Huanglian Jiedu decoction alleviates neurobehavioral damage in mice with chronic alcohol exposure through the RAS-RAF-MEK-ERK pathway.

Objective: Long-term alcohol consumption can cause organic damage to the brain, resulting in mental and nervous system abnormalities and intellectual impairment. Huanglian Jiedu decoction (HLJDD) is the classic representative of clearing heat and detoxifying. This study aimed to explore the effects and possible mechanisms of HLJDD on brain injury in chronic alcohol-exposed mice. Methods: The alcohol-exposed mice were treated with different doses of HLJDD to observe behavioral changes, hippocampal Aß1-42 deposition, number and ultrastructural changes of neurons in the hippocampus and prefrontal cortex, and expressions of synaptic proteins. On this basis, transcriptome sequencing was used to analyze the differentially expressed genes in different treatment groups, and functional enrichment analysis was performed. Then, WB and RT-PCR were used to verify the expression of the pathway. Results: Chronic alcohol exposure reduced body weight in mice, led to motor cognitive impairment, increased Aß1-42 in the hippocampus, decreased the number of neurons in the hippocampus and prefrontal cortex, and the expression of PSD95 and SYN in the hippocampus. HLJDD significantly improved the cognitive dysfunction of mice and alleviated the damage of the hippocampus and prefrontal cortex. Transcriptome sequencing results showed that the regulatory effects of HLJDD on chronic alcohol-exposed mice may be related to the RAS pathway. Further experiments confirmed that chronic alcohol exposure caused a significant increase in protein and gene expressions of the RAS-RAF-MEK-ERK pathway in mouse, and this activation was reversed by HLJDD. Conclusion: HLJDD may ameliorate brain damage caused by chronic alcohol exposure by regulating the RAS-RAF-MEK-ERK pathway.

Cortical Sulcal Abnormalities Revealed by Sulcal Morphometry in Patients with Chronic and Episodic Migraine.

Purpose: Previous studies have reported mixed results regarding the importance of cortical abnormalities in patients with migraines. However, cortical sulci, as a component of the cerebral cortex, have not been specifically investigated in migraine patients. Therefore, we aim to evaluate alterations in cortical sulcal morphology among patients with chronic migraine (CM), episodic migraine (EM), and healthy controls (HCs). Patients and Methods: In this cross-sectional study, structural magnetic resonance images were acquired from 35 patients with CM, 35 with EM, and 35 HCs. Cortical sulci were identified and reconstructed using the BrainVisa 5.0.4 software. We focused on regions involved in pain processing in which abnormal cortical structure were identified in previous neuroimaging studies. Morphometric analysis was performed to calculate sulcal parameters including mean depth, cortical thickness, and opening width. Partial correlation analyses of clinical characteristics and sulcal parameters were performed for CM, EM and the combined migraine (CM + EM) groups. Results: In comparison with HCs, both CM and EM groups showed increased opening width in bilateral insula. In comparison with HC and EM groups, CM patients showed increased cortical thickness in bilateral superior postcentral sulcus, bilateral median frontal sulcus and left superior parietal sulcus, as well as increased mean depth in the left anterior callosomarginal fissure and decreased mean depth in bilateral superior frontal sulcus and left median frontal sulcus. Migraine frequency and disease duration were both correlated with cortical thickness in bilateral superior postcentral sulcus. Conclusion: Abnormal sulcal morphometry primarily affected areas associated with pain processing in patients with migraine, with CM exhibiting more extensive abnormalities in areas related to sensory and affective processing. These changes may contribute to understanding the pathology of EM and CM.

Advancements in investigating the role of cerebral small vein loss in Alzheimer's disease-related pathological changes.

Alzheimer's disease (AD) is the prevailing type of dementia in the elderly, yet a comprehensive comprehension of its precise underlying mechanisms remains elusive. The investigation of the involvement of cerebral small veins in the advancement of AD has yet to be sufficiently explored in previous studies, primarily due to constraints associated with pathological staining techniques. However, recent research has provided valuable insights into multiple pathophysiological occurrences concerning cerebral small veins in AD, which may manifest sequentially, concurrently, or in a self-perpetuating manner. These events are presumed to be among the initial processes in the disease's progression. The impact of cerebral small vein loss on amyloid beta (Aß) clearance through the glial lymphatic system is noteworthy. There exists a potential interdependence between collagen deposition and Aß deposition in cerebral small veins. The compromised functionality of cerebral small veins can result in decreased cerebral perfusion pressure, potentially leading to cerebral tissue ischemia and edema. Additionally, the reduction of cerebral small veins may facilitate the infiltration of inflammatory factors into the brain parenchyma, thereby eliciting neuroinflammatory responses. Susceptibility-weighted imaging (SWI) is a valuable modality for the efficient assessment of cerebral small veins, precisely the deep medullary vein (DMV), and holds promise for the identification of precise and reliable imaging biomarkers for AD. This review presents a comprehensive overview of the current advancements and obstacles to the impairment of cerebral small veins in AD. Additionally, we emphasize future research avenues and the importance of conducting further investigations in this domain.

Optimization of electrical stimulation for the treatment of lower limb dysfunction after stroke: A systematic review and Bayesian network meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the treatment effect of five electrical stimulation methods commonly used in the treatment of stroke patients with lower limb dysfunction. METHODS: We implemented a systematic search of 3915 studies published up to January 2023 from eight databases and two clinical trial registries. First, two independent reviewers critically evaluated trial eligibility according to the inclusion and exclusion criteria. Next, they selected and extracted data. Then, they assessed the risk of bias. Pairwise meta-analysis and Bayesian network meta-analysis were conducted to estimate the effectiveness and ranking of the five electrical stimulation methods. RESULTS: A total of 33 trials with a final total of 2246 subjects were included in the analysis. By combining the comprehensive Rehabilitation Treatment (RT), the treatment effects of using five electrical stimulation methods were surperior to those of using RT only. In the meantime, RT+transcranial Direct Current Stimulation(tDCS) and RT+Functional Electrical Stimulation(FES) could be the optimal electric stimulation schemes for restoring lower limb motor function(SMD 8.35, 95%CI [3.05, 13.34]/ SMD 5.64, 95%CI [3.68, 7.56]), improving balance (SMD 9.80, 95%CI [0.67, 20.93]/ SMD 6.54, 95%CI [3.85, 10.95]) and activities of daily living(SMD 18.95, 95%CI [0.401, 36.9]/ SMD 15.47, 95%CI [7.89, 22.75]), and the treatment effects would be even better using RT+FES+tDCS combination. CONCLUSION: tDCS and FES superior to other electrical stimulation methods based on RT in the treatment of lower limb dysfunction after stroke.

Postoperative Intracranial Hemorrhage after an Endoscopic L5-S1 Laminectomy and Discectomy: A Case Report and Literature Review.

BACKGROUND: Postoperative intracranial hemorrhage (PIH) is a fairly rare but catastrophic perioperative complication following lumbar spine surgery. This is a case report of a 54-year-old male patient who experienced PIH 2 h after an endoscopic L5-S1 laminectomy and discectomy. CASE PRESENTATION: A 54-year-old male patient presented with right L5-S1 radiculopathy that corresponded with the picture revealed in medical imaging and the signs seen upon physical examination. Subsequently, he underwent endoscopic L5-S1 laminectomy and discectomy. The patient presented with idiopathic unconsciousness and limb twitching 2 h after surgery. An emergency cranial CT scan was obtained which demonstrated intracranial hemorrhage. Following an emergency consultation with the Department of Neurology and Neurosurgery, the patient underwent an emergency interventional thrombectomy as per their orders. The surgery was performed successfully. However, the patient's situation did not improve and he died on the second postoperative day. CONCLUSION: PIH after spinal endoscopic surgery is a rare but horrible complication. Several factors could lead to PIH. However, in this patient, the cause of PIH might be attributed to the long operation time combined with cerebrospinal fluid (CSF) leakage. Great attention should be attached to the issue of PIH development in spinal endoscopic procedures due to constant irrigation. This study aims to highlight the issue of PIH following endoscopic spinal surgery by presenting a case report of a patient who died despite successful surgery.

Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial.

BACKGROUND: Antiretroviral agents with novel mechanisms and dosing intervals could expand treatment options for people with HIV. Lenacapavir, an inhibitor of capsid protein that makes use of a unique mechanism, can be administered orally or subcutaneously. We sought to explore the efficacy of lenacapavir in various combination regimens as initial and maintenance therapy for HIV. METHODS: In a phase 2, randomised, open-label, ongoing study at 41 investigational sites in the USA and Dominican Republic, we randomly assigned adults with HIV who had not previously received antiretrovirals to four groups (2:2:2:1). Randomisation was stratified by plasma HIV-1 RNA load (≤100 000 or >100 000 copies per mL) at screening. Groups 1 and 2 both received lenacapavir (927 mg) subcutaneously every 26 weeks (after 2 weeks of oral loading [600 mg on days 1 and 2, followed by 300 mg on day 8]) with oral daily emtricitabine (200 mg) and tenofovir alafenamide (25 mg) for 28 weeks followed by subcutaneous lenacapavir (927 mg) plus oral daily tenofovir alafenamide (25 mg, group 1) or bictegravir (75 mg, group 2). Group 3 received oral daily lenacapavir (600 mg on days 1 and 2, followed by 50 mg daily) with emtricitabine (200 mg) and tenofovir alafenamide (25 mg). Group 4 received oral daily bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants and investigators were not masked to group assignment. The primary endpoint was the percentage of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 54, analysed in the full analysis set (all randomly assigned participants who received at least one dose of study drug) using only on-treatment data. The safety outcome measures were incidences of treatment-emergent adverse events and graded laboratory abnormalities, analysed in the full analysis set. This study is registered at ClinicalTrials.gov, NCT04143594. FINDINGS: Between Nov 22, 2019, and Aug 27, 2020, 249 people with HIV were screened, 183 participants were randomly assigned and 182 received a dose of antiretroviral drugs (52 in group 1, 53 in group 2, 52 in group 3, and 25 in group 4). 22 participants did not complete the full study course (five in group 1, 12 in group 2, four in group 3, and one in group 4). At week 54, virological suppression was 90% (47 of 52 patients) for group 1 (difference vs group 4: -2·6%, 95% CI -18·4 to 13·2), 85% (45 of 53) for group 2 (-7·1%, -23·4 to 9·3), 85% (44 of 52) for group 3 (-7·2%, -23·5 to 9·1), and 92% (23 of 25) for group 4. The most frequent non-injection-site adverse events with lenacapavir (subcutaneous or oral) were headache (13%, 21 of 157) and nausea (13%, 21 of 157). The most common lenacapavir-related injection-site reactions were erythema (27%, 28 of 105), swelling (23%, 24 of 105), and pain (19%, 20 of 105), which were generally mild or moderate. No serious adverse event related to study treatment occurred. Three participants discontinued subcutaneous lenacapavir because of grade 1 injection-site reactions (two for induration and one for erythema or swelling). INTERPRETATION: Lenacapavir warrants further investigation as a potential antiretroviral used orally and as injection in combination with other antiretroviral drugs. FUNDING: Gilead Sciences.

Using dual-task gait to recognize Alzheimer's disease and mild cognitive impairment: a cross-sectional study.

Background: Gait is a potential diagnostic tool for detecting mild cognitive impairment (MCI) and Alzheimer's disease (AD). Nevertheless, little attention has been paid to arm movements during walking, and there is currently no consensus on gait asymmetry. Therefore, in this study, we aimed to determine whether arm motion and gait asymmetry could be utilized for identifying MCI and AD. Methods: In total, 102 middle-aged and elderly individuals were included in the final analysis and were assigned to the following three groups: AD (n = 27), MCI (n = 35), and a normal control group (n = 40). Gait and cognitive assessments were conducted for all participants. Gait detection included a single-task gait with free-speed walking and a dual-task gait with adding a cognitive task of successive minus seven to walking. Original gait parameters were collected using a wearable device featuring the MATRIX system 2.0. Gait parameters were shortened to several main gait domains through factor analysis using principal component extraction with varimax rotation. Subsequently, the extracted gait domains were used to differentiate the three groups, and the area under the receiver operating characteristic curve was calculated. Results: Factor analysis of single-task gait identified five independent gait domains: rhythm symmetry, rhythm, pace asymmetry, arm motion, and variability. Factor analysis of the dual-task gait identified four gait domains: rhythm, variability, symmetry, and arm motion. During single-task walking, pace asymmetry was negatively correlated with MoCA scores and could distinguish between the AD group and the other two groups. Arm motion was not associated with MoCA scores, and did not exhibit adequate discrimination in either task. Conclusion: Currently, there is no reliable evidence suggesting that arm motion can be used to recognize AD or MCI. Gait asymmetry can serve as a potential gait marker for the auxiliary diagnosis of AD but not for MCI.

Comparison between collateral status and DEFUSE 3 or DAWN criteria in patient selection for endovascular thrombectomy within 6-24 hours after stroke: a protocol for meta-analysis.

INTRODUCTION: Perfusion imaging according to the DEFUSE 3 or DAWN criteria has been applied to select patients with large vascular occlusive stroke undergo endovascular therapy (EVT) in the extended time window. Emerging studies have shown that collateral blood flow-based criteria may be as effective as DEFUSE 3 and DAWN criteria for the evaluation of EVT eligibility beyond 6 hours. We will conduct a meta-analysis to compare collateral status-based criteria with DEFUSE 3 or DAWN criteria. METHODS AND ANALYSIS: We will conduct a search for the studies comparing collateral blood flow-based imaging with CT perfusion using the DEFUSE 3 or DAWN criteria in selecting patients with acute ischaemic stroke undergo EVT in the Web of Science, PubMed, EMBASE and the Cochrane Library databases between November 2017 and November 2021. We will also search the sources of grey literature, the reference lists of included studies and the newly published studies during the review period. Two investigators will independently screen the eligible studies and extract data. The study quality will be assessed by using the Newcastle-Ottawa Scale or the Cochrane risk bias tool. Stata V.17 will be used to conduct data analysis. ETHICS AND DISSEMINATION: Patient informed consent and ethics approval are not necessary as this study uses only published studies. The finding of this meta-analysis will be propagated through committee conferences or peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021281928.

Propensity score analysis for correlated subgroup effects.

As individuals may respond differently to treatment, estimating subgroup effects is important to understand the characteristics of individuals who may benefit. Factors that define subgroups may be correlated, complicating evaluation of subgroup effects, especially in observational studies requiring control of confounding variables. We address this problem when propensity score methods are used for confounding control. A common practice is to evaluate candidate subgroup identifiers one at a time without adjusting for other candidate identifiers. We show that this practice can be misleading if the treatment effect modification attributed to a candidate identifier is in truth due to the effect of other correlated true effect modifiers. Whereas jointly analyzing multiple identifiers provides estimates of the desired subgroup effects adjusted for the effects of the other identifiers, it requires the propensity scores to adequately reflect the underlying treatment selection processes and balance the covariates within each subgroup of interest. Satisfying the requirement in practice is hard since the number of strata may increase quickly, while the per stratum sample size may decrease dramatically. A practically helpful approach is utilizing the whole cohort for the propensity score estimation with modeling of interaction terms to reflect the potentially different treatment selection processes across strata. We empirically examine the performance of the whole cohort approach by itself and with subjecting the interaction terms to variable selection. Our results using both simulations and real data analysis suggest that the whole cohort approach should explore inclusion of high-order interactions in the propensity score model to ensure adequate covariate balance across strata, and that variable selection is of limited utility.

From patterned response dependency to structured covariate dependency: Entropy based categorical-pattern-matching.

Data generated from a system of interest typically consists of measurements on many covariate features and possibly multiple response features across all subjects in a designated ensemble. Such data is naturally represented by one response-matrix against one covariate-matrix. A matrix lattice is an advantageous platform for simultaneously accommodating heterogeneous data types: continuous, discrete and categorical, and exploring hidden dependency among/between features and subjects. After each feature being individually renormalized with respect to its own histogram, the categorical version of mutual conditional entropy is evaluated for all pairs of response and covariate features according to the combinatorial information theory. Then, by applying Data Could Geometry (DCG) algorithmic computations on such a mutual conditional entropy matrix, multiple synergistic feature-groups are partitioned. Distinct synergistic feature-groups embrace distinct structures of dependency. The explicit details of dependency among members of synergistic features are seen through mutliscale compositions of blocks computed by a computing paradigm called Data Mechanics. We then propose a categorical pattern matching approach to establish a directed associative linkage: from the patterned response dependency to serial structured covariate dependency. The graphic display of such a directed associative linkage is termed an information flow and the degrees of association are evaluated via tree-to-tree mutual conditional entropy. This new universal way of discovering system knowledge is illustrated through five data sets. In each case, the emergent visible heterogeneity is an organization of discovered knowledge.

Bootstrapping on undirected binary networks via statistical mechanics.

We propose a new method inspired from statistical mechanics for extracting geometric information from undirected binary networks and generating random networks that conform to this geometry. In this method an undirected binary network is perceived as a thermodynamic system with a collection of permuted adjacency matrices as its states. The task of extracting information from the network is then reformulated as a discrete combinatorial optimization problem of searching for its ground state. To solve this problem, we apply multiple ensembles of temperature regulated Markov chains to establish an ultrametric geometry on the network. This geometry is equipped with a tree hierarchy that captures the multiscale community structure of the network. We translate this geometry into a Parisi adjacency matrix, which has a relative low energy level and is in the vicinity of the ground state. The Parisi adjacency matrix is then further optimized by making block permutations subject to the ultrametric geometry. The optimal matrix corresponds to the macrostate of the original network. An ensemble of random networks is then generated such that each of these networks conforms to this macrostate; the corresponding algorithm also provides an estimate of the size of this ensemble. By repeating this procedure at different scales of the ultrametric geometry of the network, it is possible to compute its evolution entropy, i.e. to estimate the evolution of its complexity as we move from a coarse to a ne description of its geometric structure. We demonstrate the performance of this method on simulated as well as real data networks.

Robustness of topological order and formation of quantum well states in topological insulators exposed to ambient environment.

The physical property investigation (like transport measurements) and ultimate application of the topological insulators usually involve surfaces that are exposed to ambient environment (1 atm and room temperature). One critical issue is how the topological surface state will behave under such ambient conditions. We report high resolution angle-resolved photoemission measurements to directly probe the surface state of the prototypical topological insulators, Bi(2)Se(3) and Bi(2)Te(3), upon exposing to various environments. We find that the topological order is robust even when the surface is exposed to air at room temperature. However, the surface state is strongly modified after such an exposure. Particularly, we have observed the formation of two-dimensional quantum well states near the exposed surface of the topological insulators. These findings provide key information in understanding the surface properties of the topological insulators under ambient environment and in engineering the topological surface state for applications.

Distinct fermi surface topology and nodeless superconducting gap in a (Tl0.58Rb0.42)Fe1.72Se2 superconductor.

High resolution angle-resolved photoemission measurements have been carried out to study the electronic structure and superconducting gap of the (Tl0.58Rb0.42)Fe1.72Se2 superconductor with a T(c) = 32 K. The Fermi surface topology consists of two electronlike Fermi surface sheets around the Γ point which is distinct from that in all other iron-based superconductors reported so far. The Fermi surface around the M point shows a nearly isotropic superconducting gap of ∼12 meV. The large Fermi surface near the Γ point also shows a nearly isotropic superconducting gap of ∼15 meV, while no superconducting gap opening is clearly observed for the inner tiny Fermi surface. Our observed new Fermi surface topology and its associated superconducting gap will provide key insights and constraints into the understanding of the superconductivity mechanism in iron-based superconductors.

Unusual electronic structure and observation of dispersion kink in CeFeAsO parent compound of FeAs-based superconductors.

We report the first comprehensive high-resolution angle-resolved photoemission measurements on CeFeAsO, a parent compound of FeAs-based high temperature superconductors with a magnetic-structural transition at ∼150 K. In the magnetic-ordering state, four holelike Fermi surface sheets are observed near Γ(0,0), and the Fermi surface near M(±π,±π) shows a tiny electronlike pocket at M surrounded by four strong spots. The unusual Fermi surface topology deviates strongly from the band structure calculations. The electronic signature of the magnetic-structural transition shows up in the dramatic change of the quasiparticle scattering rate. A dispersion kink at ∼25 meV is observed for the first time in the parent compound of Fe-based superconductors.

Coexistence of Fermi arcs and Fermi pockets in a high-T(c) copper oxide superconductor.

In the pseudogap state of the high-transition-temperature (high-T(c)) copper oxide superconductors, angle-resolved photoemission (ARPES) measurements have seen Fermi arcs-that is, open-ended gapless sections in the large Fermi surface-rather than a closed loop expected of an ordinary metal. This is all the more puzzling because Fermi pockets (small closed Fermi surface features) have been suggested by recent quantum oscillation measurements. The Fermi arcs cannot be understood in terms of existing theories, although there is a solution in the form of conventional Fermi surface pockets associated with competing order, but with a back side that is for detailed reasons invisible to photoemission probes. Here we report ARPES measurements of Bi(2)Sr(2-x)La(x)CuO(6+delta) (La-Bi2201) that reveal Fermi pockets. The charge carriers in the pockets are holes, and the pockets show an unusual dependence on doping: they exist in underdoped but not overdoped samples. A surprise is that these Fermi pockets appear to coexist with the Fermi arcs. This coexistence has not been expected theoretically.

Menthyl 2-oxo-2H-chromene-3-carboxyl-ate.

The title compound, C(20)H(24)O(4), was synthesized from the reaction of 2-oxo-2H-chromene-3-acyl chloride and menthol. The mean plane of the ester group and that of the four essentially planar (maximum deviation 0.0112 Å) C atoms of the chair-form cyclo-hexyl ring form dihedral angles of 43.8 (3) ° and 81.8 (1)°, respectively, with the mean plane of the coumarin ring system. In the crystal structure, weak inter-molecular C-H⋯O hydrogen bonds connect the mol-ecules into a two-dimensional network.

Cinnamyl 8-meth-oxy-2-oxo-2H-chromene-3-carboxyl-ate.

In the crystal structure of the title compound, C(20)H(16)O(5), the mol-ecule assumes an E configuration with the benzene ring and chromenecarboxyl group located on opposite ends of the C=C double bond. The chromene ring system and benzene ring are oriented at a dihedral angle of 74.66 (12)°. Weak inter-molecular C-H⋯O hydrogen bonding is present in the crystal structure.