Respiratory failure as first presentation of myasthenia gravis: a case report.

Myasthenia gravis (MG) is often complicated by respiratory failure, an exacerbation known as myasthenic crisis. However, most patients with MG develop respiratory symptoms during the late course of the disease. Respiratory failure as an exclusive initial and primary complaint in patients with MG is rare and seldom reported. We herein describe a woman in her late 50s who presented with respiratory failure and was diagnosed with obesity hypoventilation syndrome at a local hospital. Her condition gradually worsened during the next 4 months and became accompanied by dysphagia. After 1 year of medical investigation, she was diagnosed in our hospital. A high level of anti-muscle-specific receptor tyrosine kinase antibody was found in her serum, and stimulation and electromyography results suggested MG. The patient's symptoms were improved by intravenous immunoglobulin and hormone therapy. This case reminds physicians to consider MG when encountering a patient who initially presents with respiratory failure.

Identification of leaf diseases in field crops based on improved ShuffleNetV2.

Rapid and accurate identification and timely protection of crop disease is of great importance for ensuring crop yields. Aiming at the problems of large model parameters of existing crop disease recognition methods and low recognition accuracy in the complex background of the field, we propose a lightweight crop leaf disease recognition model based on improved ShuffleNetV2. First, the repetition number and the number of output channels of the basic module of the ShuffleNetV2 model are redesigned to reduce the model parameters to make the model more lightweight while ensuring the accuracy of the model. Second, the residual structure is introduced in the basic feature extraction module to solve the gradient vanishing problem and enable the model to learn more complex feature representations. Then, parallel paths were added to the mechanism of the efficient channel attention (ECA) module, and the weights of different paths were adaptively updated by learnable parameters, and then the efficient dual channel attention (EDCA) module was proposed, which was embedded into the ShuffleNetV2 to improve the cross-channel interaction capability of the model. Finally, a multi-scale shallow feature extraction module and a multi-scale deep feature extraction module were introduced to improve the model's ability to extract lesions at different scales. Based on the above improvements, a lightweight crop leaf disease recognition model REM-ShuffleNetV2 was proposed. Experiments results show that the accuracy and F1 score of the REM-ShuffleNetV2 model on the self-constructed field crop leaf disease dataset are 96.72% and 96.62%, which are 3.88% and 4.37% higher than that of the ShuffleNetV2 model; and the number of model parameters is 4.40M, which is 9.65% less than that of the original model. Compared with classic networks such as DenseNet121, EfficientNet, and MobileNetV3, the REM-ShuffleNetV2 model not only has higher recognition accuracy but also has fewer model parameters. The REM-ShuffleNetV2 model proposed in this study can achieve accurate identification of crop leaf disease in complex field backgrounds, and the model is small, which is convenient to deploy to the mobile end, and provides a reference for intelligent diagnosis of crop leaf disease.

Estimating maize evapotranspiration based on hybrid back-propagation neural network models and meteorological, soil, and crop data.

Crop evapotranspiration is a key parameter influencing water-saving irrigation and water resources management of agriculture. However, current models for estimating maize evapotranspiration primarily rely on meteorological data and empirical coefficients, and the estimated evapotranspiration contains uncertainties. In this study, the evapotranspiration data of summer maize were collected from typical stations in Northern China (Yucheng Station), and a back-propagation neural network (BP) model for predicting maize evapotranspiration was constructed based on meteorological data, soil data, and crop data. To further improve its accuracy, the maize evapotranspiration model was optimized using three bionic optimization algorithms, namely the sand cat swarm optimization (SCSO) algorithms, hunter-prey optimizer (HPO) algorithm, and golden jackal optimization (GJO) algorithm. The results showed that the fusion of meteorological, soil moisture, and crop data can effectively improve the accuracy of the maize evapotranspiration model. The model showed higher accuracy with the hybrid optimization model SCSO-BP compared to the stand-alone BP neural network model, with improvements of 2.7-4.8%, 17.2-25.5%, 13.9-26.8%, and 3.3-5.6% in terms of R2, RMSE, MAE, and NSE, respectively. Comprehensively compared with existing maize evapotranspiration models, the SCSO-BP model presented the highest accuracy, with R2 = 0.842, RMSE = 0.433 mm/day, MAE = 0.316 mm/day, NSE = 0.840, and overall global evaluation index (GPI) ranking the first. The results have reference value for the calculation of daily evapotranspiration of maize in similar areas of northern China.

Atorvastatin Calcium Ameliorates Cognitive Deficits Through the AMPK/Mtor Pathway in Rats with Vascular Dementia.

AIM: In this study, the protective effects of atorvastatin calcium (AC) on nerve cells and cognitive improvement in vivo and in vitro were investigated by establishing cell models and vascular dementia (VD) rat models. BACKGROUND: VD is a neurodegenerative disease characterized by cognitive deficits caused by chronic cerebral hypoperfusion. AC has been studied for its potential to cure VD but its efficacy and underlying mechanism are still unclear. OBJECTIVE: The mechanism of action of AC on cognitive deficits in the early stages of VD is unclear. Here, the 2-vessel occlusion (2-VO) model in vivo and the hypoxia/reoxygenation (H/R) cell model in vitro was established to investigate the function of AC in VD. METHODS: The spatial learning and memory abilities of rats were detected by the Morris method. The IL-6, tumour necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) in cell supernatant was tested by ELISA kits. After behavioural experiments, rats were anaesthetized and sacrificed, and their brains were extracted. One part was immediately fixed in 4% paraformaldehyde for H&E, Nissl, and immunohistochemical analyses, and the other was stored in liquid nitrogen. All data were shown as mean ± SD. Statistical comparison between the two groups was performed by Student's t-test. A two-way ANOVA test using GraphPad Prism 7 was applied for escape latency analysis and the swimming speed test. The difference was considered statistically significant at p < 0.05. RESULTS: AC decreased apoptosis, increased autophagy, and alleviated oxidative stress in primary hippocampal neurons. AC regulated autophagy-related proteins in vitro by western blotting. VD mice improved cognitively in the Morris water maze. Spatial probing tests showed that VD animals administered AC had considerably longer swimming times to the platform than VD rats. H&E and Nissl staining showed that AC reduces neuronal damage in VD rats. Western blot and qRT-PCR indicated that AC in VD rats inhibited Bax and promoted LC3-II, Beclin-1, and Bcl-2 in the hippocampus region. AC also improves cognition via the AMPK/mTOR pathway. CONCLUSION: This study found that AC may relieve learning and memory deficits as well as neuronal damage in VD rats by changing the expression of apoptosis/autophagy-related genes and activating the AMPK/mTOR signalling pathway in neurons.

Diagnostic value of clinical deep tendon reflexes in diabetic peripheral neuropathy.

Introduction: The aim of the present study was to evaluate the diagnostic efficacy of different tendon reflexes in detecting diabetic peripheral neuropathy (DPN). Material and methods: According to the changes in tendon reflexes, all patients with diabetes were divided into three strata: impaired Achilles reflex only, impaired lower extremity reflexes, and impaired lower and upper extremity reflexes. Taking nerve conduction studies (NCS) as the gold standard, the sensitivity, specificity, and predictive ability of the tendon reflexes of these three strata, as well as the Toronto clinical scoring system (TCSS) and Michigan Neuropathy Screening Instrument (MNSI), were calculated. Then, the electrophysiological characteristics of diabetic patients with different tendon reflexes were analysed. Results: Among the 240 patients studied, 92 (38.3%) presented evidence of neuropathy, which was confirmed by abnormal NCS, while 148 (61.7%) had normal NCS results. Taking NCS as the gold standard, stratum 1 yielded a sensitivity and specificity of 93.5% and 54.7%, respectively, while stratum 3 had higher specificity (96.6%) and lower sensitivity (34.8%) when compared to stratum 1. However, stratum 2 had the highest specificity (75.7%). Conclusions: The assessment of tendon reflexes can be proposed as a test for screening diabetic polyneuropathy.

The neuroprotective effect of Dl-3-n-butylphthalide in epileptic rats via inhibiting endoplasmic reticulum stress.

INTRODUCTION: The purpose of this study is to investigate whether Dl-3-n-Butylphthalide (NBP) has a neuroprotective effect on pilocarpine-induced epileptic (EP) rats through endoplasmic reticulum stress (ERS)-mediated apoptosis. MATERIAL AND METHODS: The Sprague-Dawley rats were divided into four groups: control (CON), EP, EP + NBP 60 (NBP 60 mg/kg) and EP + NBP 120 (NBP 120 mg/kg) groups. After the successful establishment of the temporal lobe EP model using the lithium-pilocarpine, the rats were given NBP for 28 consecutive days in EP + NBP 60 and EP + NBP 120 groups. Then, the spontaneous recurrent seizure (SRS) latency, SRS frequency and seizure duration were observed in each group. In order to observe the abnormal discharge of rats, the intracranial electrodes were implanted to monitor the electroencephalogram. Nissl staining was used to observe the damage to the hippocampal CA1 neurons, TUNEL staining was employed to observe hippocampal neuronal apoptosis. Western blot was used to detect the expression of ERS and ERS-mediated apoptotic proteins. RESULTS: NBP 60 and NBP 120 decreased SRS frequency (all p < 0.05), shortened seizure duration (all p < 0.05), and reduced the abnormal discharge of the brain. Nissl staining and TUNEL staining results show that NBP protected the hippocampal neurons from damage (all p < 0.05) and inhibited hippocampal neuronal apoptosis in EP rats (all p < 0.05). NBP 60 and NBP 120 could reduce ERS and ERS-mediated apoptotic protein expression in EP rats (all p < 0.05). In addition, the therapeutic effect of NBP on epilepsy in rats is dose-dependent. The SRS frequency of the EP + NBP 120 group was lower, and the seizure duration was shorter than in the EP + NBP 60 group (all p < 0.05), and there were more neurons in the EP + NBP 120 group than in the EP + NBP 60 group ( p < 0.05). CONCLUSIONS: NBP had a significant neuroprotective effect in EP rats. Large doses of NBP are more effective than low doses. The mechanism may be associated with the inhibition of ERS and ERS-mediated apoptosis.

Erythropoietin (EPO) and Hippocampal Neurons: Effects on Sports Performance, Fitness, and Football Players with Vascular Cognitive Impairment

Objective: This study delves into the impact of erythropoietin (EPO) on hippocampal neurons and its potential implications for sports performance, fitness, and the cognitive well-being of football players facing vascular cognitive impairment. Methodology: The study employs a comprehensive approach, utilizing a rat model of vascular dementia (VaD) induced by bilateral carotid artery ligation. Exogenous EPO is administered to the VaD rat model. Observations of EPO's influence on hippocampal neurons are made, and in vitro experiments are conducted to validate the specific mechanisms at play, particularly under oxygen/glucose-deprived conditions. Results: The results reveal several noteworthy findings. VaD rats treated with EPO demonstrate significantly shorter escape latency, increased neuronal populations, and enhanced preservation of Nissl bodies in hippocampal subfields, specifically cortical area 1 (CA1) and CA2. Moreover, these rats exhibit a lower count of TUNEL-positive cells compared to the model group, with higher doses of EPO demonstrating more notable improvements in escape latency. Molecular analysis shows that EPO up-regulates key protein expressions, including phosphorylated EPO receptor (p-EPOR), p-phosphatidylinositol 3-kinase (p-PI3K), p-protein kinase B (Akt), and p-cyclic AMP response element binding protein (p-CREB). Simultaneously, it down-regulates expressions of apoptosis- and autophagy-related proteins, such as B-cell lymphoma-2-associated X protein (Bax), cleaved-Caspase 3, cleaved-Caspase 9, light chain 3β (LC3β), Beclin, autophagy-related gene 5 (ATG5), and ATG7. Notably, in vitro experiments confirm the role of the PI3K/AKT pathway in EPO's mechanisms, with implications for cognitive health. (AU)

Hormonal Balance, Photosynthesis, and Redox Reactions in the Leaves of Caragana korshinskii Kom. under Water Deficit.

To evaluate the physiological responses of Korshinsk peashrub (Caragana korshinskii Kom.) to water deficit, photosynthetic gas exchange, chlorophyll fluorescence, and the levels of superoxide anion (O2•-), hydrogen peroxide (H2O2), malondialdehyde (MDA), antioxidant enzymes, and endogenous hormones in its leaves were investigated under different irrigation strategies during the entire growth period. The results showed that leaf growth-promoting hormones were maintained at a higher level during the stages of leaf expansion and vigorous growth, and zeatin riboside (ZR) and gibberellic acid (GA) gradually decreased with an increase in water deficit. At the leaf-shedding stage, the concentration of abscisic acid (ABA) dramatically increased, and the ratio of ABA to growth-promoting hormones increased to a high level, which indicated that the rate of leaf senescence and shedding was accelerated. At the stages of leaf expansion and vigorous growth, the actual efficiency of photosystem II (PSII) (ΦPSii) was downregulated with an increment in non-photochemical quenching (NPQ) under moderate water deficit. Excess excitation energy was dissipated, and the maximal efficiency of PSII (Fv/Fm) was maintained. However, with progressive water stress, the photo-protective mechanism was inadequate to avoid photo-damage; Fv/Fm was decreased and photosynthesis was subject to non-stomatal inhibition under severe water deficit. At the leaf-shedding stage, non-stomatal factors became the major factors in limiting photosynthesis under moderate and severe water deficits. In addition, the generation of O2•- and H2O2 in the leaves of Caragana was accelerated under moderate and severe water deficits, which caused an enhancement of antioxidant enzyme activities to maintain the oxidation-reduction balance. However, when the protective enzymes were insufficient in eliminating excessive reactive oxygen species (ROS), the activity of catalase (CAT) was reduced at the leaf-shedding stage. Taken all together, Caragana has strong drought resistance at the leaf expansion and vigorous growth stages, but weak drought resistance at the leaf-shedding stage.

The economic and humanistic burden of bipolar disorder in adults in the United States.

BACKGROUND: Bipolar disorder is associated with functional impairment and diminished health-related quality of life (HRQoL). The purpose of this study was to estimate the annual per patient direct healthcare costs, indirect costs, and HRQoL of patients with bipolar disorder by depressive symptom severity and overall compared to the general population in the US. METHODS: This cross-sectional study used self-reported data from the 2020 US National Health and Wellness Survey. Adult respondents who reported bipolar disorder symptoms in the past 12 months and/or a diagnosis of bipolar disorder were identified (bipolar disorder cohort) and were further classified by depressive symptom severity based on Patient Health Questionnaire (PHQ-9) scores (none/mild = 0-9, moderate = 10-14, severe = 15-27). Annualized direct healthcare costs and indirect costs were calculated from 6-month healthcare resource utilization and work productivity, respectively. A general population cohort was constructed using 2:1 propensity score matching. Multivariate regression models of all-cause hospitalizations in the past 6 months, annualized direct healthcare costs, annualized indirect costs, and HRQoL (eg, EuroQol 5-Dimension Health Questionnaire (EQ-5D)) controlled for confounders (demographic and clinical characteristics). RESULTS: Of 3583 adults meeting pre-specified criteria for bipolar disorder, 1401 (39.1%) reported none/mild, 889 (24.8%) moderate, and 1293 (36.1%) severe depressive symptom severity. Additionally, 3285 (91.7%) were matched to 6570 adults in the general population. Compared to the general population, adjusted mean hospitalizations (0.53 vs. 0.30), annualized per patient direct healthcare costs ($20,846 vs. $11,391), and indirect costs ($14,795 vs. $9274) were significantly greater for the bipolar disorder cohort (all p < 0.001); adjusted HRQoL (EQ-5D: 0.69 vs. 0.79) was significantly worse (p < 0.001). By depressive symptom severity, adjusted mean hospitalizations (none/mild = 0.30, moderate = 0.50, severe = 0.46), direct healthcare costs ($14,389, $22,302, $21,341), and indirect costs ($10,799, $17,109, $18,470) were significantly greater for moderate and severe compared to none/mild depressive symptom severity (all p < 0.01); adjusted HRQoL (EQ-5D: 0.77, 0.67, 0.59) was significantly worse (p < 0.001). CONCLUSIONS: Among respondents with bipolar disorder, those with moderate to severe depression had greater direct healthcare costs and indirect costs as well as worse HRQoL than those with mild or no depressive symptoms. Treatment targeting reduction in depressive symptoms may reduce the economic and humanistic burden of bipolar disorder.

Longitudinal Associations Between Serum Bilirubin Level and Carotid Atherosclerosis Plaque in a Health Screening Population.

This study aimed to determine the relationship between bilirubin levels and carotid atherosclerosis (CAS) in the health screening population. After propensity score matching, this retrospective cohort study included 4360 subjects who underwent health examinations regularly in Hebei General Hospital between January 2010 and December 2019 and had no carotid plaque at baseline. After an average follow-up of 26.76 months, the main endpoint Cox regression analysis of carotid plaques was performed. After adjusting the confounding factors, Cox regression analysis showed that when serum total bilirubin (TBIL) and unconjugated bilirubin (UCB) increased by 1 standard deviation (SD), the risk of carotid plaque decreased by 7.30% (95% confidence interval (CI): 2.80-11.60%) and 15.70% (95% CI: 11.40-19.80%), respectively. When conjugated bilirubin (CB) increased by 1 SD, the risk of carotid plaques increased by 24.3% (95% CI: 19.7-29.0%). TBIL and UCB levels were negatively associated with CAS, and CB levels were positively associated with CAS.

The construction of neurogenesis-related ceRNA network of ischemic stroke treated by oxymatrine.

BACKGROUND: Known as a disease associated with high mortality, disability and a significant financial burden, ischemic stroke ranks as one of the three diseases threatening human health. Recent advances in omics technology created opportunities to uncover the mechanism in ischemic stroke occurrence and treatment. In this study, we aimed to construct the competitive endogenous RNA (ceRNA) networks of ischemic stroke treated by oxymatrine intervention. METHOD: The middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke was constructed, and oxymatrine was administered. Then RNA-Sequencing was performed and integrated analysis of mRNAs, lncRNAs and circRNAs was conducted to reveal the pharmacology of oxymatrine. Functional enrichment analysis was performed to explore the underlying mechanism of differentially expressed (DE) mRNAs. The protein-protein interaction (PPI) network of neurogenesis-related genes and long noncoding RNAs (lncRNAs)/circular RNAs (circRNAs) based ceRNA networks were constructed. RESULTS: First, this study revealed the DE-mRNAs, DE-lncRNAs and DE-circRNAs between Oxymatrine treated group and the MCAO group. Then, the common 1231 DE-mRNAs, 32 DE-lncRNAs and 31 DE-circRNAs with opposite trends were identified. The Kyoto Encyclopedia of Genes and Genomes to identify the functional enrichment of 1231 DE-mRNAs were enriched in neurogenesis-related biological processes. Based on neurogenesis-related DE-mRNAs, the PPI network was constructed, and hub genes were identified based on centrality. Finally, both the lncRNA-based and circRNAs-based ceRNA networks were constructed. CONCLUSION: In summary, this study identified novel coding and noncoding ischemic stroke targets of oxymatrine-treated MCAO. Most importantly, we identified lncRNAs and circRNAs candidates as potential oxymatrine targets and constructed the neurogenesis-related ceRNA networks.

Impact of lurasidone on health-related quality of life in adults with bipolar depression: a post-hoc analysis.

OBJECTIVE: The objective of this post-hoc analysis was to assess the impact of lurasidone monotherapy on health-related quality of life (HRQoL) in adults with bipolar depression. METHODS: Data were analyzed from a 6-week randomized, double-blind (DB), placebo-controlled trial of lurasidone monotherapy (NCT00868699) and a 6-month open label extension (OLE; NCT00868959). Patients who received lurasidone monotherapy or placebo during the DB trial were eligible to continue or switch to lurasidone monotherapy during the OLE. The 16-item Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) was collected at DB baseline, DB week 6/OLE baseline, OLE month 3, and OLE month 6. Effect size (ES) and mean changes from baseline were reported for Q-LES-Q-SF total and item scores during the DB trial and OLE, respectively. RESULTS: Of 485 patients in the DB trial (lurasidone monotherapy: n = 323; placebo: n = 162), 316 patients continued or switched to lurasidone monotherapy during the OLE. Significant improvements in Q-LES-Q-SF scores in lurasidone vs. placebo were reported for 13 of 16 items (all p < .05) at DB week 6. The greatest improvements were overall life satisfaction (ES = 0.57), social relationships (0.55), medication satisfaction (0.48), family relationships (0.46), and ability to function in daily life (0.45, all p < .001). Improvements in Q-LES-Q-SF total and item scores were sustained at OLE month 6. CONCLUSIONS: Treatment with lurasidone provided a significant improvement across HRQoL items including overall life satisfaction, social and family relationships, medication satisfaction, and ability to function in daily life. Improvements were sustained during the 6-month OLE.

OX40 enhances T cell immune response to PD-1 blockade therapy in non-small cell lung cancer.

Immune-checkpoint blockade is widely studied for cancer therapy. Although the co-inhibitory receptor Programmed death-1(PD-1) blockade benefits some non-small cell lung cancer (NSCLC) patients, a large portion of NSCLC patients still fail to respond to this immunotherapy, and the underlying mechanism is unclear. Thus, a synergistic therapy to enhance the effect of PD-1 is urgently needed to improve the poor outcome of NSCLC patients. Here, we demonstrated that effector memory T cells were increased and T cell response became stronger in PD-1 immunotherapy responders (n = 20) but not in non-responders (n = 10). The expression of co-stimulatory receptor OX40 was upregulated on T cells following PD-1 immunotherapy and was positively associated with the percentage of PD-1+T cells and the responsiveness of T cells. Combination treatment of antagonistic anti-PD-1 and agonistic anti-OX40 antibodies (Abs) promoted the proliferation and cytokines production of T cells from PBMCs of non-responders ex vivo. Consistently, anti-PD-1 and anti-OX40 therapy synergistically augmented T cell response in an in vivo mouse lung cancer model. Our study confirmed the antitumor effects of anti-PD-1/OX40 combination in lung cancer patients as well as in the murine lung cancer model, and the results provide a rationale for clinical trials evaluating the therapeutic effect of this combination of antibodies for NSCLC immunotherapy.

Deficit Irrigation at Pre-Anthesis Can Balance Wheat Yield and Water Use Efficiency under Future Climate Change in North China Plain.

BACKGROUND: Deficit irrigation (DI) is a feasible strategy to enhance crop WUE and also has significant compensation effects on yield. Previous studies have found that DI has great potential to maintain crop production as full irrigation (FI) does. Therefore, adopting DI to improve crop production and safeguard groundwater resources is of great importance in water scarce regions, e.g., the North China Plain (NCP). Under the background of global warming, it is worth investigating whether DI continues to play such a key role under future climate scenarios. METHODS: We studied the response of winter wheat yield and WUE to different DI levels at pre-anthesis under two Shared Socioeconomic Pathways (SSPs) scenarios (SSP245 and SSP585) using the Agricultural Production Systems Simulator (APSIM) model driven by 21 general circulation models (GCMs) from the Coupled Model Inter-Comparison Project phase 6 (CMIP6). Additionally, we explored the effects of different nitrogen (N) fertilizer application rates on DI. RESULTS: We found that simulated wheat yield would increase by 3.5-45.0%, with WUE increasing by 8.8-46.4% across all treatments under future climate change. Moderate deficit irrigation (DI3, ≤0.4 PAWC at the sowing to flowering stage) under the N3 (150 kg N ha-1) condition was identified as the optimum irrigation schedule for the study site under future climate change. However, compensation effects of DI3 on yield and WUE became weak in the future, which was mainly due to increased growing season rainfall projected by GCMs. In addition, we found that N fertilizer application could mitigate the effect of DI3. CONCLUSIONS: We highlight that in water scarce regions of NCP, DI remains an effective strategy to maintain higher yield and enhance water use under future climate scenarios. Results strongly suggest that moderate deficit irrigation under a 150 kg N ha-1 condition could mitigate the contradiction between production and water consumption and ensure food safety in the NCP.

Dl-3-n-Butylphthalide Improves Neuroinflammation in Mice with Repeated Cerebral Ischemia-Reperfusion Injury through the Nrf2-Mediated Antioxidant Response and TLR4/MyD88/NF-κB Signaling Pathway.

Increasing evidence shows that oxidative stress and neuroinflammation play a crucial role in the pathology of vascular dementia (VD). Previously, we have found that Dl-3-n-butylphthalide (NBP) has antioxidant and anti-inflammatory activities in VD, whereas little is known about its mechanism. Therefore, the objective of our study was to explore the contribution of nuclear factor erythroid-2 related factor 2 (Nrf2) to NBP and its effects on anti-inflammatory activity in a mouse model of VD. Our studies revealed that NBP could effectively mitigate cognitive deficits, neuron cell loss, and apoptosis in mice subjected to repeated cerebral ischemia-reperfusion (RCIR). Additionally, NBP promoted both the expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) in hippocampus tissue. NBP exhibited antioxidant activity by enhancing Nrf2 nuclear accumulation, increasing HO-1 and NQO1 expression, enhancing SOD activity, and inhibiting RCIR-induced MDA and 8-iso PGF2α generation in the hippocampus. NBP also significantly inhibited TLR4/MyD88/NF-κB signaling and suppressed microglial proliferation and the production of proinflammatory mediators in RCIR mice. Importantly, the antioxidant, antineuroinflammatory, and neuroprotective effects of NBP above were abolished by Nrf2 knockout. Collectively, these results indicated the effects of NBP on neuroinflammation were strongly associated with the Nrf2 pathway. Modulation of TLR4/MyD88/NF-κB pathway by Nrf2 is involved in the neuroprotective effect of NBP against VD induced by RCIR injury. With antioxidant and anti-neuroinflammatory properties, NBP could be a promising drug candidate for the prevention and/or treatment of VD and other neuroinflammatory disorders.

Prospective Evaluation of Exacerbations Associated with Suboptimal Peak Inspiratory Flow Among Stable Outpatients with COPD.

Purpose: A suboptimal peak inspiratory flow (PIF) against a dry powder inhaler (DPI) may result in ineffective inhalation of medications, which may affect outcomes. The primary objective of this study was to examine the association between PIF status and COPD exacerbations among outpatients with moderate to very severe COPD. Patients and Methods: This was a prospective, observational study of patients from 7 US outpatient centers. PIF was measured using an inspiratory flow meter (In-Check™ DIAL G16) set to medium low resistance. Patients were classified by suboptimal (<60 L/min) or optimal PIF (≥60 L/min). The primary outcome was the proportion of patients with moderate/severe COPD exacerbations collected by medical record review over 12 months. Secondary outcomes were time to first exacerbation and mortality. Results: Of 474 patients screened, 38.8% had suboptimal PIF, and 71 patients with optimal PIF were excluded from the study. The enrolled sample included 184 and 219 patients with suboptimal and optimal PIF, respectively. Suboptimal PIF was associated with shorter stature (66.6±4.1 vs 67.8±3.8 inches, P = 0.002), female sex (45.1 vs 34.7%, P = 0.033), Black race (27.2 vs 11.0%, P < 0.001), and greater symptom burden (CAT: 22.3±7.7 vs 19.0±7.0, P < 0.001; mMRC: 2.0±1.1 vs 1.7±1.1, P = 0.003). The proportion of patients with COPD exacerbations at 12 months was not significantly different (29.3 vs 27.9%, P = 0.751). Suboptimal PIF was associated with shorter time to first COPD exacerbation (3.8±2.7 vs 4.9±3.0 months, P = 0.048). The mortality rate at 12 months was higher in the suboptimal cohort but not significantly different (6.5 vs 2.8%, P = 0.073). Conclusion: Over one-third of outpatients with stable moderate to very severe COPD had a suboptimal PIF against a medium low resistance DPI. The phenotype of suboptimal PIF was short stature, female, and Black. Suboptimal PIF status was associated with shorter time to moderate/severe COPD exacerbations compared with optimal PIF.

The impact of lurasidone on functioning and indirect costs in adults with bipolar depression: a post-hoc analysis.

OBJECTIVE: The aim of this post-hoc analysis was to assess the impact of lurasidone monotherapy on functional impairment, productivity, and associated indirect costs in patients with bipolar depression. METHODS: Data were analyzed from a 6-week randomized, double-blind (DB; NCT00868699), placebo-controlled trial of lurasidone monotherapy and a 6-month open label extension (OLE; NCT00868959) study. Patients with bipolar depression who completed the 6-week DB trial were subsequently enrolled in the OLE. Analysis of the OLE was limited to patients who either continued lurasidone (LUR-LUR) or switched from placebo to lurasidone monotherapy (PBO-LUR). The Sheehan Disability Scale (SDS), which measures functional impairment and productivity, was collected at DB baseline, DB week 6/OLE baseline, OLE month 3, and OLE month 6. Annual indirect costs were calculated based on days lost or unproductive from work/school due to symptoms. Effect sizes (ES) in functioning and days lost/unproductive were reported for the DB trial and mean changes for the OLE. RESULTS: A total of 485 patients were enrolled in the DB trial (lurasidone: n = 323; placebo: n = 162) and 316 were in the lurasidone monotherapy group during the OLE (LUR-LUR: n = 210; PBO-LUR: n = 106). In the DB trial, improvements in functioning (work: ES = 0.36, p = .0071; social: ES = 0.55, p < .0001; family: ES = 0.50, p < .0001) were significantly greater for lurasidone compared to placebo. Reductions in days lost (ES = 0.33, p = .0050) and unproductive (ES = 0.45, p = .0001) were significantly higher for lurasidone vs. placebo. This resulted in a greater reduction in indirect costs for lurasidone vs. placebo (least squares mean (standard error) = -$32,322 ($2,100) vs. -$20,091 ($2,838)). Improvements in functioning and productivity were sustained during the 6-month OLE for both LUR-LUR and PBO-LUR. CONCLUSIONS: Lurasidone monotherapy for the treatment of bipolar depression significantly improved functioning and reduced indirect costs vs. placebo at week 6. Significant improvements in functioning and productivity were sustained for 6 months for both LUR-LUR and PBO-LUR.

Role of Different Doses of Ketamine in Postoperative Neurocognitive Function in Aged Mice Undergoing Partial Hepatectomy by Regulating the Bmal1/NMDA/NF-Κb Axis.

BACKGROUND: The current study set out to probe the function of different doses of ketamine in postoperative neurocognitive disorder (PND) in aged mice undergoing partial hepatectomy (PH) with the involvement of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1)/n-methyl-D-aspartate (NMDA)/nuclear factor-kappa B (NF-κB) axis. METHODS: First, aged mice were intraperitoneally injected with different doses of ketamine prior to surgery, followed by hepatic lobectomy. Afterward, mice cognitive function was assessed. In addition, Bmal1 mRNA expression patterns were quantified, while NMDA 2B receptor, NF-κB p65, synapsin 1, and postsynaptic density 95 (PSD95) levels were determined; the release of inflammatory factors was detected, and ionized calcium-binding adapter molecule-1 expression was measured to quantify microglia activation. In addition, Bmal1-knockout (Bmal1-KO) mice were intraperitoneally injected with a subanesthetic dose of ketamine to verify the mechanism of Bmal1 in regulating the NMDA 2B subunit (NR2B)/NF-κB axis to affect PH in aged patients. RESULTS: After PH, hippocampal-dependent memory was impaired, and synapsin 1 and PSD95 levels were downregulated. On the other hand, PH diminished Bmal1 expression but elevated NR2B and NF-κB p65 levels and anesthetic doses of ketamine further regulated the Bmal1/NMDA/NF-κB axis. In Bmal1-KO mice, the NMDA/NF-κB axis was activated, the release of inflammatory cytokines was promoted, and hippocampus-dependent memory was impaired, which were reversed by a subanesthetic dose of ketamine. CONCLUSION: Altogether, findings obtained in our study indicated that a subanesthetic dose of ketamine activated Bmal1, downregulated the NMDA/NF-κB axis, and reduced inflammation and microglia activation to alleviate PND in aged mice undergoing PH.

Development of MDS-Based Predication Model for COPD Severity in Nursing Home Residents.

BACKGROUND: Assessing chronic obstructive pulmonary disease (COPD) severity is challenging in nursing home (NH) residents due to incomplete symptom assessments and exacerbation history. OBJECTIVE: The objective of this study was to predict COPD severity in NH residents using the Minimum Data Set (MDS), a clinical assessment of functional capabilities and health needs. METHODS: A cohort analysis of prospectively collected longitudinal data was conducted. Residents from geographically varied Medicare-certified NHs with age ≥60 years, COPD diagnosis, and ≥6 months NH residence at enrollment were included. Residents with severe cognitive impairment were excluded. Demographic characteristics, medical history, and MDS variables were extracted from medical records. The care provider-completed COPD Assessment Test (CAT) and COPD exacerbation history were used to categorize residents by Global Initiative for Chronic Lung Disease (GOLD) A to D groups. Multivariate multinomial logit models mapped the MDS to GOLD A to D groups with stepwise selection of variables. RESULTS: Nursing home residents (N = 175) were 64% women and had a mean age of 77.9 years. Among residents, GOLD B was most common (A = 13.1%; B = 44.0%; C = 5.7%; D = 37.1%). Any long-acting bronchodilator (LABD) use and any dyspnea were significant predictors of GOLD A to D groups. The predicted MDS-GOLD group (A = 6.9%; B = 52.6%; C = 4.6%; D = 36.0%) showed good model fit (correctly predicted = 60.6%). Nursing home residents may underuse group-recommended LABD treatment (no LABD: B = 53.2%; C = 80.0%; D = 40.0%). CONCLUSION AND RELEVANCE: The MDS, completed routinely for US NH residents, could potentially be used to estimate COPD severity. Predicted COPD severity with additional validation could provide a map to evidence-based treatment guidelines and may help to individualize treatment pathways for NH residents.

Clinical observation of pulmonary lymphoepithelioma-like carcinoma.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) of the lung is a rare type of non-small cell lung cancer (NSCLC), and researches of it are still not enough. METHODS: In this study, we retrospectively analyzed 36 patients with LELC diagnosed in the Fifth Affiliated Hospital of Sun Yat-sen University and Zhaoqing First People's Hospital from January 2014 to June 2021, to investigate the clinical manifestations, tumor markers, treatment, and prognosis of LELC. Clinical data including age, gender, smoking history, family history of cancers, Epstein-Barr virus (EBV) encoding RNA (EBER) status, gene mutations, programmed death-ligand 1 (PD-L1) expression, treatment, and prognosis. RESULTS: There was a total of 36 participants in this study, 16 males and 20 females, the median age was 57 years (37-76 years). A total of 22 cases (61.1%) were advanced (stage III and IV), and EBER was 94.4% positive. Most patients were treated with surgery, platinum chemotherapy, or radiotherapy. At the time of 31 June 2021, 33 participants had survived, and the longest survival time was 72 months. Lung LELC was more common in old participants (≥59 years) and was not associated with smoking history. Expression of PD-L1 was positive in the majority (27 cases, 75%) and participants with positive PD-L1 expression tended to have longer progression-free survival (PFS) and overall survival (OS) time than those with negative PD-L1 expression. CONCLUSIONS: Pulmonary LELC usually occurs in non-smoking patients and is associated with EBV infection. Common treatments for tumors include multimodal therapy. The expression of PD-1 may be related to the prognosis of LELC, but more studies are needed to support further optimization of the treatment of LELC.