Identification and Root Cause Analysis of the Visible Particles Commonly Encountered in the Biopharmaceutical Industry.

Visible particle is an important issue in the biopharmaceutical industry, and it may occur across all the stages in the life cycle of biologics. Upon the occurrence of visible particles, it is often necessary to conduct chemical identification and root cause analysis to safeguard the safety and efficacy of the biotherapeutic products. In this article, we present a number of typical particles and relevant root cause analysis in the categories of extrinsic, intrinsic and inherent particles that are commonly encountered in the biopharma industry. In particular, the optical images of particles obtained both in situ and after isolation are provided, along with the spectral and elemental information. The particle identification was carried out with multiple microscopic and microspectroscopic techniques, including stereo optical microscopy, Fourier transform infrared microscopy, confocal Raman microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. Both commercial and in-house spectral databases were used for comparison and identification. In addition to particle identification, our significant efforts are placed on the root cause analysis of the addressed particles with the intention to provide a relatively whole picture of the particle related issues and practical references to particle mitigation for our peers in the biopharmaceutical industry.

Drug deconjugation-assisted peptide mapping by LC-MS/MS to identify conjugation sites and quantify site occupancy for antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a heterogeneous mixture of conjugated species with varied drug loadings. Depending on conjugation sites, linkers and drugs can exhibit different stability as influenced by the solvent-accessibility and local charge, resulting in different ADC efficacy, pharmacokinetics, and toxicity. Conjugation site analysis is critical for ADC structural characterization to assure product quality and consistency. It enables early conjugation studies at site-specific levels, confirms the absence of unexpected products to support conjugation process development, and aids in ensuring lot-to-lot consistency for comparability studies. Peptide mapping using liquid chromatography-tandem mass spectrometry is the industry standard method for analyzing conjugation sites. However, some concerns remain for this approach as the large and hydrophobic drug moieties often result in poor MS/MS fragmentation quality and impede the identification of conjugation sites. Additionally, the ionization discrepancy between conjugated and unconjugated peptides can lead to a relatively large bias for site occupancy calculation. In this work, we present a simple drug deconjugation-assisted peptide mapping method to identify and quantify the drug conjugation for ADCs with protease-cleavable linkers. Papain-based drug deconjugation was used to remove the highly hydrophobic drug moiety, which significantly improved the quantitation accuracy of conjugation level and the fragmentation quality. Sample preparation conditions were optimized to avoid introducing artificial modifications, allowing the tracking of initial sample status and subsequent changes of quality attributes during process development and stability assessment. This method was applied to analyze thermally-stressed ADC samples to monitor changes of site-specific conjugation levels, DAR, succinimide hydrolysis of the linker, and various PTMs. We believe this is an effective and straightforward tool for conjugation site analysis while simultaneously monitoring multiple quality attributes for ADCs with protease-cleavable linkers.

Preparation of metal-organic framework @molecularly imprinted polymers for extracting N-nitrosamines in salted vegetables.

In this paper, the novel metal-organic framework @molecularly imprinted polymers were prepared and applied in extracting N-nitrosamines from salted vegetables. The imprinted polymers were coated on the surface of MIL-101 using multi-dummy template molecules (5-nonanol, benzhydrol and N-formylpyrrolidine). The characterization and adsorbing experiments showed that the hybrid imprinted polymers presented spherical particles with typically core-shell structure, and exhibited high adsorption capacity (maximum capacity: 46.85 mg/g) and fast equilibrium rate (only 5 min) for N-nitrosamines. Various parameters (sample loading solvent, pH, washing solvent, elution solvent and elution volume) affecting solid-phase extraction were optimized. Under the optimum conditions, the solid-phase extraction process based on the hybrid polymers combined with high performance liquid chromatography-ultraviolet detection method was established and applied to analyze N-nitrosamines in different salted vegetables. The results showed that the developed method produced the linear relationship between the peak areas versus the N-nitrosamines concentrations of 0.2-10 µg/g with limit of detections from 20.6 to 76.1 ng/g. The spiked recovery of N-nitrosamines in the salted vegetable samples was in the range of 66-100.5 % with relative standard deviation from 0.1 to 3.4 %. Those results demonstrated that the established method was sensitive and efficient for directly enriching and analyzing trace N-nitrosamines in salted vegetables.

Head and Neck Hemangiopericytoma: A Rare Case Report and Literature Review.

Hemangiopericytomas (HPCs) are rare vascular tumors, and head and neck hemangiopericytoma (HNHPC) accounts for 11% to 16% of all HPCs, possibly occurring at any age. However, according to a recent study, HNHPC was most frequently observed in middle-aged adults and had a slight predominance of female patients. In the present case, we report the successful treatment of HNHPC.

LAR Downregulation Protects the Astrocytic U251 and Cocultured SH-SY5Y Cells in a Rotenone-Induced Parkinson's Disease Cell Model.

Leukocyte common antigen-related protein tyrosine phosphatase (LAR) is a member of the protein tyrosine phosphatase family that serves as a key regulator of cellular survival. It is also involved in neurodevelopment and brain disorders. This study was designed to investigate the role of LAR in a cell-based model of Parkinson's disease (PD) in which U251 and SH-SY5Y cells were used as models of astrocytes and dopaminergic neurons, respectively. Cell viability, cell death, cell morphology, protein phosphorylation and expression, ATP levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential were analyzed in the wild-type (WT) and heterozygous LAR-knockout astrocytoma U251 cells to assess the cell state, signal transduction, and mitochondrial function. LAR downregulation showed a protective effect in rotenone-exposed U251 cells by increasing cell viability, reducing cell mortality, and restoring appropriate cellular morphology. LAR downregulation enhanced IGF-1R phosphorylation and downstream signal transduction as evidenced by increases in the Akt and GSK-3ß phosphorylation, as well as the upregulation of NRF2 and HO-1. The downregulation of LAR also augmented DJ-1 levels in these cells. The enhanced Akt and GSK-3ß phosphorylation contributed to a reduced Bax/Bcl2 ratio and suppressed apoptosis after rotenone exposure. Heterozygous LAR-knockout U251 cells exhibited higher mitochondrial function evidenced by increased mitochondrial membrane potential, ATP contents, and reduced ROS production compared to the WT cells following rotenone exposure. Further studies showed that the astrocytic protection mediated by the heterozygous knockout of LAR was associated with the activation of Akt. A specific Akt inhibitor, MK2206, reduced the cell viability, Akt and GSK3ß phosphorylation, and HO-1 and NRF2 expression in U251 cells exposed to rotenone. Astrocytes provide structural and metabolic support to maintain neuronal health. Astrocytic glial cell-derived neurotrophic factor (GDNF) production is vital for dopaminergic neuron survival. Heterozygous LAR-knockout U251 cells produced higher amounts of GDNF than the WT cells. The SH-SY5Y cells cocultured with heterozygous LAR-knockout U251 cells exhibited greater viability than that of cells cocultured with WT U251 cells in response to rotenone. Together, these findings demonstrate that the heterozygous knockout of LAR in astrocytes can play a key role in protecting both astrocytic cells and cocultured neurons in a rotenone-induced cell-based model of PD. This neuroprotective effect is attributable to the augmentation of IGF1R-Akt-GDNF signaling and the maintenance of astrocytic mitochondrial function.

Evaluation of prevention and treatment effects of fibroblast growth factor-21 in BLM-induced pulmonary fibrosis.

Pulmonary fibrosis is a progressive and fatal fibrotic lung disease and associated with a high mortality rate. In the study, the prevention and treatment effects of fibroblast growth factor-21 (FGF-21) in bleomycin (BLM)-induced pulmonary fibrosis were investigated in vivo and vitro. In the prevention of pulmonary fibrosis studies, the results showed that interdict of FGF-21 could reduce the related gene and protein expression levels of pulmonary fibrosis. In addition, FGF-21 significantly reduced both the aggregation of inflammatory cells and deposition of collagen in the lung by histopathology. In therapy of pulmonary fibrosis studies, the results indicated that treatment with FGF-21 resulted in an amelioration of the pulmonary fibrosis in mice with reductions of the pathological score, collagen deposition and transforming growth factor (TGF)-ß and α-smooth muscle actin (α-SMA) expressions in the lung tissues at fibrotic stage, and late administration was also able to reduce the degree of pulmonary fibrosis and even better than these in the prevention group. Furthermore, BLM-induced THP-1 macrophage model was verified using FGF-21; the result showed that FGF-21 decreased the related gene expression level of pulmonary fibrosis. FGF-21 may have preventive and therapeutic effects on BLM-induced pulmonary fibrosis via inhibiting myofibroblast differentiation and inflammatory. Thus, FGF-21 represents a potential drug for the prevention and treatment of pulmonary fibrosis.

Rosmarinic Acid Attenuates Rotenone-Induced Neurotoxicity in SH-SY5Y Parkinson's Disease Cell Model through Abl Inhibition.

Rosmarinic acid (RA) is a natural polyphenolic compound with antioxidative property. With the present study, we aimed to evaluate the neuroprotective role of RA on Parkinson's disease using rotenone induced SH-SY5Y cell model of Parkinson's disease, the underlying mechanism of action of RA was also investigated. Cell viability, cell morphology, apoptosis, signaling protein phosphorylation and expression, cellular reactive oxygen species (ROS) production, ATP content, and mitochondrial membrane potential were tested in SH-SY5Y cells. RA showed a neuroprotective effect in a rotenone-induced SH-SY5Y cell model of Parkinson's disease with dose-dependent manner, it reduced cell apoptosis and restored normal cell morphology. RA not only decreased levels of α-synuclein and Tau phosphorylation but also elevated the contents of AMPK phosphorylation, Akt phosphorylation, and PGC-1α. RA restored the reduced mitochondrial membrane potential and ATP content as well as inhibited rotenone-induced ROS overproduction. Further findings demonstrated that the neuroprotective role of RA was partially due to the inhibition of Abl tyrosine kinase. RA treatment suppressed the hyperphosphorylation of Abl Y412 and CrkII Y221 induced by rotenone. Nilotinib, a specific inhibitor of Abl, elicited a similar neuroprotective effect as that of RA. The present study indicates that RA has a property of neuroprotection against rotenone, and the neuroprotective effect is partially attributed to the inhibition of Abl.

Role of Mitophagy-based TLR9 Signal Pathway in Neonatal Ventilator-induced Lung Injury.

The study focused on the role of mitophagy in neonatal ventilator-induced lung injury (VILI). Immunoassays were used to study the TLR9 signaling pathway of neonatal VILI, expected to provide a feasible solution for neonatal VILI. The mice were randomly divided into four groups, group A: spontaneous breathing group; group B: normal tidal volume (VT) group (VT=9mL/kg); group C: high VT group (VT=39mL/kg); and group D: ODN2088 (400µg/ Only) intervention + high VT group. The four groups were compared for the expression of inflammatory factors. It was found that as the culture time increased, the expression of TLR9, MyD88, and NF-κBp65 in the lung tissue of the large VT group was significantly higher than those in the spontaneous breathing group and normal VT group, and the differences were statistically significant; and TLR9 inhibitors could activate the TLR9-MyD88 signaling pathway to up-regulate the expression of NF-κB, mediating the release of inflammatory factors to cause VILI.

Preparation of metal-organic framework @molecularly imprinted polymers for extracting strobilurin fungicides from agricultural products.

The core-shell metal-organic framework coated with molecularly imprinted polymers (ZIF-8@MIPs) were successfully synthesized by surface imprinting technique, and applied as adsorbents for solid-phase extraction of strobilurin fungicides. The obtained hybrid complex was characterized in detail, and their adsorbing and recognition performance were evaluated. The results showed that ZIF-8@MIPs presented typically core-shell structure with MIP shell (about 20 nm), and exhibited larger adsorption capacity (102.5 mg g-1) and fast adsorption ability (only 5 min). Under the optimized conditions, a sensitive, efficient and reliable method for determining six strobilurin fungicides in different agricultural products based on ZIF-8@MIPs coupling with high performance liquid chromatography-tandem mass spectrometry was established. This method showed good linearity with correlation coefficients higher than 0.9990. With spiked at three different concentration levels in agricultural products (apple, pear, banana, Chinese cabbage, cabbage, cucumber), the good recoveries (83.5-129.0%) with relative standard deviations from 0.5 to 10.2% were obtained. The limit of detections and the limit of quantifications were 0.01-1.12 ng g-1 and 0.03-3.73 ng g-1, respectively. Those results demonstrated good potential application of ZIF-8@MIPs for enriching and separating trace strobilurin fungicides in agricultural samples.

Characteristics of Mussels-Derived Carbon Dots and Their Applications in Bio-Imaging and Detection of Riboflavin.

A simple and green strategy has been demonstrated for the synthesis of carbon dots (CDs) from mussels. The chemical structure and optical properties of mussels-derived CDs prepared at different reaction temperatures (140, 160, and 180 °C) were evaluated. The average size of synthesized fluorescent CDs decreased from 2.06 to 1.30 nm as reaction temperatures increased from 140 to 180 °C. The fluorescence quantum yield of CDs could reach up to 15.20%. The surface of CDs was rich in functional groups such as -OH, -NH2, and -COOH, providing CDs with good water solubility and biocompatibility. Furthermore, the mussel-derived CDs have been successfully applied in bio-imaging for onion endothelium cells, HepG2 cells, and zebrafish. In addition, CDs could be employed as a biosensor for riboflavin detection. Therefore, mussels are a promising carbon resource for preparing N-doped CDs for bio-imaging and monitoring riboflavin.

Unmet Healthcare Needs and Their Determining Factors among Unwell Migrants: A Comparative Study in Shanghai.

The purpose of this study was to analyze the health status and unmet healthcare needs, and the impact of related factors, of unwell migrants in Shanghai. A total of 10,938 respondents, including 934 migrants and 10,004 non-migrants, were interviewed in Shanghai's Sixth Health Service Survey. Descriptive statistics were utilized to present the prevalence of health status and unmet healthcare needs. Binary logistic regression analysis was performed to explore the relationships between predisposing factors, enabling factors, need factors, and health-related behavior and unmet healthcare needs in the Anderson health service utilization model. This study indicated the percentages of migrants having a fair or poor self-evaluated health status (21.09%) and suffering from chronic diseases (72.91%) were lower than those of non-migrants (28.34% and 88.64%, respectively). Migrants had higher percentages of unmet hospitalization needs (88.87%), unmet outpatient care needs (44.43%), and self-medication (23.98%) than those of non-migrants (86.24%, 37.95%, 17.97%, respectively). Migrants enrolled in Urban Employee Basic Medical Insurance were more likely to utilize hospitalization services (OR = 1.457) than those enrolled in other health insurances or uninsured. Need factors had impacts on unwell migrants' unmet healthcare needs. Other factors, including age and health behavior, were also found to significantly affect unwell migrants' unmet health service needs. Specific gaps continue to exist between unwell migrants and non-migrants regarding the accessibility of local health services. Flexible policies, such as enhancing the health awareness of migrants and eliminating obstacles for migrants to access medical services, should be implemented to provide convenient and affordable healthcare services to unwell migrants.

Effect of vitamin D3 on hyperplasia of mammary glands in experimental rats.

BACKGROUND: 1,25(OH)2D3/vitamin D3 receptor (VD3/VDR) signaling pathway can inhibit the occurrence of breast cancer in many ways. We used vitamin D3 to interfere with Hyperplasia of mammary glands (HMG) model rats, and to explore the intervention effect of vitamin D3 on HMG. METHODS: We divided 42 female rats into six groups randomly: blank control group, hyperplasia model group, negative control group, and vitamin D3 (VD3) groups of low-dose (LVD, 5 µg/kg), medium-dose (MVD, 10 µg/kg), and high-dose (HVD, 20 µg/kg). We established HMG model in all groups except for the blank control group, then different dose of VD3 was intraperitoneal injected for VD3 groups and normal saline (NS) was given to the negative control group. After the experiment, the body weights, heights and diameters of nipples, and the thickness of the mammary gland of rats were measured. The serum content of sex hormone and VD3 were detected by enzyme-linked immunosorbent assay (ELISA). The tissues of mammary glands were analyzed by hematoxylin and eosin (HE) stain, and the expression of estrogen receptor α (ERα), progesterone receptor (PR), and VDR were detected by immunohistochemical (IHC) stain. Similarly, the total protein expression of ERα, PR, and VDR were measured by western blot. RESULTS: Compared with the hyperplasia group, rats in the VD3 groups displayed a marked decrease of the thickness of the mammary glands and the height and diameter of the nipples. The serum estrogen (E2), testosterone (T), luteinizing hormone (LH), and VD3 was markedly decreased in all VD3 groups (P<0.05). The IHC results showed that ERα and PR was decreased in all three VD3 groups; however, VDR was increased. Western blot demonstrated that both ERα and PR were reduced in VD3 groups, while the VDR level was significantly enhanced. Overall, the findings suggested that VD3 could be used in HMG treatment. CONCLUSIONS: Supplementation of VD3 could markedly decrease the mammary gland thickness, nipple diameter, and nipple height of rats, accompanied by the decrease of serum E2, T, and LH. Intervention with VD3 can lead to decreased expression of ERa and PR, in conjunction with the increase of VDR.

Comprehensive Analysis of Sinonasal Inverted Papilloma Expression Profiles Identifies Long Non-Coding RNA AKTIP as a Potential Biomarker.

Long noncoding RNAs (lncRNAs) are a novel class of potential biomarkers and therapeutic targets for the treatment of neoplasms. The purpose of this study was to explore the expression profile, potential functions, and diagnostic and clinical significance of lncRNAs in sinonasal inverted papilloma (SNIP). The expression profiles of lncRNAs and mRNAs were analyzed using a microarray. The potential functions and clinical implications of specific lncRNAs were further analyzed by bioinformatics and statistical methods. Microarray analysis identified 1,668 significantly upregulated and 1,767 downregulated lncRNAs in SNIP. Several mRNAs coexpressed with lncRNAs were enriched in some biological processes and cellular signaling pathways related to tumorigenesis. Lnc-AKTIP might interact with a variety of tumor-associated proteins and transcription factors, such as PCBP2, IRF-1, and p53. Receiver operating characteristic curve analysis for lnc-AKTIP showed an area under the curve of 0.939. Notably, its expression level was significantly decreased in SNIP tissues versus normal tissues and was associated with SNIP staging. Lnc-AKTIP may serve as a valuable diagnostic biomarker and a therapeutic target for SNIP.

Preparation of flower-like molybdenum disulfide for solid-phase extraction of N-nitrosoamines in environmental water samples.

In this paper, a flower-like molybdenum disulfide material was prepared by hydrothermal method and was first used as adsorbents in the solid-phase extraction process for enriching N-nitrosoamines. Molybdenum disulfide exhibited three-dimensional petal-like microspheres with about 500 nm in diameter. The relevant analyte extraction and elution parameters (sample volumes, solution pH, washing solvents, elution solvents, and elution volumes) were optimized to improve the solid-phase extraction efficiency. The solid-phase extraction process coupled with high-performance liquid chromatography-tandem mass spectrometry for determining N-nitrosoamines in environmental water samples was established. The limits of detection were in the range of 0.01-0.05 ng/mL. The satisfactory recoveries (68.9-106.1%) were obtained at three different spiked concentrations (2, 5, and 8 ng/mL) in water samples, and the relative standard deviations were between 1.96 and 8.38%. This proposed method not only showed high sensitivity and good reusability but also provided a new adsorbent for enriching trace N-nitrosoamines in environmental water samples.

Interpreting Interaction Effects in Generalized Linear Models of Nonlinear Probabilities and Counts.

Psychology research frequently involves the study of probabilities and counts. These are typically analyzed using generalized linear models (GLMs), which can produce these quantities via nonlinear transformation of model parameters. Interactions are central within many research applications of these models. To date, typical practice in evaluating interactions for probabilities or counts extends directly from linear approaches, in which evidence of an interaction effect is supported by using the product term coefficient between variables of interest. However, unlike linear models, interaction effects in GLMs describing probabilities and counts are not equal to product terms between predictor variables. Instead, interactions may be functions of the predictors of a model, requiring nontraditional approaches for interpreting these effects accurately. Here, we define interactions as change in a marginal effect of one variable as a function of change in another variable, and describe the use of partial derivatives and discrete differences for quantifying these effects. Using guidelines and simulated examples, we then use these approaches to describe how interaction effects should be estimated and interpreted for GLMs on probability and count scales. We conclude with an example using the Adolescent Brain Cognitive Development Study demonstrating how to correctly evaluate interaction effects in a logistic model.

Making sense of some odd ratios: A tutorial and improvements to present practices in reporting and visualizing quantities of interest for binary and count outcome models.

OBJECTIVE: Generalized linear models (GLMs) such as logistic and Poisson regression are among the most common statistical methods for modeling binary and count outcomes. Though single-coefficient tests (odds ratios, incidence rate ratios) are the most common way to test predictor-outcome relations in these models, they provide limited information on the magnitude and nature of relations with outcomes. We assert that this is largely because they do not describe direct relations with quantities of interest (QoIs) such as probabilities and counts. Shifting focus to QoIs makes several critical nuances of GLMs more apparent. METHOD: To bolster interpretability of these models, we provide a tutorial on logistic and Poisson regression and suggestions for enhancements to current reporting practices for predictor-outcome relations in GLMs. RESULTS: We first highlight differences in interpretation between traditional linear models and GLMs, and describe common misconceptions about GLMs. In particular, we highlight that link functions (a) introduce nonconstant relations between predictors and outcomes and (b) make predictor-QoI relations dependent on levels of other covariates. Each of these properties causes interpretation of GLM coefficients to diverge from interpretations of linear models. Next, we argue for a more central focus on QoIs (probabilities and counts). Finally, we propose and provide graphics and tables, with sample R code, for enhancing presentation and interpretation of QoIs. CONCLUSIONS: By improving present practices in the reporting of predictor-outcome relations in GLMs, we hope to maximize the amount of actionable information generated by statistical analyses and provide a tool for building a cumulative science of substance use disorders. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Synthesis of metal-organic framework @molecularly imprinted polymer adsorbents for solid phase extraction of organophosphorus pesticides from agricultural products.

The novel core-shell structural zeolitic imidazolate framework-8 @molecularly imprinted polymers were successfully synthesized by surface imprinting technique and used as adsorbents for solid-phase extraction of organophosphorus pesticides. The obtained hybrid composites were characterized by scanning electron microscopy, transmission electron microscopy and Fourier-transform infrared, and their adsorbing and recognition performance were evaluated by binding experiments. The results showed that zeolitic imidazolate framework-8 @molecularly imprinted polymers presented a typically core-shell structure with molecularly imprinted shell (about 50 nm) homogeneously polymerized on the surface of zeolitic imidazolate framework-8 core, and exhibited specific recognition towards organophosphorus pesticides with fast adsorption capacity. The adsorption and desorption conditions including sample loading solvent, sample pH, washing and elution solvent were optimized. Under optimum conditions, the solid-phase extraction based on zeolitic imidazolate framework-8 @molecularly imprinted polymers combined with high liquid chromatography-tandem mass spectrometry method for determining organophosphorus pesticides was established and exhibited good linearity (R2 ≥ 0.9927) in the range of 1-200 µg/L. With spiked at three different concentration levels in agricultural products (cauliflower, radish, pear, muskmelon), the recoveries ranged from 82.5% to 123.0% with relative standard deviations lower than 8.24%. The developed method was sensitive, convenient and efficient. More importantly, this study could provide a promising strategy for designing new adsorbents with extremely fast mass transfer rate for other potential trace contaminants.

Advances in Surface-Enhanced Raman Scattering-Based Aptasensors for Food Safety Detection.

Owing to the excellent performances of high sensitivity, high specificity, on-site detection, and multiplexing capability, surface-enhanced Raman scattering (SERS)-based aptasensors have performed prosperous applications and gained impressive progress in food safety. Herein, we reviewed the SERS-based aptasensors from the principles to specific applications in food safety. First, the sensor-working principles, SERS label design and preparation are introduced. Then, the popular platforms in the aptasensors are summarized with their advantages and disadvantages, followed by their representative applications. Further, the specific applications of developing SERS-based aptasensors in food safety are systematically provided. Moreover, the multiplex analysis using SERS labels are highlighted. Finally, challenges and perspectives for improving the SERS-based aptasensor performance are also discussed, aiming to give some proposes for researchers to choose suitable SERS-based aptasensors according to specific applications.

The expression of PHB2 in the cochlea: Possible relation to age-related hearing loss.

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly, but its mechanism remains unclear. Scaffold protein prohibitin 2 (PHB2) has been widely involved in aging and neurodegeneration. However, the role of PHB2 in ARHL is undeciphered to date. To investigate the expression pattern and the role of PHB2 in ARHL, we used C57BL/6 mice and HEI-OC1 cell line as models. In our study, we have found PHB2 exists in the cochlea and is expressed in hair cells, spiral ganglion neurons, and HEI-OC1 cells. In mice with ARHL, mitophagy is reduced and correspondingly the expression level of PHB2 is decreased. Moreover, after H2 O2 treatment the mitophagy is activated and the PHB2 expression is increased. These findings indicate that PHB2 may exert an important role in ARHL through mitophagy. Findings from this study will be helpful for elucidating the mechanism underlying the ARHL and for providing a new target for ARHL treatment.

Construction of a risk prediction model for Alzheimer's disease in the elderly population.

BACKGROUND: Dementia is one of the greatest global health and social care challenges of the twenty-first century. The etiology and pathogenesis of Alzheimer's disease (AD) as the most common type of dementia remain unknown. In this study, a simple nomogram was drawn to predict the risk of AD in the elderly population. METHODS: Nine variables affecting the risk of AD were obtained from 1099 elderly people through clinical data and questionnaires. Least Absolute Shrinkage Selection Operator (LASSO) regression analysis was used to select the best predictor variables, and multivariate logistic regression analysis was used to construct the prediction model. In this study, a graphic tool including 9 predictor variables (nomogram-see precise definition in the text) was drawn to predict the risk of AD in the elderly population. In addition, calibration diagram, receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to verify the model. RESULTS: Six predictors namely sex, age, economic status, health status, lifestyle and genetic risk were identified by LASSO regression analysis of nine variables (body mass index, marital status and education level were excluded). The area under the ROC curve in the training set was 0.822, while that in the validation set was 0.801, suggesting that the model built with these 6 predictors showed moderate predictive ability. The DCA curve indicated that a nomogram could be applied clinically if the risk threshold was between 30 and 40% (30 to 42% in the validation set). CONCLUSION: The inclusion of sex, age, economic status, health status, lifestyle and genetic risk into the risk prediction nomogram could improve the ability of the prediction model to predict AD risk in the elderly patients.