Miracle-dz/UniFAR-FTUs huggingface dataset:
Synaptic Regulation by OPRM1 Variants in Reward Neurocircuitry

Mu-opioid receptors (MORs) are the primary site of action of opioid drugs, both licit and illicit. Susceptibility to opioid addiction is associated with variants in the gene encoding the MOR, OPRM1. Varying with ethnicity, ∼25% of humans carry a single nucleotide polymorphism (SNP) in OPRM1 (A118G). This SNP produces a nonsynonymous amino acid substitution, replacing asparagine (N40) with aspartate (D40), and has been linked with an increased risk for drug addiction. While a murine model of human OPRM1 A118G (A112G in mouse) recapitulates most of the phenotypes reported in humans, the neuronal mechanisms underlying these phenotypes remain elusive. Here, we investigated the impact of A118G on opioid regulation of synaptic transmission in mesolimbic VTA dopaminergic neurons. Using electrophysiology, we showed that both inhibitory and excitatory inputs to VTA dopaminergic neurons projecting to the NAc medial shell were suppressed by the MOR agonists DAMGO and morphine, which caused a shift in the excitatory/inhibitory balance and an increased action potential firing rate. Mice carrying the 112G/G allele exhibited lower sensitivity to DAMGO and morphine compared with major allele carriers (112A/A). Paradoxically, DAMGO produced facilitatory effects on mEPSCs, which were mediated by presynaptic GABAB receptors. However, this was only prominent in homozygous major allele carriers, which could explain a stronger shift in action potential firing in 112A/A mice. This study provides a better understanding on the neurobiological mechanisms that may underlie risk of addiction development in carriers of the A118G SNP in OPRM1. SIGNIFICANCE STATEMENT The pandemic of opioid drug abuse is associated with many socioeconomic burdens. The primary brain target of opioid drugs is the μ-opioid receptor (MOR), encoded by the OPRM1 gene, which is highly polymorphic in humans. Using a mouse model of the human OPRM1 A118G single nucleotide polymorphism (SNP) (A112G in mice), we demonstrated that MOR and GABAB signaling coordinate in regulating mesolimbic dopamine neuronal firing via presynaptic regulation. The A118G SNP affects MOR-mediated suppression of GABA and glutamate release, showing weaker efficacy of synaptic regulation by MORs. These results may shed light on whether MOR SNPs need to be considered for devising effective therapeutic interventions.
Clinical parameters outperform molecular subtypes for predicting outcome in bladder cancer: Results from multiple cohorts including TCGA.

PURPOSE Studies report molecular subtypes within muscle invasive bladder cancer (MIBC) predict clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict clinical outcome. METHODS Institutional cohort-1 (n=52; MIBC: 39), Oncomine-dataset (MIBC: 151) and The Cancer Genome Atlas (TCGA)-dataset (MIBC: 402) were subtyped by simplified panels (MCG-1; MCG-Ext) that included only transcripts common among published studies, and analyzed for predicting metastasis, cancer-specific survival (CSS), overall-survival (OS), and recurrence-free survival (RFS). TCGA-dataset was further analyzed using Lund-Taxonomy, BC-Molecular Taxonomy Group Consensus (Consensus), and mRNA-subtype (TCGA-2017) classifications. RESULTS MIBC specimens from cohort-1 and Oncomine-dataset showed intra-tumor heterogeneity for transcript/protein expression. MCG-1 subtypes did not predict outcome in univariate or Kaplan-Meier analyses. In multivariate analyses, N-stage (P≤0.007), T-stage (P≤0.04), M-stage (P=0.007) and/or age (P=0.01) predicted metastasis, CSS/OS and/or cisplatin-based adjuvant-chemotherapy response. In the TCGA-dataset, publications report that subtypes risk-stratify patients for OS. Consistently, MCG-1 and MCG-Ext subtypes associated with OS, but not RFS, in univariate and Kaplan-Meier analyses. TCGA-dataset includes low-grade specimens (21/402) and subtypes associated with tumor-grade (P=0.005). However, MIBC is rarely low-grade (<1%). Among only high-grade specimens, MCG-1 and MCG-Ext subtypes could not predict OS. Subtypes by Consensus, TCGA-2017 and Lund-Taxonomy associated with tumor-grade (P<0.0001) and OS (P=0.01-<0.0001) univariately. Regardless of classification, subtypes had ∼50%-60% sensitivity and specificity to predict OS/RFS. In multivariate analyses, N-stage and lymphovascular-invasion consistently predicted RFS (P=0.039) and OS (P=0.003). CONCLUSION Molecular subtypes reflect bladder tumor heterogeneity and associate with tumor-grade. In multiple cohorts/subtyping-classifications, clinical parameters outperform subtypes for predicting outcome.
Properties of persistent sodium conductance and calcium conductance of layer V neurons from cat sensorimotor cortex in vitro.

Properties of the persistent sodium conductance and the calcium conductance of layer V neurons from cat sensorimotor cortex were examined in an in vitro slice preparation by use of a single microelectrode, somatic voltage clamp, current clamp, intra- and extracellular application of blocking agents, and extracellular ion substitution. The persistent sodium current (INaP) attained its steady level within 2-4 ms of a step change in voltage at every potential where it could be examined directly [to about 40 mV positive to resting potential (RP)]. Because of its fast onset INaP can be activated during a single excitatory postsynaptic potential (EPSP) and can influence the subsequent voltage time course and cell excitability. Application of a depolarizing holding potential greater than or equal to 20 mV positive to RP could inactivate spikes, thus allowing examination of INaP at voltages positive to spike threshold. At every potential where INaP was visible, it was mixed with a slow outward current. After depressing potassium currents with blocking agents, INaP could be observed during depolarizations to about 40 mV positive to RP where it is normally hidden by the larger outward currents. Indirect evidence suggests that INaP is present and large during prolonged depolarizations greater than 50 mV positive to RP. INaP was blocked by intracellular injection of the lidocaine derivative QX-314, as well as by extracellular tetrodotoxin (TTX). INaP was much more sensitive to QX-314 than was the height and rate of rise of the spike. This observation and the results in paragraph 3 above are best explained by separate INaP and spike sodium channels. After blockade of INaP and sodium spikes, Ca2+ spikes could be evoked only if potassium currents were first depressed. The Ca2+-dependent nature of the regenerative potentials was indicated by their disappearance when Co2+ or Mn2+ was substituted for Ca2+ in the perfusate and by the appearance of greatly enhanced potentials of similar form when Ba2+ was substituted for Ca2+. Ba2+ substitution greatly enhanced evoked and spontaneous synaptic potentials. Prolonged-plateau action potentials could be evoked in the presence of TTX and Ba2+. Ca2+ spike threshold was 30-40 mV positive to RP, which is significantly more positive than sodium spike threshold. Results of voltage clamp in the normal perfusate and in the presence of Ca2+-blockers or Ba2+ indicated that little or no Ca2+ conductance is activated in the voltage range 25 mV positive to RP where INaP is the dominant ionic current. (ABSTRACT TRUNCATED AT 400 WORDS)
Left Ventricular Flow Analysis.

BACKGROUND Cardiac remodeling, after a myocardial insult, often causes progression to heart failure. The relationship between alterations in left ventricular blood flow, including kinetic energy (KE), and remodeling is uncertain. We hypothesized that increasing derangements in left ventricular blood flow would relate to (1) conventional cardiac remodeling markers, (2) increased levels of biochemical remodeling markers, (3) altered cardiac energetics, and (4) worsening patient symptoms and functional capacity. Methods Thirty-four dilated cardiomyopathy patients, 30 ischemic cardiomyopathy patients, and 36 controls underwent magnetic resonance including 4-dimensional flow, BNP (brain-type natriuretic peptide) measurement, functional capacity assessment (6-minute walk test), and symptom quantification. A subgroup of dilated cardiomyopathy and control subjects underwent cardiac energetic assessment. Left ventricular flow was separated into 4 components: direct flow, retained inflow, delayed ejection flow, and residual volume. Average KE throughout the cardiac cycle was calculated. RESULTS Patients had reduced direct flow proportion and direct-flow average KE compared with controls ( P<0.0001). The residual volume proportion and residual volume average KE were increased in patients ( P<0.0001). Importantly, in a multiple linear regression model to predict the patient's 6-minute walk test, the independent predictors were age (β=-0.3015; P=0.019) and direct-flow average KE (β=0.280, P=0.035; R2 model, 0.466, P=0.002). In contrast, neither ejection fraction nor left ventricular volumes were independently predictive. CONCLUSIONS This study demonstrates an independent predictive relationship between the direct-flow average KE and a prognostic measure of functional capacity. Intracardiac 4-dimensional flow parameters are novel biomarkers in heart failure and may provide additive value in monitoring new therapies and predicting prognosis.
Regional variations of care in home care and long-term care: a retrospective cohort study.

BACKGROUND Many aging adults undergo progressive loss of autonomy, develop increasingly complex medical needs and experience multiple care transitions. We sought to determine the degree of variation in rates of transfer from home care services and long-term care in several Canadian jurisdictions. METHODS In this retrospective cohort study, we examined transitions from home care services and long-term care to different possible end states: change in health stability (getting better or worse), transfer to hospital, transfer to another care setting or death. We used standardized interRAI assessments from long-term care and home care linked to hospital records (data from the Discharge Abstract Database and National Ambulatory Care Reporting System) from 2010 to 2016. Multistate modelling was used to adjust for patients with complex health status and transitions in care. RESULTS We report data for 254 664 patients in home care programs and 162 045 residents in long-term care. Compared with patients in Ontario, patients requiring home care services in Alberta and British Columbia had increased odds of being admitted to hospital regardless of the underlying severity of illness (the adjusted odds ratios [OR] ranged from 2.08 to 3.77 in Alberta and from 1.28 to 1.46 in BC). Residents in long-term care in Alberta and BC had less than half the odds of being transferred to hospital, independent of all other factors, when compared with long-term care residents in Ontario (the adjusted OR ranged from 0.38 to 0.39 in Alberta and from 0.33 to 0.44 in BC). INTERPRETATION Significant variations in transfer rates were observed between provinces, even after controlling for individual patient characteristics. These results suggest that transfers to hospital are largely driven by health care policies, health care professional practice patterns and available infrastructure rather than individual patient needs.
Controlling Electronic Devices with Brain Rhythms/Electrical Activity Using Artificial Neural Network (ANN)

The purpose of this research study was to explore the possibility to develop a brain-computer interface (BCI). The main objective was that the BCI should be able to recognize brain activity. BCI is an emerging technology which focuses on communication between software and hardware and permitting the use of brain activity to control electronic devices, such as wheelchairs, computers and robots. The interface was developed, and consists of EEG Bitronics, Arduino and a computer; moreover, two versions of the BCIANNET software were developed to be used with this hardware. This BCI used artificial neural network (ANN) as a main processing method, with the Butterworth filter used as the data pre-processing algorithm for ANN. Twelve subjects were measured to collect the datasets. Tasks were given to subjects to stimulate brain activity. The purpose of the experiments was to test and confirm the performance of the developed software. The aim of the software was to separate important rhythms such as alpha, beta, gamma and delta from other EEG signals. As a result, this study showed that the Levenberg–Marquardt algorithm is the best compared with the backpropagation, resilient backpropagation, and error correction algorithms. The final developed version of the software is an effective tool for research in the field of BCI. The study showed that using the Levenberg–Marquardt learning algorithm gave an accuracy of prediction around 60% on the testing dataset.
Functional Limitations and Disability in Persons Living with HIV in South Africa and United States: Similarities and Differences

Persons living with HIV (PLHIV) may experience disability. We compared disability among PLHIV in the United States and South Africa and investigated associations with health and demographic characteristics. Secondary analysis of cross-sectional data using medical records and questionnaires including the World Health Organization Disability Assessment Schedule (WHO-DAS) 2.0 12-item version (range: 0-36, with higher scores indicative of more severe disability). Between-country differences for the presence of disability were assessed with logistic regression and differences in severity using multiple regression. Eighty-six percent of US participants reported disability, compared to 51.3% in South Africa. The mean WHO-DAS score was higher in the United States (12.09 ± 6.96) compared to South Africa (8.3 ± 6.27). Participants with muscle pain, depression, or more years since HIV diagnosis were more likely to report disability. Being female or depressed was associated with more severity. Being adherent to anti-retroviral therapy (ART) and employed were associated with less severity. Because muscle pain and depression were predictive factors for disability, treatment of those problems may help mitigate disability in PLHIV.
Analysis of the challenges in implementing guidelines to prevent the spread of multidrug-resistant gram-negatives in Europe

Objective The main objective of the study was to investigate major differences among European countries in implementing infection prevention and control (IPC) measures and reasons for reduced compliance. Design An online survey including experts in IPC and a gap analysis were conducted to identify major limitations in implementing IPC guidelines. Setting Europe. Main outcome measures Four areas were targeted: (1) healthcare structure, (2) finances, (3) culture and (4) education and awareness. Perceived compliance to IPC measures was classified as low (<50%), medium (50% to 80%) and high (>80%). Countries were classified in three regions: North-Western Europe (NWE), Eastern Europe (EE) and Southern Europe (SE). Results In total, 482 respondents from 34 out of 44 (77.3%) European countries participated. Respondents reported availability of national guidelines to control multidrug-resistant Gram-negatives (MDR-GN) in 20 countries (58.0%). According to participants, compliance with IPC measures ranged from 17.8% (screening at discharge) to 96.0% (contact precautions). Overall, three areas were identified as critical for the compliance rate: (1) number of infection control staff, (2) IPC dedicated educational programmes and (3) number of clinical staff. Analysis of reasons for low compliance showed high heterogeneity among countries: participants from NWE and SE deemed the lack of educational programmes as the most important, while those from EE considered structural reasons, such as insufficient single bed rooms or lacking materials for isolation, as main contributors to the low compliance. Conclusions Although national guidelines to reduce the spread of MDR-GN are reported in the majority of the European countries, low compliance with IPC measures was commonly reported. Reasons for the low compliance are multifactorial and vary from region to region. Cross-country actions to reduce the spread of MDR-GN have to consider structural and cultural differences in countries. Locally calibrated interventions may be fruitful in the future.
血小板淋巴细胞比值作为非小细胞肺癌预后因素的meta分析

背景与目的 目前研究显示，血小板淋巴细胞比值（platelet lymphocyte ratio, PLR）在肾细胞癌、食管癌、胃癌、肝癌以及结肠癌中均有重要的预后价值。 本研究旨在通过meta分析，评估PLR对非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的预后价值。 方法 使用计算机电子系统对PubMed、EMBASE、Web of Science、Medline、Cochrane Library、中国知网、中国生物医学文献数据库、维普、万方数据库进行系统文献检索，查阅研究PLR与总生存期（overall survival, OS）和无病生存期（disease-free survival, DFS）之间关联的文献。 提取每个符合条件的研究数据，使用风险比率（hazard risk, HR）和95%置信区间（95% confidence interval, 95%CI）进行系统评价分析以评估PLR的预后价值，检索时限为建库至2018年11月。 结果 我们共纳入15篇研究文献涉及5524名患者进行系统评价分析。 Meta分析结果显示：较高PLR组的OS明显低于较低PLR组的OS（HR=1.69, 95%CI: 1.45-1.97, P < 0.000, 01, I2=46.2%, P异质性=0.026）；较高PLR组的DFS明显低于较低PLR组的DFS（HR=1.41, 95%CI: 1.14-1.74, P=0.001, I2=46.2%, P异质性=0.026）。 亚组分析显示，按种族、样本大小、PLR临界值和治疗方法分组后，PLR较高组的OS仍明显低于PLR较低组（P < 0.05）。 结论 PLR增高与NSCLC患者预后不良有关，因此PLR可能作为NSCLC患者重要的生物预测标记，但其临床应用仍需要未来通过更多的研究来验证。
Frequency and Quantity of Egg Intake Is Not Associated with Dyslipidemia: The Hellenic National Nutrition and Health Survey (HNNHS)

Background: Gaps remain on the safety of egg intake on cardiovascular health, setting the study’s aim to investigate the association between quantity and frequency of egg consumption, with established dyslipidemia. Methods: Study participants (N = 3558, 40.3% males) included individuals from the Hellenic National and Nutrition Health Survey (HNNHS), of national representation. Quantity and frequency of egg consumption was determined. Minimally adjusted, multivariable logistic and linear analysis were used to assess egg consumption and dyslipidemia. Results: The more frequent egg consumption compared to no or rare egg consumption significantly decreased the odds of dyslipidemia in the minimally adjusted (Odds Ratio (OR) for frequency: 0.83; 95% Confidence Interval (CI): 0.752, 0.904; OR for quantified frequency: 0.87; 95% CI: 0.796, 0.963) and the fully adjusted models (OR for frequency: 0.80; 95% CI: 0.718, 0.887; OR for quantified frequency: 0.85; 95%CI: 0.759, 0.945). Level of serum cholesterol and LDL-c were significantly lower with higher frequency and quantified frequency of egg consumption in all models. Conclusion: Eggs do not increase the risk of dyslipidemia and can be consumed as part of a healthy diet that is high in fiber and low in saturated fat, without excessive energy intake, by all individuals.
Hippocampal contributions to recollection in retrograde and anterograde amnesia

Lesions restricted to the hippocampal formation and/or extended hippocampal system (hippocampal formation, fornix, mammillary bodies, and anterior thalamic nuclei) can disrupt conscious recollection in anterograde amnesia, while leaving familiarity‐based memory relatively intact. Familiarity may be supported by extra‐hippocampal medial temporal lobe (MTL) structures. Within‐task dissociations in recognition memory best exemplify this distinction in anterograde amnesia. The authors report for the first time comparable dissociations within recognition memory in retrograde amnesia. An amnesic patient (A.D.) with bilateral fornix and septal nuclei lesions failed to recognize details pertaining to personal past events only when recollection was required, during recognition of episodic details. His intact recognition of generic and semantic details pertaining to the same events was ascribed to intact familiarity processes. Recollective processes in the controls were reflected by asymmetrical Receiver's Operating Characteristic curves, whereas the patient's Receiver's Operating Characteristic was symmetrical, suggesting that his inferior recognition performance on episodic details was reliant on familiarity processes. Anterograde and retrograde memories were equally affected, with no temporal gradient for retrograde memories. By comparison, another amnesic person (K.C.) with extensive MTL damage (involving extra‐hippocampal MTL structures in addition to hippocampal and fornix lesions) had very poor recognition and no recollection of either episodic or generic/semantic details. These data suggest that the extended hippocampal system is required to support recollection for both anterograde and retrograde memories, regardless of their age. © 2006 Wiley‐Liss, Inc.
Density-functional geometry optimization of the 150,000-atom photosystem-I trimer.

We present a linear-scaling method based on the use of density-functional theory (DFT) for the system-wide optimization of x-ray structural coordinates and apply it to optimize the 150,000 atoms of the photosystem-I (PS-I) trimer. The method is based on repetitive applications of a multilevel ONIOM procedure using the PW916-31G(d) DFT calculations for the high level and PM3 for the lower level; this method treats all atoms in the structure equivalently, a structure in which the majority of the atoms can be considered as part of some internal "active site. " To obtain a realistic single structure, some changes to the original protein model were necessary but these are kept to a minimum in order that the optimized structure most closely resembles the original x-ray one. Optimization has profound effects on the perceived electronic properties of the cofactors, with, e.g., optimization lowering the internal energy of the chlorophylls by on average 53 kcal mol(-1) and eliminates the enormous 115 kcal mol(-1) energy spread depicted by the original x-ray heavy-atom coordinates. A highly precise structure for PS-I results that is suitable for analysis of device function. Significant qualitative features of the structure are also improved such as correction of an error in the stereochemistry of one of the chlorophylls in the "special pair" of the reaction center, as well as the replacement of a water molecule with a metal cation in a critical region on the C3 axis. The method also reveals other unusual features of the structure, leading both to suggestions concerning device functionality and possible mutations between gene sequencing and x-ray structure determination. The optimization scheme is thus shown to augment the molecular modeling schemes that are currently used to add medium-resolution structural information to the raw scattering data in order to obtain atomically resolved structures. System-wide optimization is now a feasible process and its use within protein x-ray data refinement should be considered.
Incorporating hard constraints into non-rigid registration via nonlinear programming

Non-rigid image registration is a key technique in medical image analysis. In conventional non-rigid registration, the whole image is deformed in a non-rigid fashion. However, in some clinical applications, the registration process is required to maintain rigidity in some parts of the image (e.g. bones) while other parts of the image (e.g. soft tissues) can deform in a non-rigid fashion. In this paper, we employ nonlinear programming techniques to solve the registration problem efficiently while ensuring feasibility of the solution with respect to rigidity constraints. Our approach differs from others from an optimization perspective: Unlike the frequently used regularization formulation that incorporates soft constraints into energy function, we impose the local rigidity requirements as hard constraints. The constrained optimization problem is solved by nonlinear programming. The nonlinear programming formulations allow us to exploit the constraints in order to reduce the dimensionality of the optimization problem. In addition, we use dense registration framework to control the deformation at every voxel explicitly. Therefore, unconstrained voxels are not affected by the method. Experimental results from synthetic and MR images of the knee show that our method converges to the optimal solution faster and satisfies the rigidity constraints of the transformation during registration process. The result is a more realistic estimation of rigid and non-rigid deformations.