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The present study aimed to explore the association of plasma neurofilament light chain (NfL) levels with depression and anxiety in Parkinson's disease (PD). This prospective study enrolled 116 patients with PD and 38 healthy controls, and found plasma NfL levels were higher in patients with depression or anxiety than in those without these symptoms. Binary logistic regression identified NfL concentration as an independent predictor of depression and anxiety in PD. In conclusion, elevated plasma NfL may be associated with severity of depression and anxiety in PD patients and may serve as a diagnostic biomarker of PD with moderate to severe depression or anxiety.

We aimed to perform a combined analysis of cortical thickness and functional connectivity to explore their association with cognitive impairment in Parkinson's disease (PD). A total of 53 PD and 15 healthy control subjects were enrolled. PD patients were divided into PD with normal cognition (PD-NC, n = 25), PD with mild cognitive impairment (PD-MCI, n = 11), and PD with dementia (PDD, n = 17). In some analyses, the PD-MCI and PDD groups were aggregated to represent "PD patients with cognitive impairment". Cognitive status was assessed with the Mini-Mental State Examination (MMSE). Anatomical magnetic resonance imaging and resting-state functional connectivity analysis were performed in all subjects. First, surface-based morphometry measurements of cortical thickness and voxels with cortical thickness reduction were detected. Then, regions showing reduced thickness were analyzed for changes in resting-state functional connectivity in PD involving cognitive impairment. Our results showed that, compared with PD-NC, patients with cognitive impairment showed decreased cortical thickness in the left superior temporal, left lingual, right insula, and right fusiform regions. PD-MCI patients showed these alterations in the right lingual region. Widespread cortical thinning was detected in PDD subjects, including the left superior temporal, left fusiform, right insula, and right fusiform areas. We found that cortical thinning in the left superior temporal, left fusiform, and right temporal pole regions positively correlated with MMSE score. In the resting-state functional connectivity analysis, we found a decrease in functional connectivity between the cortical atrophic brain areas mentioned above and cognition-related brain networks, as well as an increase in functional connectivity between those region and the cerebellum. Alterations in cortical thickness may result in a dysfunction of resting-state functional connectivity, contributing to cognitive decline in patients with PD. However, it is more probable that the relation between structure and FC would be bidirectional,and needs more research to explore in PD cognitve decline.

The aim of this study was to investigate the prevalence of rapid eye movement behavior disorder (RBD) in Chinese patients with multiple system atrophy (MSA) and to compare motor and non-motor symptoms and sleep disturbance of MSA patients with and without RBD. A total of 55 patients who were consecutively admitted to West China Hospital of Sichuan University from 2016 to 2019 and subsequently diagnosed with probable MSA were enrolled in this cross-sectional study. The diagnosis of RBD was based on the results of video polysomnography (PSG) and a history of abnormal sleep-related behaviors. The patients were divided into two groups: those with RBD and those without. These two groups were then compared in terms of severity of motor symptoms (Unified Multiple System Arophy Rating Scale) and non-motor symptoms (Non-Motor Symptoms Scale, Mini-Mental State Examination score, Epworth Sleepiness Scale, Fatigue Severity Scale, Pittsburgh Sleep Quality Index, REM Sleep Behavior Disorder Screening Questionnaire, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale) and sleep parameters as recorded on PSG. Of the 55 patients (35 males), 18 (33%, 13 males) were diagnosed with RBD. Patients with or without RBD did not differ in demographic characteristics, clinical features, or sleep parameters based on PSG. There was no difference in motor and non-motor symptoms between MSA patients with or without RBD, indicating that the presence of RBD may not be significantly associated with the severity of motor or non-motor dysfunction in MSA.

Restless legs syndrome (RLS) is a common neurological disorder of unclear pathophysiology that appears to involve an iron deficiency in the brain. Some studies, but not others, suggest that intravenous injection of iron can reduce RLS severity.The databases Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed were searched for randomized controlled trials, cohort studies and case-control studies of intravenous iron therapy to treat RLS. Eligible studies were meta-analyzed using Stata 12.0.This analysis indicated that IV iron was more efficacious than placebo in treating RLS (OR: 4.71,95%CI 4.21-5.21,p 0.0001). According to sub-group analysis, either IV ferric carboxymaltose (FCM) or iron sucrose was more efficacious than placebo in treating RLS. Adverse events did not differ significantly between patients receiving intravenous iron or placebo (OR 1.68, 95%CI 0.92-3.07, p = 0.093). The present study also indicated after accepting IV iron treatment the IRLS score in RLS patients decreased (OR = 6.75,95%CI 4.02-9.49, p 0.0001). The subgroup analysis showed that IV iron dextran, iron sucrose, and FCM could alleviate the IRLS score.The available evidence suggests that intravenous iron is effective and tolerable for patients with RLS regardless of peripheral iron status.

Studies have suggested that obesity is associated with better prognosis among individuals with various types of neurodegenerative diseases, and while some studies suggest that the same is true of amyotrophic lateral sclerosis (ALS), other works cast doubt on this conclusion. Therefore, we conducted a meta-analysis to systematically evaluate the role of body mass index in the prognosis of ALS. PubMed was systematically searched to identify eligible articles, and data on long-term survival were meta-analyzed in terms of hazard ratios (HR) with corresponding 95% confidence intervals (CI). Level of heterogeneity among studies and publication bias were estimated. A total of 17 studies with 9991 ALS patients were included in the review. Each increase of 1 kg/m

In this paper, we show that for sufficiently strong atomic interactions, there exist analytical solutions of current-carrying nonlinear Bloch states at the Brillouin zone edge to the model of spin-orbit-coupled Bose-Einstein condensates (BECs) with symmetric spin interaction loaded into optical lattices. These simple but generic exact solutions provide an analytical demonstration of some intriguing properties which have neither an analog in the regular BEC lattice systems nor in the uniform spin-orbit-coupled BEC systems. It is an analytical example for understanding the superfluid and other related properties of the spin-orbit-coupled BEC lattice systems., 9 pages, 6 figures, a couple of typos in equation are corrected

We theoretically explore the tunneling dynamics for the tight-binding (TB) model of a single spin-orbit-coupled atom trapped in an optical lattice subjected to lattice shaking and to time-periodic Zeeman field. By means of analytical and numerical methods, we demonstrate that the spin-orbit (SO) coupling adds some new results to the tunneling dynamics in both multiphoton resonance and far-off-resonance parameter regimes. When the driving frequency is resonant with the static Zeeman field (multi-photon resonances), we obtain an unexpected new dynamical localization (DL) phenomenon where the single SO-coupled atom is restricted to making perfect two-site Rabi oscillation accompanied by spin flipping.By using the unconventional DL phenomenon, we are able to generate a ratchetlike effect which enables directed atomic motion towards different directions and accompanies periodic spin-flipping under the action of SO coupling. For the far-off-resonance case, we show that by suppressing the usual inter-site tunneling alone, it is possible to realize a type of spin-conserving second-order tunneling between next-nearest-neighboring sites, which is not accessible in the conventional lattice system without SO coupling. We also show that simultaneous controls of the usual inter-site tunneling and the SO-coupling-related second-order-tunneling are necessary for quasienergies flatness (collapse) and completely frozen dynamics to exist. These results may be relevant to potential applications such as spin-based quantum information processing and design of novel spintronics devices., 12 pages, 7 figures

The aim of this study is to explore whether the single nucleotide polymorphism rs2275294 in the ZNF512B gene is related to the length of survival of patients with amyotrophic lateral sclerosis (ALS). This prospective study examined 212 patients with ALS, who were genotyped at the rs2275294 locus in ZNF512B using the ligase method. Genotype was compared with clinical data and survival. Kaplan–Meier survival analysis and Cox hazard regression were used to identify risk factors of shorter survival. Our results were meta-analyzed together with previous work in order to examine the potential association between the rs2275294-C allele and survival. Of the 212 patients, 166 carried the CC + CT genotype at the rs2275294 locus, while 46 carried the TT genotype. Patients with the C allele showed significantly shorter survival than those without it (34.13 ± 1.9 vs. 45.32 ± 5.7 months, p = 0.036). Cox analysis identified the C allele and time from symptom onset to diagnosis as risk factors for shorter survival. Meta-analysis of 447 patients in China and Japan confirmed the rs2275294-C allele to be an independent risk factor of shorter survival in ALS patients. The C allele at the rs2275294 locus in ZNF512B is a risk factor for shorter survival in patients with ALS.

Respiratory failure in patients with Guillain-Barre syndrome (GBS) can lead to serious complications and dysfunctions, emphasizing the importance of early detection. The C-reactive protein-to-albumin ratio (CAR) is emerging as a novel inflammatory marker for predicting neurological outcome. We aimed to identify the association of CAR with respiratory failure and short-term outcome in GBS patients. A total of 200 patients diagnosed with GBS were retrospectively analyzed. Data were collected from an electronic database. The associations of C-reactive protein (CRP), albumin, and CAR at admission with outcomes were evaluated by logistic regression analysis. Using receiver operating characteristic curves, we calculated the cutoff value for the CAR and compared its discriminatory power with that of C-reactive protein alone. Fifty-two (26%) patients showed poor short-term outcome, and 50 (25%) developed respiratory failure. CAR > 0.21 was an independent predictor of respiratory failure, and CAR > 0.19 was an independent predictor of poor short-term outcome. CAR showed a better predictive value than CRP alone. In addition, the c-index of the predictive nomogram for respiratory failure was higher when it included CAR (0.962) than when it did not (0.958). A similar result was observed for the predictive nomogram for poor short-term outcome (0.953 vs 0.947). CAR > 0.21, a novel inflammatory biomarker, is independently associated with the occurrence of respiratory failure in GBS patients, while CAR > 0.19 is independently associated with poor short-term outcome. CAR may help identify GBS patients at high risk of poor prognosis.

We find a different mechanism for suppression of decay in an open one-dimensional lattice system, which originates from a dark Floquet state, a sink state to which the system is asymptotically driven, whose overall probability is determined only by the parameters of the periodic driving field. The zero-quasienergy of dark Floquet state has been shown to be not a real zero, but a vanishingly small negative imaginary number which will cause undesirable physical effect in long-time evolution of quantum states, which is extremely different from the conservative counterpart. Another important finding is that the value of the system's effective decay, determined by the size of the non-zero imaginary part of the dark-Floquet-state-related quasienergy, depends not on how many localized lossy sites there are but on which one of the lossy sites is nearest to the driven site. Thus, for specially designed local dissipation, by controlling the driving parameters, it is possible for us to drive the system to a dark Floquet state with a much lower level of overall probability loss as compared to the undriven case and with good stability over enough longer evolution time. These results are applicable to the multisite lattice system with an odd number of sites and may be significant for long-time control of decay in a vast family of multistate physical systems with localized dissipation., 11 pages,10 figures

Amyotrophic lateral sclerosis (ALS), one of the motor neuron diseases, appears to be caused by genetic and environmental risk factors. However, the influence of Pro34Ser variant of CHCHD10 gene in increasing risk of ALS remains indeterminate. This study conducted a meta-analysis to establish the association between Pro34Ser variant of CHCHD10 gene and risk of ALS. PubMed, Web of Science, and Embase databases were systematically searched for genome-wide association studies or case–control studies published up to March 28, 2020, on the association between Pro34Ser variant and risk of ALS. Data from eligible studies were extracted and analyzed. Twelve case–control studies involving 7442 patients with sporadic ALS and 75,371 controls were analyzed. The Pro34Ser variant was not associated with increased risk of ALS disease based on fixed-effects meta-analysis (Pro34Ser-positive vs Pro34Ser-negative: OR 1.23, 95% CI 0.90 to 1.69, P = 0.201). Existing evidence suggests that Pro34Ser variant in CHCHD10 is not associated with risk of ALS, particularly in Caucasian participants. However, our results ought to be validated using large, well-designed studies, especially in Asian and African populations.

Introduction Guillain-Barre syndrome (GBS) is one of the most common causes of acute flaccid paralysis, with up to 20%-30% of patients requiring mechanical ventilation. The aim of our study was to develop and validate a mechanical ventilation risk nomogram in a Chinese population of patients with GBS. Methods A total of 312 GBS patients were recruited from January 1, 2015, to June 31, 2018, of whom 17% received mechanical ventilation. The least absolute shrinkage and selection operator (LASSO) regression model was used to select clinicodemographic characteristics and blood markers that were then incorporated, using multivariate logistic regression, into a risk model to predict the need for mechanical ventilation. The model was characterized and assessed using the C-index, calibration plot, and decision curve analysis. The model was validated using bootstrap resampling in a prospective study of 114 patients recruited from July 1, 2018, to July 10, 2019. Results The predictive model included hospital stay, glossopharyngeal and vagal nerve deficits, Hughes functional grading scale scores at admission, and neutrophil/lymphocyte ratio (NLR). The model showed good discrimination with a C-index value of 0.938 and good calibration. A high C-index value of 0.856 was reached in the validation group. Decision curve analysis demonstrated the clinical utility of the mechanical ventilation nomogram. Conclusions A nomogram incorporating hospital stay, glossopharyngeal and vagal nerve deficits, Hughes functional grading scale scores at admission, and NLR may reliably predict the probability of requiring mechanical ventilation in GBS patients.

Deep-brain stimulation is a well-established, effective treatment for patients with advanced Parkinson’s disease. Recent studies examining rates of suicide attempts and suicides after deep-brain stimulation in the bilateral subthalamic nucleus have reported varying results. Using this systematic review and meta-analysis, we aim to obtain a comprehensive understanding of suicidality in Parkinson’s patients after subthalamic nucleus deep brain stimulation. We systematically examined Medline, PubMed, Web of Science, and Embase databases to identify studies published before November 2019 that measured rates of suicidality in Parkinson’s patients who underwent subthalamic nucleus stimulation. A meta-analysis of the data from the included studies was conducted using Stata 12.0. A total of 18 studies met the eligibility criteria of this study. We found that the pooled rate of suicidal ideation was 4% (95% CI 0.00–7.2%, range 2–17%). The pooled rate of suicide attempts was 1% (95% CI 1.0–2.0%), while the pooled rate of suicide was 1% (95% CI 0.0–1.0%). Our findings indicate a relatively high rate of suicidality among Parkinson’s patients after subthalamic nucleus deep-brain stimulation. It is important for clinicians to carefully monitor psychiatric disorders, especially suicidal ideation and suicide attempts, in Parkinson’s patients before and after subthalamic nucleus deep-brain stimulation.

The generation of ATP through oxidative phosphorylation is an essential metabolic function for Mycobaterium tuberculosis (Mtb), regardless of the growth environment. The type II NADH dehydrogenase (Ndh-2) is the conduit for electrons into the pathway, and is absent in the mammalian genome, thus making it a potential drug target. Herein, we report the identification of two types of small molecules as selective inhibitors for Ndh-2 through a multicomponent high-throughput screen. Both compounds block ATP synthesis, lead to effects consistent with loss of NADH turnover, and importantly, exert bactericidal activity against Mtb. Extensive medicinal chemistry optimization afforded the best analogue with an MIC of 90 nM against Mtb. Moreover, the two scaffolds have differential inhibitory activities against the two homologous Ndh-2 enzymes in Mtb, which will allow precise control over Ndh-2 function in Mtb to facilitate the assessment of this anti-TB drug target.

Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented blood meal, with IC50 values ranging from 33 to 575 nM, and were fully active against strains with preexisting resistance to common insecticides. Based on allometric scaling of preclinical pharmacokinetics data, we predict that a single human median dose of 260 mg (IQR, 177-407 mg) for afoxolaner, or 410 mg (IQR, 278-648 mg) for fluralaner, could provide an insecticidal effect lasting 50-90 days against mosquitoes and Phlebotomus sand flies. Computational modeling showed that seasonal mass drug administration of such a single dose to a fraction of a regional population would dramatically reduce clinical cases of Zika and malaria in endemic settings. Isoxazolines therefore represent a promising new component of drug-based vector control.

This study investigated the potential association between levels of plasma neurofilament light chain (NfL) and cognitive function in patients suffering from Parkinson's disease (PD) in P.R. China.We collected a total of 168 participants (130 PD patients and 38 healthy controls),and evaluated the relationship of plasma NfL levels with cognitive dysfunction in PD patients. Our results shown that plasma NfL levels increased with an increase in cognitive impairment across the three groups of PD patients: PD with normal cognition (PD-NC), 17.9 ± 8.9 pg/ml; PD with mild cognitive impairment (PD-MCI),21.9 ± 10.3 pg/ml; and PD dementia (PDD), 35.7 ± 21.7 pg/ml. Higher MMSE scores were associated with lower plasma NfL levels (r = -0.49, 95% CI -0.61 to -0.34, p 0.0001). Our results associating plasma NfL levels with cognitive dysfunction in PD are consistent with previous studies carried out in several countries/district, based on our meta-analysis.

Parasitic filarial nematodes cause debilitating infections in people in resource-limited countries. A clinically validated approach to eliminating worms uses a 4- to 6-week course of doxycycline that targetsWolbachia, a bacterial endosymbiont required for worm viability and reproduction. However, the prolonged length of therapy and contraindication in children and pregnant women have slowed adoption of this treatment. Here, we describe discovery and optimization of quinazolines CBR417 and CBR490 that, with a single dose, achieve >99% elimination ofWolbachiain the in vivoLitomosoides sigmodontisfilarial infection model. The efficacious quinazoline series was identified by pairing a primary cell-based high-content imaging screen with an orthogonal ex vivo validation assay to rapidly quantifyWolbachiaelimination inBrugia pahangifilarial ovaries. We screened 300,368 small molecules in the primary assay and identified 288 potent and selective hits. Of 134 primary hits tested, only 23.9% were active in the worm-based validation assay, 8 of which contained a quinazoline heterocycle core. Medicinal chemistry optimization generated quinazolines with excellent pharmacokinetic profiles in mice. Potent antiwolbachial activity was confirmed inL. sigmodontis,Brugia malayi, andOnchocerca ochengiin vivo preclinical models of filarial disease and in vitro selectivity againstLoa loa(a safety concern in endemic areas). The favorable efficacy and in vitro safety profiles of CBR490 and CBR417 further support these as clinical candidates for treatment of filarial infections.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both genetic and environmental risk factors. Previous studies trying to find an association between ALS and unc-13 homolog A (UNC13A) gene variants have shown inconsistent results. This study aimed to conduct a meta-analysis of the association between the C allele of rs12608932, a single-nucleotide polymorphism located in an intron of UNC13A, and risk of ALS and patient survival. PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed databases were systematically searched for genome-wide association studies or case-control studies published up to January 2019 on the association between this variant in UNC13A and risk and/or prognosis of ALS. Data from eligible studies were extracted and analyzed. The pooled data (28,072 patients with sporadic ALS and 56,545 controls) showed that rs12608932(C) was associated with an increased risk of ALS (OR = 1.13, 95%CI 1.07–1.20). Subgroup analysis revealed that rs12608932(C) increased the risk of sporadic ALS in non-Asian individuals, including those from the USA and Europe (OR 1.17, 95%CI 1.10–1.25, P

Objective: The objective of the present study was to meta-analyze relevant literature to gain a comprehensive understanding of the potential relationship between serum uric acid levels and risk of benign paroxysmal positional vertigo (BPPV). Methods: The databases of PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed were systematically searched for observational case-control studies of the association between BPPV and serum uric acid levels published up to October 2018. Data from eligible studies were meta-analyzed using Stata 12.0. Results: A total of 12 studies were included in the analysis. There was a strong tendency for serum uric acid levels to be associated with risk of BPPV among studies conducted in China (OR 0.69, 95%CI -0.01 to 1.40, p = 0.053), but not among studies outside China (OR 1.07, 95%CI -1.08 to 3.22, p = 0.33). Across all studies, serum uric acid level was significantly higher among individuals with BPPV than among controls (OR 0.78, 95%CI 0.15 to 1.41, p = 0.015), yet it did not independently predict risk of the disorder (OR 1.003, 95%CI 0.995 to 1.012, p = 0.471). Conclusion: The available evidence suggests that BPPV is associated with elevated levels of serum uric acid, but these levels may not be an independent risk factor of BPPV.

Purpose Up to 20–30% of patients with Guillain-Barre syndrome (GBS) suffer serious clinical manifestations such as respiratory failure. We aim to determine whether two new prognostic biomarkers, the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), could reliably predict respiratory failure in GBS.we Materials and methods Data from 426 patients diagnosed at our center with GBS between January 2015 and July 2019 were retrospectively analyzed. Data were collected from the hospital database. Logistic regression and receiver operating characteristic curves were used to examine whether NLR alone, PLR alone or the combination, as measured at admission, could predict respiratory failure during hospitalization. Nomograms for predicting respiratory failure in GBS individuals were established, and predictive accuracy was evaluated using Harrell's concordance index (C-index). Results A total of 74 (17%) patients developed respiratory failure during hospitalization, and this was predicted independently by neutrophil count, NLR, PLR, and a combined “NLR-PLR” index, with the combined index performing best. The C-index of nomograms was 0.952 (95%CI 0.930–0.974) when NLR-PLR was included, or 0.933 (95%CI 0.911–0.955) when it was excluded. Conclusions The prognostic biomarkers NLR and PLR may be independent predictors of respiratory failure in GBS. Combining the two indices may be more effective than either one on its own.

Recent studies have shown an association between migraine and restless legs syndrome (RLS), but RLS prevalence among individuals with migraine differs substantially across studies. The present work aimed to comprehensively assess available evidence to estimate RLS prevalence among individuals with migraine and non-migraine controls. Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed databases were searched for observational and case-control studies of RLS prevalence among individuals with migraine. Eligible studies were meta-analyzed using Stata 12.0 software. Pooled RLS prevalence in migraine was 19%, and the prevalence was lower in Asia (16%) than outside Asia (21%). Pooled RLS prevalence was 18.8% among individuals with migraine with aura, and 18.5% among individuals with migraine without aura; the RLS prevalence in migraine with aura (MA) was higher than that of migraine without aura (MO) (OR 1.17, 95%CI 1.01–1.34; p = 0.037). Pooled RLS prevalence in a case-control study was significantly higher among individuals with migraine (17.9%) than among non-migraine controls (7.1%) (OR 2.65, 95%CI 2.26–3.10; p

Objective Multiple sclerosis (MS) is related to the demyelination of intracranial nerves at multiple sites, while restless legs syndrome (RLS) appears to be caused by dysfunction of the dopaminergic system. Since RLS prevalence is higher among MS patients than in the general population, we carried out an updated meta-analysis to understand whether the two diseases might be associated. Method Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed databases were searched for observational and case-controlled studies of RLS prevalence in MS. Eligible studies were meta-analyzed using Stata 12.0. Results Pooled RLS prevalence among MS patients of various ethnicities was 26%, and prevalence was lower in Asia (20%) than outside Asia (27%). Prevalence was higher among cross-sectional studies (30%) than among case–control studies (23%). RLS prevalence was higher among female than male MS patients (26% vs. 17%), and it was higher among MS patients than among healthy controls (OR 3.96, 95%CI 3.29–4.77, p Conclusion Our meta-analysis updates the most recent meta-analysis in 2013 and provides perhaps the first reliable pooled estimate of RLS prevalence in MS. The available evidence strongly suggests that RLS risk is higher among MS patients than healthy controls.

Obstructive sleep apnea (OSA) is associated with higher rates of postoperative delirium. The relationship between preoperative OSA risk and postoperative delirium and coma in thoracic surgery patients hospitalized in the intensive care unit (ICU) is not well understood. This study tests the hypothesis that thoracic surgery patients hospitalized in ICU with a higher preoperative risk for OSA are more likely to develop postoperative delirium and coma, resulting in longer hospital stays.Preoperative OSA risk was measured using the STOP-BANG questionnaire. STOP-BANG scores of greater than or equal to 3 were defined as intermediate-high risk for OSA; 128 patients who underwent major thoracic surgery completed the STOP-BANG questionnaire preoperatively. The Richmond Agitation and Sedation Scale was used to assess level of consciousness. The Confusion Assessment Method for the ICU was used to assess for delirium. Linear regression was used to assess the relationship between risk of OSA and outcome measures. Results were adjusted for age, sex, body mass index, Charlson Comorbidity Index, instrumental activities of daily living, and surgery type.A total of 96 of 128 patients (76%) were in the intermediate-high-risk OSA group. Adjusted analyses showed that the intermediate-high-risk OSA group had a longer duration of postoperative ICU delirium and coma compared with the low-risk OSA group (1.4 ± 1.3 days versus 0.9 ± 1.4 days; P = 0.04). Total number of hospital days was not significantly different.Higher preoperative risk for OSA in thoracic surgery patients was associated with a longer duration of postoperative delirium and coma.

Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X‐ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9. A crystal structure of CYP2C9 in complex with a TCA1 analog revealed the similar interaction patterns to the DprE1–TCA1 complex. Guided by the structures, an optimized molecule was generated with differential inhibitory activities against DprE1 and CYP2C9, which provides insights for development of a clinical candidate to treat TB.

Fibrosis, a disease in which excessive amounts of connective tissue accumulate in response to physical damage and/or inflammatory insult, affects nearly every tissue in the body and can progress to a state of organ malfunction and death. A hallmark of fibrotic disease is the excessive accumulation of extracellular matrix-secreting activated myofibroblasts (MFBs) in place of functional parenchymal cells. As such, the identification of agents that selectively inhibit the transdifferentiation process leading to the formation of MFBs represents an attractive approach for the treatment of diverse fibrosis-related diseases. Herein we report the development of a high throughput image-based screen using primary hepatic stellate cells that identified the antifungal drug itraconazole (ITA) as an inhibitor of MFB cell fate in resident fibroblasts derived from multiple murine and human tissues (i.e., lung, liver, heart, and skin). Chemical optimization of ITA led to a molecule (CBR-096-4) devoid of antifungal and human cytochrome P450 inhibitory activity with excellent pharmacokinetics, safety, and efficacy in rodent models of lung, liver, and skin fibrosis. These findings may serve to provide a strategy for the safe and effective treatment of a broad range of fibrosis-related diseases.

We propose a simple method of combined synchronous modulations to generate the analytically exact solutions for a parity-time symmetric two-level system. Such exact solutions are expressible in terms of simple elementary functions and helpful for illuminating some generalizations of appealing concepts originating in the Hermitian system. Some intriguing physical phenomena, such as stabilization of a non-Hermitian system by periodic driving, non-Hermitian analogs of coherent destruction of tunneling (CDT) and complete population inversion (CPI), are demonstrated analytically and confirmed numerically. In addition, by using these exact solutions we derive a pulse area theorem for such non-Hermitian CPI in the parity-time symmetric two-level system. Our results may provide an additional possibility for pulse manipulation and coherent control of the parity-time symmetric two-level system., Comment: 7 pages, 4 figures

We theoretically investigate light propagation in two coupled nonlinear waveguides with a certain static propagation constant detuning between two waveguides and with the linear refractive index modulated along the propagation direction. By slowly varying the amplitude of modulation, we steer the light to the desired output waveguide when equal amounts of lights are launched into each waveguide. We reveal that depending on the sign of the static propagation constant mismatch (detuning) between two waveguides, the launched light can be completely switched to either of waveguides. Additionally, we numerically examine the performances of light switching for general inputs and modulation amplitudes, and show that the localization of output light is robust against small to moderate variations in the final modulation amplitude, phase difference and intensity distribution of input field between two waveguides. More importantly, according to the principle of the proposed scheme, we are capable of steering the output light to the targeted waveguide at extremely low input power. In theory, our findings can be explained qualitatively by means of adiabatic navigation of the so-called nonlinear Floquet states. Keywords: Light tunneling, Adiabatic passage, Nonlinear waveguides

In this study, we have studied the quantum tunneling of a single spin-orbit-coupled atom held in a periodically modulated optical lattice with an impurity. At the pseudocollapse points of quasienergy bands, where the dynamical localization takes place globally, two types of local second-order tunneling processes appear beyond expectation between the two nearest-neighbor sites of the impurity with the spin unchanged and with impurity site population negligible all the time, when the impurity potential is far off-resonant with the driving field. Though tunneling behaviors of the two types seem to be the same, they are believed to involve two distinct mechanisms: one is related to spin-independent process, while the other is to spin-dependent tunneling process. The two types of second-order processes can be identified by means of resonant tunneling with or without spin-flipping by tuning the impurity potential to be in resonance with the driving field. In the Floquet picture, the second-order processes are manifested as subtle and fine avoided crossings of quasienergy spectrums near the pseudocollapse region. These results are confirmed analytically on the basis of effective three-site model and multiple-time-scale asymptotic perturbative method, and may be exploited for engineering the spin-dependent quantum transport in realistic experiments., Comment: 15 pages, 7 figures

We propose a mechanism for realization of exact control of parity-time (PT) symmetry by using a periodically modulated nonlinear optical coupler with balanced gain and loss. It is shown that for certain appropriately chosen values of the modulation parameters, we can construct a family of exact analytical solutions for the two-mode equations describing the dynamics of such nonlinear couplers. These exact solutions give explicit examples that allow us to precisely manipulate the system from nonlinearity-induced symmetry breaking to PT symmetry, thus providing an analytical approach to the all-optical signal control in nonlinear PT-symmetric structures., Comment: 8 pages, 4 figures

Patients with intractable epilepsy (IE) exhibit an increased risk of premature death, psychosocial dysfunction and decreasing quality of life. The present study aimed to investigate the alteration in the expression of Rho7 in brain tissue from patients with IE, and to examine the association between Rho7 protein expression and IE. Temporal lobe samples were collected from the temporal lobes of 33 patients with IE patients and 10 age‑ and gender‑matched histologically healthy controls. Immunohistochemical staining was conducted to assess the number of Rho7‑positive cells. In addition, double‑label immunofluorescent staining was performed to examine the cellular localization of Rho7. The protein expression of Rho7 was examined using western blotting. Marked immunoreactivity for Rho7 was detected in the IE group, while faint and scattered immunoreactive staining was observed in the control group. The count of Rho7 positive cells in the IE patients was significantly increased compared with the control subjects (23.47±3.9% vs. 12.09±1.05%; P

The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ∼100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring-opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC(90) = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds.

Ene reactions of iminonitroso agents with olefins were investigated in both solution and solid phase. Reactions afforded allyl hydroxylamine products in up to 99% yield and with high regioselectivity. A Cu(I)-mediated enantioselective nitroso ene reaction gave an ene product with up to 40% ee.

Retro iminonitroso Diels-Alder reactions were investigated in both solution and solid phase. In thermal or Cu(I)-mediated reactions, interconversion of various nitroso cycloadducts occurred in the presence of separate dienes. Up to 99% of conversion was observed. Use of chiral ligands in the Cu(I)-medicated reactions gave new cycloadducts enantioselectively.

A series of novel sterol analogs was prepared using nitroso Diels-Alder reactions with ergosterol. Most cycloaddition reactions proceeded in an excellent regio- and stereoselective fashion. Further N-O bond cleavage of cycloadducts generated compounds with biological activity in PC-3 and MCF-7 cancer cell lines.

A remarkably efficient method for derivatization of complex diene-containing natural products by using stabilized iminonitroso Diels-Alder reactions is described. Turimycin H3, ergosterol, reductiomycin, isoforocidin, colchicine and thebaine were found to react with nitrosopyridines in a highly efficient regio- and stereoselective fashion. Preliminary bioactivity evaluations of turimycin cycloadducts are reported.

Infections caused by antibiotic-resistant bacteria are a rising public health threat and make the identification of new antibiotics a priority. From a cell-based screen for bactericidal compounds against Mycobacterium tuberculosis under nutrient-deprivation conditions we identified auranofin, an orally bioavailable FDA-approved antirheumatic drug, as having potent bactericidal activities against both replicating and nonreplicating M. tuberculosis. We also found that auranofin is active against other Gram-positive bacteria, including Bacillus subtilis and Enterococcus faecalis, and drug-sensitive and drug-resistant strains of Enterococcus faecium and Staphylococcus aureus. Our biochemical studies showed that auranofin inhibits the bacterial thioredoxin reductase, a protein essential in many Gram-positive bacteria for maintaining the thiol-redox balance and protecting against reactive oxidative species. Auranofin decreases the reducing capacity of target bacteria, thereby sensitizing them to oxidative stress. Finally, auranofin was efficacious in a murine model of methicillin-resistant S. aureus infection. These results suggest that the thioredoxin-mediated redox cascade of Gram-positive pathogens is a valid target for the development of antibacterial drugs, and that the existing clinical agent auranofin may be repurposed to aid in the treatment of several important antibiotic-resistant pathogens.

Treatment of acylnitroso-Diels–Alder [2.2.1] bicyclic adducts 2a – b with indium triflate in an alcohol solvent induces ring-opening reactions to afford monocyclic anti-1,2-, anti-1,4-, and syn-1,4-hydroxamic acids with good to excellent regio- and stereoselectivity (up to 7:86:7). Treatment of [2.2.2] bicyclic nitroso adducts 2c – d under similar reaction conditions generates only anti-1,2- and anti-1,4-hydroxamic acids with anti-1,4-product being predominant (up to 17:83).

Diels—Alder reactions of colchicine (I) with iminonitroso agents (II) afford the ring-C modified alkaloids (III) and (IV) as regioisomeric adducts.

Treatment of acylnitroso-Diels–Alder [2.2.1] bicyclic adducts 2a – b with indium triflate in an alcohol solvent induces ring-opening reactions to afford monocyclic anti-1,2-, anti-1,4-, and syn-1,4-hydroxamic acids with good to excellent regio- and stereoselectivity (up to 7:86:7). Treatment of [2.2.2] bicyclic nitroso adducts 2c – d under similar reaction conditions generates only anti-1,2- and anti-1,4-hydroxamic acids with anti-1,4-product being predominant (up to 17:83).