB-hypo and DLB-hyper in the disease group. The multivariate linear regression model showed that DLB-hypo was associated with language, visuospatial, visual memory, and frontal/executive functions; whereas DLB-hyper was responsible for attention and verbal memory. There was significant interaction between DLB-hypo and DLB-hyper for verbal and visual memory, which was substantially affected by DLB-hyper in relatively preserved DLB-hypo status. A linear mixed model showed that DLB-hypo was associated with longitudinal cognitive outcomes, regardless of cognitive status, and DLB-hyper contributed to cognitive decline only in the MCI-LB group. The present study suggests that DLB-hypo and DLB-hyper may be independent of each other and differentially affect the baseline and longitudinal cognitive function in patients with DLB.

Abstract Background Cholesterol is an essential component of the neuronal cell membrane and is crucial for neuronal function; however, the role of cholesterol levels in Parkinson’s disease (PD) is debatable. This study investigated the complex relationship between total cholesterol (TC) levels, body mass index (BMI), and cognition in patients with PD. Methods This study included 321 drug-naïve patients with PD who underwent dopamine transporter (DAT) imaging and baseline neuropsychological tests. Multivariate linear regression and Cox regression models were used to investigate the effect of TC levels on the composite score of each cognitive domain and dementia conversion after adjusting for covariates, respectively. Interaction analyses were performed to examine the interaction effect between TC levels and BMI on baseline cognition and dementia conversion. Results TC levels and cognition showed no significant relationship after adjusting for potential confounders. A significant interaction effect between TC levels and BMI was observed in frontal/executive function and dementia conversion. Further analyses showed that TC levels were positively associated with frontal/executive function in the under-/normal weight group (β = 0.205, p = 0.013), whereas a negative relationship existed between TC levels and frontal/executive function in the obese group (β = − 0.213, p = 0.017). Cox regression analyses also showed the differential effects of TC levels on dementia conversion according to BMI (under-/normal weight group: hazard ratio [HR] = 0.550, p = 0.013; obese group: HR = 2.085, p = 0.014). Conclusions This study suggests a cross-over interaction between TC levels and BMI on cognitive symptoms in PD.

Abstract Fine needle aspiration (FNA) biopsy of thyroid nodules is a safe, cost-effective, and accurate diagnostic method for detecting thyroid cancer. However, about 10% of initial FNA biopsy samples from patients are non-diagnostic and require repeated FNA, which delays the diagnosis and appropriate care. On-site evaluation of the FNA sample can be performed to filter out non-diagnostic FNA samples. Unfortunately, it involves a time-consuming staining process, and a cytopathologist has to be present at the time of FNA. To bypass the staining process and expert interpretation of FNA specimens at the clinics, we developed a deep learning-based ensemble model termed FNA-Net that allows in situ screening of adequacy of unstained thyroid FNA samples smeared on a glass slide which can decrease the non-diagnostic rate in thyroid FNA. FNA-Net combines two deep learning models, a patch-based whole slide image classifier and Faster R-CNN, to detect follicular clusters with high precision. Then, FNA-Net classifies sample slides to be non-diagnostic if the total number of detected follicular clusters is less than a predetermined threshold. With bootstrapped sampling, FNA-Net achieved a 0.81 F1 score and 0.84 AUC in the precision-recall curve for detecting the non-diagnostic slides whose follicular clusters are less than six. We expect that FNA-Net can dramatically reduce the diagnostic cost associated with FNA biopsy and improve the quality of patient care.

IntroductionQuantitative, multiplexed imaging is revealing complex spatial relationships between phenotypically diverse tumor infiltrating leukocyte populations and their prognostic implications. The underlying mechanisms and tissue structures that determine leukocyte distribution within and around tumor nests, however, remain poorly understood. While presumed players in metastatic dissemination, new preclinical data demonstrates that blood and lymphatic vessels (lymphovasculature) also dictate leukocyte trafficking within tumor microenvironments and thereby impact anti-tumor immunity. Here we interrogate these relationships in primary human cutaneous melanoma. MethodsWe established a quantitative, multiplexed imaging platform to simultaneously detect immune infiltrates and tumor-associated vessels in formalin-fixed paraffin embedded patient samples. We performed a discovery, retrospective analysis of 28 treatment-naïve, primary cutaneous melanomas. ResultsHere we find that the lymphvasculature and immune infiltrate is heterogenous across patients in treatment naïve, primary melanoma. We categorized five lymphovascular subtypes that differ by functionality and morphology and mapped their localization in and around primary tumors. Interestingly, the localization of specific vessel subtypes, but not overall vessel density, significantly associated with the presence of lymphoid aggregates, regional progression, and intratumoral T cell infiltrates. DiscussionWe describe a quantitative platform to enable simultaneous lymphovascular and immune infiltrate analysis and map their spatial relationships in primary melanoma. Our data indicate that tumor-associated vessels exist in different states and that their localization may determine potential for metastasis or immune infiltration. This platform will support future efforts to map tumor-associated lymphovascular evolution across stage, assess its prognostic value, and stratify patients for adjuvant therapy.

Altered glycolytic metabolism has been associated with chemoresistance in acute myeloid leukemia (AML). However, there are still aspects that need clarification, as well as how to explore these metabolic alterations in therapy. In the present study, we aimed to elucidate the role of glucose metabolism in the acquired resistance of AML cells to cytarabine (Ara-C) and to explore it as a therapeutic target. Resistance was induced by stepwise exposure of AML cells to increasing concentrations of Ara-C. Ara-C-resistant cells were characterized for their growth capacity, genetic alterations, metabolic profile, and sensitivity to different metabolic inhibitors. Ara-C-resistant AML cell lines, KG-1 Ara-R, and MOLM13 Ara-R presented different metabolic profiles. KG-1 Ara-R cells exhibited a more pronounced glycolytic phenotype than parental cells, with a weaker acute response to 3-bromopyruvate (3-BP) but higher sensitivity after 48 h. KG-1 Ara-R cells also display increased respiration rates and are more sensitive to phenformin than parental cells. On the other hand, MOLM13 Ara-R cells display a glucose metabolism profile similar to parental cells, as well as sensitivity to glycolytic inhibitors. These results indicate that acquired resistance to Ara-C in AML may involve metabolic adaptations, which can be explored therapeutically in the AML patient setting who developed resistance to therapy.

Abstract Motor reserve (MR) may explain why individuals with similar pathological changes show marked differences in motor deficits in Parkinson’s disease (PD). In this study, we investigated whether estimated individual MR was linked to local striatal volume (LSV) in PD. We analyzed data obtained from 333 patients with drug naïve PD who underwent dopamine transporter scans and high-resolution 3-tesla T1-weighted structural magnetic resonance images. Using a residual model, we estimated individual MRs on the basis of initial UPDRS-III score and striatal dopamine depletion. We performed a correlation analysis between MR estimates and LSV. Furthermore, we assessed the effect of LSV, which is correlated with MR estimates, on the longitudinal increase in the levodopa-equivalent dose (LED) during the 4-year follow-up period using a linear mixed model. After controlling for intracranial volume, there was a significant positive correlation between LSV and MR estimates in the bilateral caudate, anterior putamen, and ventro-posterior putamen. The linear mixed model showed that the large local volume of anterior and ventro-posterior putamen was associated with the low requirement of LED initially and accelerated LED increment thereafter. The present study demonstrated that LSV is crucial to MR in early-stage PD, suggesting LSV as a neural correlate of MR in PD.

Abstract We evaluated the patterns of quantitative electroencephalography (EEG) in patients with Alzheimer’s disease (AD), Lewy body disease (LBD), and mixed disease. Sixteen patients with AD, 38 with LBD, 20 with mixed disease, and 17 control participants were recruited and underwent EEG. The theta/alpha ratio and theta/beta ratio were measured. The relationship of the log-transformed theta/alpha ratio (TAR) and theta/beta ratio (TBR) with the disease group, the presence of AD and LBD, and clinical symptoms were evaluated. Participants in the LBD and mixed disease groups had higher TBR in all lobes except for occipital lobe than those in the control group. The presence of LBD was independently associated with higher TBR in all lobes and higher central and parietal TAR, while the presence of AD was not. Among cognitively impaired patients, higher TAR was associated with the language, memory, and visuospatial dysfunction, while higher TBR was associated with the memory and frontal/executive dysfunction. Increased TBR in all lobar regions and temporal TAR were associated with the hallucinations, while cognitive fluctuations and the severity of Parkinsonism were not. Increased TBR could be a biomarker for LBD, independent of AD, while the presence of mixed disease could be reflected as increased TAR.

Pelvic pain and vaginal bleeding are common symptoms in postpartum women presenting to the emergency room (ER). Pelvic ultrasonography plays a crucial role in evaluating symptomatic postpartum patients by allowing a rapid diagnosis and treatment initiation. The main goal of imaging is to distinguish between causes of pelvic pain and vaginal bleeding that may be managed conservatively and those requiring emergent intervention. This pictural essay focuses on the ultrasonographic features of common postpartum conditions for which patients may present to the ER with vaginal bleeding and pelvic pain, including retained products of conception, endometritis, uterine arteriovenous malformation, uterine artery pseudoaneurysm, ovarian vein thrombosis, bladder flap hematoma, and uterine dehiscence/rupture.

Objective To investigate whether there is a link between cognitive function and motor reserve (i.e., individual capacity to cope with nigrostriatal dopamine depletion) in patients with newly diagnosed Parkinson’s disease (PD). Methods A total of 163 patients with drug-naïve PD who underwent 18F-FP-CIT PET, brain MRI, and a detailed neuropsychological test were enrolled. We estimated individual motor reserve based on initial motor deficits and striatal dopamine depletion using a residual model. We performed correlation analyses between motor reserve estimates and cognitive composite scores. Diffusion connectometry analysis was performed to map the white matter fiber tracts, of which fractional anisotropy (FA) values were well correlated with motor reserve estimates. Additionally, Cox regression analysis was used to assess the effect of initial motor reserve on the risk of dementia conversion. Results The motor reserve estimate was positively correlated with the composite score of the verbal memory function domain (γ = 0.246) and with the years of education (γ = 0.251). Connectometry analysis showed that FA values in the left fornix were positively correlated with the motor reserve estimate, while no fiber tracts were negatively correlated with the motor reserve estimate. Cox regression analysis demonstrated that higher motor reserve estimates tended to be associated with a lower risk of dementia conversion (hazard ratio, 0.781; 95% confidence interval, 0.576–1.058). Conclusion The present study demonstrated that the motor reserve estimate was well correlated with verbal memory function and with white matter integrity in the left fornix, suggesting a possible link between cognition and motor reserve in patients with PD.

IntroductionConcomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies.MethodsWe enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status.ResultsThere was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone.DiscussionThis study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

Abstract Levodopa-induced dyskinesia (LID), a long-term motor complication in Parkinson’s disease (PD), is attributable to both presynaptic and postsynaptic mechanisms. However, no studies have evaluated the baseline structural changes associated with LID at a subcortical level in PD. A total of 116 right-handed PD patients were recruited and based on the LID latency of 5 years, we classified patients into those vulnerable to LID (PD-vLID, n = 49) and those resistant to LID (PD-rLID, n = 67). After adjusting for covariates including dopamine transporter (DAT) availability of the posterior putamen, we compared the subcortical shape between the groups and investigated its association with the onset of LID. The PD-vLID group had lower DAT availability in the posterior putamen, higher parkinsonian motor deficits, and faster increment in levodopa equivalent dose than the PD-rLID group. The PD-vLID group had significant inward deformation in the right thalamus compared to the PD-rLID group. Inward deformation in the thalamus was associated with an earlier onset of LID at baseline. This study suggests that independent of presynaptic dopamine depletion, the thalamus is a major neural substrate for LID and that a contracted thalamic shape at baseline is closely associated with an early development of LID.

Ultrasonography is often the initial modality used to evaluate patients found to have abnormal liver function tests (LFTs) in the emergency department. While an assessment for biliary ductal dilatation and obstruction remains one of the main questions to answer, radiologists should also be aware of the ultrasonographic appearance of other conditions that can cause abnormal LFTs. This may be crucial for the management and disposition of patients in the emergency department. This article reviews the ultrasonographic features of diseases that may cause abnormal LFTs.

Objectives: To evaluate the detection rate of clinically significant prostate cancer (csPCa) in Magnetic resonance imaging and ultrasonography (MRI/US) fusion biopsy in patients with biopsy-naïve men for varying prostate-specific antigen (PSA) levels. Since MRI can efficiently detect csPCa compared to standard transrectal ultrasound (TRUS) guided biopsy; however, the optimal PSA threshold for its use is unclear. Materials and methods: We retrospectively reviewed those who underwent MRI/US-fusion and standard biopsy from January 2016 to June 2018. Patients were divided into three groups: PSA 10 ng/mL. Propensity scoring was performed to balance the characteristics of the different biopsy groups, and the detection rate of csPCa was compared. Results: Data from a total of 670 males were included in the analysis (standard TRUS, n = 333; MRI/US fusion, n = 337). Prior to matching, patients who received MRI/US-fusion biopsy had lower prostate volume. Propensity score matching balanced this characteristic and generated a cohort comprising 195 patients from each group. In the matched cohort, patients with PSA 4–10 ng/mL had a significantly increased risk of csPCa by MRI/US-fusion vs. standard biopsy (35.0% vs. 26.6%, P = 0.033). However, patients with PSA 10 ng/mL had csPCa found by MRI/US-fusion versus standard biopsy (78.0% vs. 80.0%, P = 0.596). In multivariate logistic analysis among patients with PSA 4-10 ng/mL, MRI/US-fusion biopsy (odds ratio: 2.46, 95% confidence interval = 1.31–4.60, P = 0.005) were significantly associated with a detection of csPCa. Conclusions: Detection of csPCa by MRI/US-fusion biopsy is more efficient in patients with biopsy-naïve men with PSA 4–10 ng/mL. However, standard TRUS biopsy may identify csPCa in patients with PSA

The interaction between regulatory T (Treg) cells and self-reactive T cells is a crucial mechanism for maintaining immune tolerance. In this study, we investigated the cross-activation of Treg cells by self-antigens and its impact on self-reactive CD8+ T cell responses, with a focus on the P53 signaling pathway. We discovered that major histocompatibility complex (MHC) I-restricted self-peptides not only activated CD8+ T cells but also induced the delayed proliferation of Treg cells. Following HLA-A*0201-restricted Melan-A-specific (pMelan) CD8+ T cells, we observed the direct expansion of Treg cells and concurrent suppression of pMelan+CD8+ T cell proliferation upon stimulation with Melan-A peptide. Transcriptome analysis revealed no significant alterations in specific signaling pathways in pMelan+CD8+ T cells that were co-cultured with activated Treg cells. However, there was a noticeable upregulation of genes involved in P53 accumulation, a critical regulator of cell survival and apoptosis. Consistent with such observation, the blockade of P53 induced a continuous proliferation of pMelan+CD8+ T cells. The concurrent stimulation of Treg cells through self-reactive TCRs by self-antigens provides insights into the immune system’s ability to control activated self-reactive CD8+ T cells as part of peripheral tolerance, highlighting the intricate interplay between Treg cells and CD8+ T cells and implicating therapeutic interventions in autoimmune diseases and cancer immunotherapy.

Parkinson’s disease (PD) and osteoporosis are degenerative diseases that have shared pathomechanisms. To investigate the associations of skull bone density with nigrostriatal dopaminergic degeneration and longitudinal motor prognosis in female patients with PD. We analyzed the data of 260 drug-naïve female PD patients aged ≥50 years old who were followed-up for ≥3 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging. We measured skull bone density as a surrogate marker for systemic bone loss by calculating the Hounsfield unit (HU) in computed tomography scans. A Cox proportional hazard model was built to compare the rates of levodopa-induced dyskinesia (LID) or wearing-off according to skull HU. Longitudinal changes in levodopa-equivalent dose (LED) during a 3-year follow-up were assessed using a linear mixed model. A lower skull HU was associated with lower baseline DAT availability in striatal subregions; however, this relationship was not significant after adjusting for age, disease duration, body mass index, and white matter hyperintensities. After adjusting for confounding factors, a lower skull HU was significantly associated with an increased risk of LID development (hazard ratio = 1.660 per 1 standard deviation decrease, p = 0.007) and wearing-off (hazard ratio = 1.613, p = 0.016) in younger (

Abstract To evaluate the implication of 18F-fluorodeoxyglucose (FDG)- and dopamine transporter (DAT)-positron emission tomography (PET) in the diagnosis and clinical symptoms of dementia with Lewy bodies (DLB), 55 DLB patients and 49 controls underwent neuropsychological evaluation and FDG-, DAT-, and 18F-Florbetaben (FBB) PET. DAT- and FDG-uptake and FDG/DAT ratio were measured in the anterior and posterior striatum. The first principal component (PC1) of FDG subject residual profiles was identified for each subject. Receiver operating characteristic curve analyses for the diagnosis of DLB were performed using FDG- and DAT-PET biomarkers as predictors, and general linear models for motor severity and cognitive scores were performed adding FBB standardized uptake value ratio as a predictor. Increased metabolism in the bilateral putamen, vermis, and somato-motor cortices, which characterized PC1, was observed in the DLB group, compared to the control group. A combination of posterior putamen FDG/DAT ratio and PC1 showed the highest diagnostic accuracy (91.8% sensitivity and 96.4% specificity), which was significantly greater than that obtained by DAT uptake alone. Striatal DAT uptake and PC1 independently contributed to motor severity and language, memory, frontal/executive, and general cognitive dysfunction in DLB patients, while only PC1 contributed to attention and visuospatial dysfunction.

Abstract Background Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data. Results Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice (TYRP1, GPNMB, LYST, DCT, and MITF). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP, and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls (p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects. Conclusions We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.

Abstract We investigated the efficacy of donepezil for mild cognitive impairment in Parkinson’s disease (PD-MCI). This was a prospective, non-randomized, open-label, two-arm study. Eighty PD-MCI patients were assigned to either a treatment or control group. The treatment group received donepezil for 48 weeks. The primary outcome measures were the Korean version of Mini-Mental State Exam and Montreal Cognitive Assessment scores. Secondary outcome measures were the Clinical Dementia Rating, Unified Parkinson’s Disease Rating Scale part III, Clinical Global Impression scores. Progression of dementia was assessed at 48-week. Comprehensive neuropsychological tests and electroencephalography (EEG) were performed at baseline and after 48 weeks. The spectral power ratio of the theta to beta2 band (TB2R) in the electroencephalogram was analyzed. There was no significant difference in the primary and secondary outcome measures between the two groups. However, the treatment group showed a significant decrease in TB2R at bilateral frontotemporoparietal channels compared to the control group. Although we could not demonstrate improvements in the cognitive functions, donepezil treatment had a modulatory effect on the EEG in PD-MCI patients. EEG might be a sensitive biomarker for detecting changes in PD-MCI after donepezil treatment.

An 8-bit switched-capacitor multiply-and-accumulator (MAC) in 65nm CMOS is presented. Based on a cascaded low-power ring-amplifier-based switched-capacitor DACs, the MAC circuit features a programmable accumulation length in MAC computation. Fabricated in 65nm CMOS, the prototype MAC circuit achieves a precision-scaled energy efficiency of 1.32fJ per MAC operation, which is comparable to other state-of-the-art MAC circuits, along with best-in-class linearity. The noise performance has been verified using four real-world convolutional neural networks (CNNs) and 10,000-image data sets with up to 1,000 classes with an accuracy drop of less than 2% compared to the baseline 32-bit floating-point MAC.

Abstract Background Nanophthalmos has a significant genetic background and disease-causing mutations have been recently been reported in the myelin regulatory factor (MYRF) gene. We report clinical features in a patient with nanophthalmos and a Thr518Met MYRF mutation. Case presentation A three-year-old male was discovered to have nanophthalmos after first presenting to the emergency department for a frontal headache, eye pain, emesis, and lethargy. Imaging studies (CT and MRI) were negative except for increased posterior fossa cerebrospinal fluid. Subsequent examinations revealed nanophthalmos (short axial eye lengths 18.1 mm OD and 18.3 mm OS), microcornea, and a large crystalline lens. Peripheral chorioretinal pigment abnormalities were also observed. He experienced episodes of marked ocular hypertension (53 mmHg OD and 60 mmHg) likely due to intermittent angle closure precipitated by nanophthalmos. The ocular hypertension was responsive to topical medicines. Genetic analysis of known nanophthalmos genes MFRP and TMEM98 were negative, while a novel mutation, Thr518Met was detected in MYRF. The Thr518Met mutation was absent from 362 matched normal controls and was extremely rare in a large population database, allele frequency of 0.000024. The Thr518Met mutation altered a highly conserved amino acid in the MYRF protein and three of four algorithms suggested that this mutation is likely pathogenic. Finally, molecular modeling showed that the Thr518Met mutation is damaging to MYRF structure. Together these data suggest that the Thr518Met mutation causes nanophthalmos. Conclusions Nanophthalmos may present at an early age with features of angle closure glaucoma and a Thr518Met mutation in MYRF was detected in a patient with nanophthalmos. Prevalence data, homology data, mutation analysis data, and protein modeling data suggest that this variant is pathogenic and may expand the phenotypic range of syndromic nanophthalmos caused by MYRF mutations to include central nervous system abnormalities (increased posterior fossa cerebrospinal fluid).

The concept of cognitive reserve (CR) in Alzheimer’s disease (AD) explains the differences between individuals in their susceptibility to AD-related pathologies. An enhanced CR may lead to less cognitive deficits despite severe pathological lesions. Parkinson’s disease (PD) is also a common neurodegenerative disease and is mainly characterized by motor dysfunction related to striatal dopaminergic depletion. The degree of motor deficits in PD is closely correlated to the degree of dopamine depletion; however, significant individual variations still exist. Therefore, we hypothesized that the presence of motor reserve (MR) in PD explains the individual differences in motor deficits despite similar levels of striatal dopamine depletion. Since 2015, we have performed a series of studies investigating MR in de novo patients with PD using the data of initial clinical presentation and dopamine transporter PET scan. In this review, we summarized the results of these published studies. In particular, some premorbid experiences (i.e., physical activity and education) and modifiable factors (i.e., body mass index and white matter hyperintensity on brain image studies) could modulate an individual’s capacity to tolerate PD pathology, which can be maintained throughout disease progression.

Abstract Objective We aimed to investigate the association of the serum urate level with cortical thickness and white matter integrity in multiple system atrophy (MSA). Methods We recruited 75 MSA patients and 42 controls who underwent brain MRI and measured serum urate level at baseline. Using cortical thickness and tract‐based spatial statistics analyses, we investigated the correlation between serum urate levels and cortical thickness or diffusion tensor imaging (DTI) measures in controls and MSA patients. Interaction effects were analyzed to find different patterns of correlation according to sex and clinical subtype. We evaluated the relationship between serum urate levels, DTI measures, and total UMSARS score, using path analysis. Results Serum urate levels showed a positive correlation with FA values in the corpus callosum and a negative correlation with MD values in widespread regions including cerebellar, brainstem, and cerebral white matter in patients with MSA. Both sexes showed a negative correlation between serum urate levels and MD values without significant interaction effect. In subgroup analysis according to subtype, patients with cerebellar subtype showed a negative correlation. Serum urate levels did not correlated with cortical thickness. Path analysis showed that MD values in middle and inferior cerebellar peduncle mediated the association between serum urate level and total UMSAR score. Interpretation The present study demonstrated that serum urate levels played a pivotal role in white matter disintegrity and clinical disability in MSA. It would provide an evidence of the role of urate as a potential neuroprotective factor against white matter neurodegeneration in MSA.

Antibody applications in cancer immunotherapy involve diverse strategies, some of which redirect T cell-mediated immunity via engineered antibodies. Affinity is a trait that is crucial for these strategies, as optimal affinity reduces unwanted side effects while retaining therapeutic function. Antibody-antigen pairs possessing a broad affinity range are required to define optimal affinity and to investigate the affinity-associated functional profiles of T cell-engaging strategies such as bispecific antibodies and chimeric antigen receptor-engineered T cells. Here, we demonstrate the unique binding characteristic of the developed antibody clone MVR, which exhibits robust binding to B-lymphoid cell lines. Intriguingly, MVR specifically recognizes the highly polymorphic human leukocyte antigen (HLA)-DR complex and exhibits varying affinities that are dependent upon the HLA-DRB1 allele type. Remarkably, MVR binds to the conformational epitope that consists of two hypervariable regions. As an application of MVR, we demonstrate an MVR-engineered chimeric antigen receptor (CAR) that elicits affinity-dependent function in response to a panel of target cell lines that express different HLA-DRB1 alleles. This tool evaluates the effect of affinity on cytotoxic killing, polyfunctionality, and activation-induced cell death of CAR-engineered T cells. Collectively, MVR exhibits huge potential for the evaluation of the affinity-associated profile of T cells that are redirected by engineered antibodies.

Objective To investigate whether baseline olfactory dysfunction in Parkinson’s disease (PD) patients is associated with baseline and longitudinal motor and cognitive function. Methods We recruited 228 drug-naïve PD patients who were followed for a mean of 6 years. Patients underwent the Cross-Cultural Smell Identification Test (CCSIT), a neuropsychological test, and N-(3-[18F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane positron emission tomography within 6 months of the baseline evaluation. Olfactory dysfunction was categorized as normosmia (CCSIT score ≥ 9), hyposmia (CCSIT score 5–8), and anosmia (CCSIT score ≤ 4). During the follow-up period, we investigated changes in the levodopa-equivalent dose (LED) and the occurrence of wearing-off, levodopa-induced dyskinesia, and dementia. Results Among the PD patients, 80.7% were hyposmic at the time of diagnosis, and 26.1% were anosmic. Baseline olfactory dysfunction was not associated with either initial parkinsonian motor symptoms or with the longitudinal LED increment and motor complications. Meanwhile, the anosmic group had lower baseline scores on the Korea version of the Boston Naming Test and Stroop color reading test than the normosmic and hyposmic groups. The anosmic group exhibited a higher rate of conversion to dementia than the normosmic [adjusted hazard ratio (HR) 3.99, 95% confidence interval (CI) 1.08–14.72] and hyposmic (adjusted HR 2.48, 95% CI 1.15–5.32) PD groups, regardless of baseline motor deficits and cognitive status. Conclusion Baseline olfactory dysfunction was not associated with motor deficits and complications, but it was associated with cognitive dysfunction and prognosis, suggesting that severe olfactory impairment may reflect early cortical involvement, probably in the frontotemporal region, and rapid spreading of Lewy body pathology.

In patients presenting for an evaluation of pregnancy in the first trimester, transvaginal ultrasound is the modality of choice for establishing the presence of an intrauterine pregnancy; evaluating pregnancy viability, gestational age, and multiplicity; detecting pregnancy-related complications; and diagnosing ectopic pregnancy. In this pictorial review article, the sonographic appearance of a normal intrauterine gestation and the most common complications of pregnancy in the first trimester in the acute setting are discussed.

Abstract Objective To investigate whether the burden of white matter hyperintensities (WMHs) is associated with the risk of developing levodopa‐induced dyskinesia (LID) in Parkinson’s disease (PD). Methods According to the Clinical Research Center for Dementia of South Korea WMH visual rating scale, 336 patients with drug‐naïve early stage PD (follow‐up >3 years) were divided into two groups of PD with minimal WMHs (PD‐WMH–; n = 227) and moderate‐to‐severe WMHs (PD‐WMH+; n = 109). The Cox regression model was used to estimate the hazard ratio for the development of LID in the PD‐WMH + group compared with the PD‐WMH– group, while adjusting for age at PD onset, sex, striatal dopamine depletion, and PD medication dose. Additionally, we assessed the effects of WMH burden rated by the Scheltens scale and regional WMH distribution on the development of LID. Results Patients in the PD‐WMH + group were older and had more severe parkinsonian motor signs despite comparable striatal dopamine transporter availability than those in the PD‐WMH– group. Patients in the PD‐WMH + group had a higher risk of developing LID (hazard ratio, 2.66; P

It is difficult to determine the pathoanatomical correlates of dystonia because of its complex pathophysiology, and most cases with secondary dystonia are associated with basal ganglia lesions. Moreover, it is a challenging issue that patients with abnormal postures accompanied by other neurological findings in the affected body part (e.g., sensory loss) can be diagnosed with true dystonia or pseudodystonia. Here, we report a case of abnormal postures with loss of proprioception in the left extremities after right dorsal pontine hemorrhage.

In order to estimate the crack depth in concrete using time-of-flight, finite element analysis and experiments were performed on non-cracked concrete blocks and 45 mm and 70 mm vertical cracks. As a result of measuring the time-of-flight change by changing the positions of the transmitter and receiver, it was confirmed that the finite element analysis results agreed with the experimental results, and high accuracy was confirmed by various formulas for calculating the depth of defects using the obtained experimental measurements for comparison. In addition to the verification of the simulation and experimental theory, research was conducted through actual field cases, and methodologies for crack detection and depth evaluation for concrete structures were presented, and furthermore, the expected effects of improving the soundness and safety of structures were shown.

Abstract Objective The precise pathogenesis or neural correlates underlying levodopa‐induced dyskinesia (LID) remains poorly understood. There is growing evidence of the involvement of the cerebellum in Parkinson's disease (PD). The present study evaluated the role of motor cerebellar connectivity in determining vulnerability to LID. Methods We enrolled 25 de novo patients with PD who developed LID within 5 years of levodopa treatment, 26 propensity score‐matched PD patients who had not developed LID, and 24 age‐ and sex‐matched healthy controls. We performed a comparative analysis of resting‐state functional connectivity (FC) between the motor cerebellum and whole brain between the groups. Results The patients with PD had increased FC bewteen the motor cerebellum and posterior cortical and cerebellar regions, while no gray matter regions had decreased FC with the motor cerebellum compared to the control participant. The patients with PD who were vulnerable to the development of LID had a significantly higher FC between the motor cerebellum lobule VIIIb and the left inferior frontal gyrus than those who were resistant to LID development. The connectivity of the motor cerebellum and left inferior frontal gyrus was negatively correlated with the latency from PD onset to the occurrence of LID. Interpretation Increased FC between the motor cerebellum and left inferior frontal gyrus in de novo patients with PD could be an important determinant of vulnerability to LID.

Objective Ample evidence has suggested that age at onset of Parkinson’s disease (PD) is associated with heterogeneous clinical features in individuals. We hypothesized that this may be attributed to different patterns of nigrostriatal dopamine loss. Methods A total of 205 consecutive patients with de novo PD who underwent 18F-FP-CIT PET scans (mean follow-up duration, 6.31 years) were divided into three tertile groups according to their age at onset of parkinsonian motor symptoms. Striatal dopamine transporter (DAT) availability was compared between the old- (n = 73) and young-onset (n = 66) groups. In addition, the risk of developing freezing of gait (FOG) and longitudinal requirements for dopaminergic medications were examined. Results The old-onset PD group (mean age at onset, 72.66 years) exhibited more severe parkinsonian motor signs than the young-onset group (52.58 years), despite comparable DAT availability in the posterior putamen; moreover, the old-onset group exhibited more severely decreased DAT availability in the caudate than the young-onset group. A Cox regression model revealed that the old-onset PD group had a higher risk for developing FOG than the young-onset group [hazard ratio 2.523, 95% confidence interval (1.239–5.140)]. The old-onset group required higher doses of dopaminergic medications for symptom control than the young-onset group over time. Conclusion The present study demonstrated that the old-onset PD group exhibited more severe dopamine loss in the caudate and were more likely to develop gait freezing, suggesting that age at onset may be one of the major determinants of the pattern of striatal dopamine depletion and progression of gait disturbance in PD.

Abstract Objective We evaluated disruption of the white matter (WM) network related with Alzheimer's disease (AD) and Lewy body disease (LBD), which includes Parkinson's disease and dementia with Lewy bodies. Methods We consecutively recruited 37 controls and 77 patients with AD‐related cognitive impairment (ADCI) and/or LBD‐related cognitive impairment (LBCI). Diagnoses of ADCI and LBCI were supported by amyloid PET and dopamine transporter PET, respectively. There were 22 patients with ADCI, 19 patients with LBCI, and 36 patients with mixed ADCI/LBCI. We investigated the relationship between ADCI, LBCI, graph theory‐based network measures on diffusion tensor images, and cognitive dysfunction using general linear models after controlling for age, sex, education, deep WM hyperintensities (WMH), periventricular WMH, and intracranial volume. Results LBCI, especially mixed with ADCI, was associated with increased normalized path length and decreased normalized global efficiency. LBCI was related to the decreased nodal degree of left caudate, which was further associated with broad cognitive dysfunction. Decreased left caudate nodal degree was associated with decreased fractional anisotropy (FA) in the brain regions vulnerable to LBD. Compared with the control group, the LBCI group had an increased betweenness centrality in the occipital nodes, which was associated with decreased FA in the WM adjacent to the striatum and visuospatial dysfunction. Conclusion Concomitant ADCI and LBCI are associated with the accentuation of LBCI‐related WM network disruption centered in the left caudate nucleus. The increase of occipital betweenness centrality could be a characteristic biologic change associated with visuospatial dysfunction in LBCI.

Background. This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods. This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0×105 cells/kg; medium-dose, 6.0×105 cells/kg; high-dose, 9.0×105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results. One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion. The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Wood plastic composites (WPCs) specimens containing high-density polyethylene (HDPE) and wood pruning waste were manufactured and evaluated for their mechanical properties. Pecan waste was used as an accessible and sustainable source in this study, and the effects of its particle size and concentration on WPC strengths were evaluated. Pecan waste was milled and sieved to various particle sizes, and testing samples were fabricated by mixing them in a twin-screw extruder and injection molding. A coupling agent was used to create a stable bond between the HDPE and wood. Both tensile modulus and strength were increased with an increasing pecan flour concentration up to about 60 weigh percent. A micromechanical model is proposed for predicting the mechanical properties of the wood flour/fiber reinforce composite. This model uses a correction factor of an elliptical of carried sizes and shapes. The preliminary results of the model have a high correlation with the experimental values of the composite in all mesh sizes.

Engineered T cells with chimeric antigen receptor (CAR) are emerging as an effective cancer therapy. Here the authors show that CAR T cells recognizing self-MHC can be ‘tuned’ ex vivo via CAR downregulation and CAR T cell death to generate a CAR T pool specifically targeting tumor cells with high MHC expression.

Background/Aims: The signal transducer and activator of transcription 6 (STAT6) transcription factor mediates PPARγ-regulated gene expression in macrophages. However, it remains largely unknown how proximal membrane signaling events initiated by apoptotic cell recognition upregulate PPARγ expression and activate the lung homeostatic program. Methods: The STAT6 inhibitor AS1517499 was used to determine the role of STAT6 in mediating PPARγ activity, anti-inflammatory effects, and anti-fibrotic effects induced by apoptotic cell instillation after bleomycin treatment into C57BL/6 mice. Bronchoalveolar lavage fluid, alveolar macrophages and lungs were harvested at days 2, 7, and 14 and then analyzed by real-time PCR, immunoblotting, ELISA, immunocytochemistry and immunohistochemistry assays. Results: Our data demonstrate that apoptotic cell instillation after bleomycin results in prolonged enhancement of STAT6 phosphorylation in alveolar macrophages and lung. Co-administration of the STAT6 inhibitor, AS1517499, reversed the enhanced PPARγ expression and activity induced by apoptotic cell instillation after bleomycin treatment. By reducing the expression of PPARγ target genes, including CD36, macrophage mannose receptor, and arginase 1, AS1517499 inhibited efferocytosis and restored pro-inflammatory cytokine expression, neutrophil recruitment, protein levels, hydroxyproline content, and expression of fibrosis markers, including type 1 collagen α2, fibronectin, and α-smooth muscle actin. STAT6 inhibition reversed the expression profile of hepatocyte growth factor and interleukin-10. Conclusion: These results indicate that prolonged STAT6 activation following one-time apoptotic cell instillation facilitates continuous PPARγ activation, resulting in the resolution of bleomycin-induced lung inflammation and fibrosis.

Ectopic pregnancy is the implantation of a fertilized egg outside the uterine endometrial cavity. For women presenting to the emergency department with abdominal pain and/or vaginal bleeding, ectopic pregnancy is an important diagnostic consideration. The diagnosis is made based on laboratory values and ultrasound imaging findings. The ultrasound appearance of both normal early pregnancy and ectopic pregnancy are variable and often subtle, presenting diagnostic challenges for radiologists. This pictorial essay describes and illustrates the sonographic findings of ectopic pregnancy and reviews the differential diagnoses that can mimic ectopic pregnancy on ultrasound. With the possibility of medical management, the value of early detection and prompt initiation of treatment has increased in improving clinical outcomes and preventing the complications of ectopic pregnancy.

Adoptive cell therapy (ACT) using tumor-reactive T cells is a promising form of immunotherapy to specifically target cancer. However, the survival and functional maintenance of adoptively transferred T cells remains a challenge, ultimately limiting their efficacy. Here, we evaluated the use of recombinant IL7-Fc in ACT. In a lymphopenic murine melanoma model, IL7-Fc treatment led to the enhanced inhibition of tumor growth with an increased number of adoptively transferred CD8+ T cells in tumor tissue and tumor-draining lymph nodes. Additionally, IL7-Fc further enhanced anti-tumor responses that were induced by recombinant human IL2 in the same mouse model. In contrast, in an immunocompetent murine melanoma model, IL7-Fc dampened the anti-tumor immunity. Further, IL7-Fc decreased the proliferation of adoptively transferred and immune-activated tumor-reactive CD8+ T cells in immunocompetent mice by inducing the massive expansion of endogenous T cells, thereby limiting the space for adoptively transferred T cells. Our data suggest that IL7-Fc is principally beneficial for enhancing the efficacy of tumor-reactive T-cells in lymphopenic conditions for the ACT.

Familial hyperekplexia, also called startle disease, is a rare neurological disorder characterized by excessive startle responses to noise or touch. It can be associated with serious injury from frequent falls, apnea spells, and aspiration pneumonia. Familial hyperekplexia has a heterogeneous genetic background with several identified causative genes; it demonstrates both dominant and recessive inheritance in the α1 subunit of the glycine receptor (GLRA1), the β subunit of the glycine receptor and the presynaptic sodium and chloride-dependent glycine transporter 2 genes. Clonazepam is an effective medical treatment for hyperekplexia. Here, we report genetically confirmed familial hyperekplexia patients presenting early adult cautious gait. Additionally, we review clinical features, mode of inheritance, ethnicity and the types and locations of mutations of previously reported hyperekplexia cases with a GLRA1 gene mutation.

Purpose: This study explores the characteristics of STV service to empirically examine effects of the services on adoption and usage of STV to lead sustained growth of the STV industry. Methodology/Approach: This study employs structural equation modeling as a quantitative approach, to examine causal relationships between service characteristics and user intentions. The survey collects 212 data only from actual users of STV, who have experienced STV functions or services, in South Korea. Findings: The results of service-oriented model based on extended Technology Acceptance Model (TAM) indicate that ‘interactivity’, ‘content quality’, and ‘simplicity’ as service characteristics influence intention to use STV. Research Limitation/implication: First, the STV industry should establish a distribution structure that generates sufficient profits for content providers as done in Smartphone market. Second, Services of STV should be provided to allow two-way communication and to allow users to engage in active interactions with other users. Originality/Value of paper: This study makes contributions to research on both new products and service adoption by providing richer explanations of the mechanisms acting on the actual use of STV. Given that STV is considered a key appliance for the next generation of social media and smart appliance, our findings offer new directions on how to realize high quality services in the STV industry.

Ultrasonography is the ideal noninvasive imaging modality for evaluation of scrotal abnormalities. It is capable of differentiating the most important etiologies of acute scrotal pain and swelling, including epididymitis and testicular torsion, and is the imaging modality of choice in acute scrotal trauma. In patients presenting with palpable abnormality or scrotal swelling, ultrasonography can detect, locate, and characterize both intratesticular and extratesticular masses and other abnormalities. A 12-17 MHz high frequency linear array transducer provides excellent anatomic detail of the testicles and surrounding structures. In addition, vascular perfusion can be easily assessed using color and spectral Doppler analysis. In most cases of scrotal disease, the combination of clinical history, physical examination, and information obtained with ultrasonography is sufficient for diagnostic decision-making. This review covers the normal scrotal anatomy as well as various testicular and scrotal lesions.