1.Incidence and prognosis of olfactory and gustatory dysfunctions related to infection of SARS-CoV-2 Omicron strain: a national multi-center survey of 35 566 population.
Meng Fan LIU ; Rui Xia MA ; Xian Bao CAO ; Hua ZHANG ; Shui Hong ZHOU ; Wei Hong JIANG ; Yan JIANG ; Jing Wu SUN ; Qin Tai YANG ; Xue Zhong LI ; Ya Nan SUN ; Li SHI ; Min WANG ; Xi Cheng SONG ; Fu Quan CHEN ; Xiao Shu ZHANG ; Hong Quan WEI ; Shao Qing YU ; Dong Dong ZHU ; Luo BA ; Zhi Wei CAO ; Xu Ping XIAO ; Xin WEI ; Zhi Hong LIN ; Feng Hong CHEN ; Chun Guang SHAN ; Guang Ke WANG ; Jing YE ; Shen Hong QU ; Chang Qing ZHAO ; Zhen Lin WANG ; Hua Bin LI ; Feng LIU ; Xiao Bo CUI ; Sheng Nan YE ; Zheng LIU ; Yu XU ; Xiao CAI ; Wei HANG ; Ru Xin ZHANG ; Yu Lin ZHAO ; Guo Dong YU ; Guang Gang SHI ; Mei Ping LU ; Yang SHEN ; Yu Tong ZHAO ; Jia Hong PEI ; Shao Bing XIE ; Long Gang YU ; Ye Hai LIU ; Shao wei GU ; Yu Cheng YANG ; Lei CHENG ; Jian Feng LIU
Chinese Journal of Otorhinolaryngology Head and Neck Surgery 2023;58(6):579-588
Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female
;
Humans
;
Adolescent
;
SARS-CoV-2
;
Smell
;
COVID-19/complications*
;
Cross-Sectional Studies
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COVID-19 Vaccines
;
Incidence
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Olfaction Disorders/etiology*
;
Taste Disorders/etiology*
;
Prognosis
2.Cortical thickness and cognitive impairment in patients with amyotrophic lateral sclerosis.
Shan YE ; Ping Ping JIN ; Nan ZHANG ; Hai Bo WU ; Lin SHI ; Qiong ZHAO ; Kun YANG ; Hui Shu YUAN ; Dong Sheng FAN
Journal of Peking University(Health Sciences) 2022;54(6):1158-1162
OBJECTIVE:
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with high morbidity and mortality. There are about 5%-15% of ALS patients combining with frontotemporal lobe degeneration (FTLD) at the same time and 50% of patients combing with cognitive function changes. The analysis of cortical thickness based on MRI is an important imaging method to evaluate brain structure. The aim of the study was to explore the changes of brain structure in ALS patients by cortical thickness analysis, and to explore the correlation between the brain structure and cognitive function.
METHODS:
In the study, 18 ALS patients treated in Department of Neurology, Peking University Third Hospital and 18 normal controls (age, gender and education level matched) were included. 3D magnetization prepared rapid gradient echo imaging (MPRAGE) sequence MRI was performed and the cortical thickness was analyzed. At the same time, all the ALS patients took neuropsychology assessments, including: mini-mental state examination (MMSE), verbal fluency test (VFT), Stroop color word test (SCWT), prospective memory (PM), emotional picture perception and recognition, and faux pas story test.
RESULTS:
After cognitive assessment, two ALS patients had cognitive impairment. One was in accordance with ALS-frontotemporal dementia (FTD) diagnosis and the other one was in accordance with ALS cognitive impairment (ALSci) diagnosis. In all the 18 ALS patients and 18 normal controls, the cortical thickness of the left medial orbitofrontal lobe and the medial temporal lobe were significantly reduced (P < 0.05) in ALS group by the vertex-wise comparison. Cortical thickness of the left entorhinal cortex, the left inferior temporal gyrus, the left medial orbitofrontal lobe and the left insular lobe was significantly reduced (P < 0.05) by the region-wise comparison. However, when only concluded the 16 ALS non-cognitive impairment patients, there was no significant difference between the two groups (P>0.05). There were correlations between the scores of prospective memory, emotional picture perception and recognition, faux pas story test and the cortical thickness of their corresponding regions (P < 0.05).
CONCLUSION
The cortical thickness of ALS patients are correlated with neuropsychological scores which may reflect the changes of cortical structure corresponding to the cognitive assessment, and may provide help for the early diagnosis of cognitive changes in ALS patients.
Humans
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Amyotrophic Lateral Sclerosis/diagnostic imaging*
;
Neurodegenerative Diseases
;
Frontotemporal Dementia/psychology*
;
Neuropsychological Tests
;
Cognitive Dysfunction/etiology*
;
Magnetic Resonance Imaging/methods*
3.Network Meta-analysis of Chinese patent medicine in treatment of unstable angina pectoris.
Lu-Miao ZHANG ; Ting-Hai DU ; Lin-Lin NIU ; Lu-Yao WANG ; Jun-Nan LI ; Ping-Fan MA ; Rui YU
China Journal of Chinese Materia Medica 2021;46(3):703-711
Network Meta-analysis was used to compare the efficacy and safety of Chinese patent medicines in the treatment of unstable angina pectoris. PubMed, Cochrane Library, CNKI, Wanfang, VIP and other databases were retrieved by computers from the establishment of the databases to June 2020. Randomized controlled trials(RCTs) of Chinese patent medicines for the treatment of unstable angina pectoris were collected. Two investigators independently screened out the literatures, and extracted data according to the inclusion and exclusion criteria. The quality of the included RCTs was evaluated according to the bias risk assessment tool recommended by the Cochrane System Reviewer Manual, and the Stata 13.0 software was used for data analysis and mapping. Through screening, 28 eligible studies were finally included, with the sample size of 2 885 cases, involving 8 Chinese patent medicines. The results of the network Meta-analysis showed that in terms of total effective rate for angina symptom improvement, the order was as follows: Shenshao Capsules > Naoxintong Capsules > Ginkgo Ketone Ester Dripping Pills > Compound Danshen Dripping Pills > Ginkgo Leaf Tablets > Shexiang Baoxin Pills > Tongxinluo Capsules > Yindan Xinnaotong Soft Capsules; in terms of total effective rate for ECG curative effect, the order was as follows: Ginkgo Ketone Ester Dripping Pills>Compound Danshen Dripping Pills > Tongxinluo Capsules > Shenshao Capsules > Shexiang Baoxin Pills > Yindan Xinnaotong Soft Capsules; in terms of hypersensitivity-C-reactive protein curative effect, the order was as follows: Tongxinluo Capsules > Shenshao Capsules > Ginkgo Leaf Tablets>Compound Danshen Dropping Pills> Shexiang Baoxin Pills > Naoxintong Capsules > Yindan Xinnaotong Soft Capsules > Ginkgo Ketone Ester Dropping Pills. Chinese patent medicine combined with conventional therapy can improve the clinical efficacy of unstable angina pectoris. Due to the differences in the quantity and quality of the included studies, the order results of Chinese patent medicines need to be further verified.
Angina, Unstable/drug therapy*
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China
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Drugs, Chinese Herbal
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Humans
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Medicine, East Asian Traditional
;
Network Meta-Analysis
;
Nonprescription Drugs
4.COVID-ONE-hi:The One-stop Database for COVID-19-specific Humoral Immunity and Clinical Parameters
Xu ZHAOWEI ; Li YANG ; Lei QING ; Huang LIKUN ; Lai DAN-YUN ; Guo SHU-JUAN ; Jiang HE-WEI ; Hou HONGYAN ; Zheng YUN-XIAO ; Wang XUE-NING ; Wu JIAOXIANG ; Ma MING-LIANG ; Zhang BO ; Chen HONG ; Yu CAIZHENG ; Xue JUN-BIAO ; Zhang HAI-NAN ; Qi HUAN ; Yu SIQI ; Lin MINGXI ; Zhang YANDI ; Lin XIAOSONG ; Yao ZONGJIE ; Sheng HUIMING ; Sun ZIYONG ; Wang FENG ; Fan XIONGLIN ; Tao SHENG-CE
Genomics, Proteomics & Bioinformatics 2021;19(5):669-678
Coronavirus disease 2019(COVID-19),which is caused by SARS-CoV-2,varies with regard to symptoms and mortality rates among populations.Humoral immunity plays critical roles in SARS-CoV-2 infection and recovery from COVID-19.However,differences in immune responses and clinical features among COVID-19 patients remain largely unknown.Here,we report a database for COVID-19-specific IgG/IgM immune responses and clinical parameters(named COVID-ONE-hi).COVID-ONE-hi is based on the data that contain the IgG/IgM responses to 24 full-length/truncated proteins corresponding to 20 of 28 known SARS-CoV-2 proteins and 199 spike protein peptides against 2360 serum samples collected from 783 COVID-19 patients.In addition,96 clinical parameters for the 2360 serum samples and basic information for the 783 patients are integrated into the database.Furthermore,COVID-ONE-hi provides a dashboard for defining samples and a one-click analysis pipeline for a single group or paired groups.A set of samples of interest is easily defined by adjusting the scale bars of a variety of parameters.After the"START"button is clicked,one can readily obtain a comprehensive analysis report for further interpretation.COVID-ONE-hi is freely available at www.COVID-ONE.cn.
5.Comparison of neoadjuvant chemotherapy followed by surgery vs. surgery alone for locally advanced gastric cancer: a meta-analysis.
Jian-Hong YU ; Zao-Zao WANG ; Ying-Chong FAN ; Mao-Xing LIU ; Kai XU ; Nan ZHANG ; Zhen-Dan YAO ; Hong YANG ; Cheng-Hai ZHANG ; Jia-Di XING ; Ming CUI ; Xiang-Qian SU
Chinese Medical Journal 2021;134(14):1669-1680
BACKGROUND:
The neoadjuvant chemotherapy is increasingly used in advanced gastric cancer, but the effects on safety and survival are still controversial. The objective of this meta-analysis was to compare the overall survival and short-term surgical outcomes between neoadjuvant chemotherapy followed by surgery (NACS) and surgery alone (SA) for locally advanced gastric cancer.
METHODS:
Databases (PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar) were explored for relative studies from January 2000 to January 2021. The quality of randomized controlled trials and cohort studies was evaluated using the modified Jadad scoring system and the Newcastle-Ottawa scale, respectively. The Review Manager software (version 5.3) was used to perform this meta-analysis. The overall survival was evaluated as the primary outcome, while perioperative indicators and post-operative complications were evaluated as the secondary outcomes.
RESULTS:
Twenty studies, including 1420 NACS cases and 1942 SA cases, were enrolled. The results showed that there were no significant differences in overall survival (P = 0.240), harvested lymph nodes (P = 0.200), total complications (P = 0.080), and 30-day post-operative mortality (P = 0.490) between the NACS and SA groups. However, the NACS group was associated with a longer operation time (P < 0.0001), a higher R0 resection rate (P = 0.003), less reoperation (P = 0.030), and less anastomotic leakage (P = 0.007) compared with SA group.
CONCLUSIONS
Compared with SA, NACS was considered safe and feasible for improved R0 resection rate as well as decreased reoperation and anastomotic leakage. While unbenefited overall survival indicated a less important effect of NACS on long-term oncological outcomes.
Humans
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Neoadjuvant Therapy
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Stomach Neoplasms/surgery*
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Treatment Outcome
6.Association of Overlapped and Un-overlapped Comorbidities with COVID-19 Severity and Treatment Outcomes: A Retrospective Cohort Study from Nine Provinces in China.
Yan MA ; Dong Shan ZHU ; Ren Bo CHEN ; Nan Nan SHI ; Si Hong LIU ; Yi Pin FAN ; Gui Hui WU ; Pu Ye YANG ; Jiang Feng BAI ; Hong CHEN ; Li Ying CHEN ; Qiao FENG ; Tuan Mao GUO ; Yong HOU ; Gui Fen HU ; Xiao Mei HU ; Yun Hong HU ; Jin HUANG ; Qiu Hua HUANG ; Shao Zhen HUANG ; Liang JI ; Hai Hao JIN ; Xiao LEI ; Chun Yan LI ; Min Qing LI ; Qun Tang LI ; Xian Yong LI ; Hong De LIU ; Jin Ping LIU ; Zhang LIU ; Yu Ting MA ; Ya MAO ; Liu Fen MO ; Hui NA ; Jing Wei WANG ; Fang Li SONG ; Sheng SUN ; Dong Ting WANG ; Ming Xuan WANG ; Xiao Yan WANG ; Yin Zhen WANG ; Yu Dong WANG ; Wei WU ; Lan Ping WU ; Yan Hua XIAO ; Hai Jun XIE ; Hong Ming XU ; Shou Fang XU ; Rui Xia XUE ; Chun YANG ; Kai Jun YANG ; Sheng Li YUAN ; Gong Qi ZHANG ; Jin Bo ZHANG ; Lin Song ZHANG ; Shu Sen ZHAO ; Wan Ying ZHAO ; Kai ZHENG ; Ying Chun ZHOU ; Jun Teng ZHU ; Tian Qing ZHU ; Hua Min ZHANG ; Yan Ping WANG ; Yong Yan WANG
Biomedical and Environmental Sciences 2020;33(12):893-905
Objective:
Several COVID-19 patients have overlapping comorbidities. The independent role of each component contributing to the risk of COVID-19 is unknown, and how some non-cardiometabolic comorbidities affect the risk of COVID-19 remains unclear.
Methods:
A retrospective follow-up design was adopted. A total of 1,160 laboratory-confirmed patients were enrolled from nine provinces in China. Data on comorbidities were obtained from the patients' medical records. Multivariable logistic regression models were used to estimate the odds ratio (
Results:
Overall, 158 (13.6%) patients were diagnosed with severe illness and 32 (2.7%) had unfavorable outcomes. Hypertension (2.87, 1.30-6.32), type 2 diabetes (T2DM) (3.57, 2.32-5.49), cardiovascular disease (CVD) (3.78, 1.81-7.89), fatty liver disease (7.53, 1.96-28.96), hyperlipidemia (2.15, 1.26-3.67), other lung diseases (6.00, 3.01-11.96), and electrolyte imbalance (10.40, 3.00-26.10) were independently linked to increased odds of being severely ill. T2DM (6.07, 2.89-12.75), CVD (8.47, 6.03-11.89), and electrolyte imbalance (19.44, 11.47-32.96) were also strong predictors of unfavorable outcomes. Women with comorbidities were more likely to have severe disease on admission (5.46, 3.25-9.19), while men with comorbidities were more likely to have unfavorable treatment outcomes (6.58, 1.46-29.64) within two weeks.
Conclusion
Besides hypertension, diabetes, and CVD, fatty liver disease, hyperlipidemia, other lung diseases, and electrolyte imbalance were independent risk factors for COVID-19 severity and poor treatment outcome. Women with comorbidities were more likely to have severe disease, while men with comorbidities were more likely to have unfavorable treatment outcomes.
Adult
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Aged
;
COVID-19/virology*
;
China/epidemiology*
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Comorbidity
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Female
;
Humans
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Male
;
Middle Aged
;
Retrospective Studies
;
Severity of Illness Index
;
Treatment Outcome
7.Quality Control of Dynamic Volatile Components in Lonicerae Japonicae Flos and Lonicerae Flos
Hai-ying LI ; Qi-meng FAN ; Yu-ting HE ; Peng HE ; Min-cun WANG ; Run-nan LIU ; Zhuo ZHOU ; Xue-bing QIAN ; Xian-ping ZENG ; Mei-feng XIAO ; Fu-yuan HE
Chinese Journal of Experimental Traditional Medical Formulae 2020;26(22):148-155
Objective:The molecular connectivity index method and total statistical moment method were used to control the quality of traditional Chinese medicine (TCM), and the stability and consistency of volatile components of Lonicerae Japonicae Flos and Lonicerae Flos were clarified. Method:Volatile oils in Lonicerae Japonicae Flos and Lonicerae Flos from different producing areas was extracted for GC-MS determination with electron bombardment ion source, ion source temperature of 230 ℃, and detection range of
8.Precise tooth preparation technique guided by 3D printing guide plate with quantitative hole.
Chun-Xu LIU ; Jing GAO ; Yu-Wei ZHAO ; Lin FAN ; Lu-Ming JIA ; Nan HU ; Zi-Yu MEI ; Bo DONG ; Qian-Qian ZHANG ; Hai-Yang YU
West China Journal of Stomatology 2020;38(3):350-355
The minimum amount of tooth preparation that can be fully controlled is crucial in achieving long-term, stable, and effective aesthetic restoration, which is also a major difficulty in aesthetic restoration. The tooth preparation can be imple-mented efficiently and accurately through digital technology based on the fixed-deep hole guiding technology. Prior the actual tooth preparation, the technology first designs the virtual contour, layering, and virtual occlusion of the prosthesis on the computer. Then, virtual tooth preparation is carried out by cutting back according to the virtual prosthesis. Next, the virtual drilling operation plan is designed according to the shape of the virtual tooth preparation and the contour of the abutment tooth. Finally, the tooth preparation guide plate is designed and printed in 3D. It realizes the whole process of quantitative and precise guidance of dental preparation, visualizes the restoration space, reduces the clinical operation time, and guarantees the quality of dental preparation. It also promotes the improvement of the teaching quality of digital practical exercises.
Bone Plates
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Esthetics, Dental
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Printing, Three-Dimensional
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Tooth
;
Tooth Preparation
9. Analysis of Key Techniques in Development of Primary Standard of Classical Prescription of Chinese Medicine
Qi-meng FAN ; Peng HE ; Hai-ying LI ; Run-nan LIU ; Yu-ting HE ; Hui-hui LIANG ; Wen-long LIU ; Yi-qun ZHOU ; Fu-yuan HE
Chinese Journal of Experimental Traditional Medical Formulae 2019;25(15):202-209
Research and development of classical prescription of Chinese medicine has become one of the hot spots in the research of traditional Chinese medicine (TCM), and the successful development of the primary standard is crucial to the application of the classical prescription of Chinese medicine. Primary standard of classical prescription is not only the benchmark to measure the quality of preparation of classical prescription, but also the material basis of whole prescription. The development and quality control mode of single component of western medicine is not suitable for the development of TCM preparation with integral medicinal function. Thus, it is very urgent to develop an exclusive research and development model for TCM. In order to break through the quality control technology of primary standard of classical prescription, and comprehensively and accurately elucidate the transmission rule of the component group value of medicinal materials-decoction pieces-primary standard of classical prescription with the present modern science and technology, the genetic polymorphism of TCM, extraction kinetics, total quantum statistical moment (similarity) method of fingerprint and supramolecular imprinting template were combined and applied to the development of primary standard of classical prescription. In this way, the development and quality control of TCM will be realized in a real sense and the development of classical prescription of Chinese medicine will be accelerated and promoted.
10.Cross-sectional study on clinic behavior and therapeutic status of patients with psoriatic arthritis in multi-center.
Yu Hui LI ; Bo SU ; Fu An LIN ; Ya Nan FEI ; Xiao Xia YU ; Wen Qiang FAN ; Hai Ying CHEN ; Xue Wu ZHANG ; Yuan JIA
Journal of Peking University(Health Sciences) 2019;51(6):1014-1018
OBJECTIVE:
To investigate and analyse the features of treatment behavior and standardized therapeutic status of patients with psoriatic arthritis (PsA).
METHODS:
Out patients diagnosed with PsA in People's Hospital of Peking University, Haidian Hospital, People's Hospital of Jianyang City, Central Hospital of Xinxiang City, Integrated Traditional Chinese and Western Medicine Hospital of Cangzhou City, The Third Hospital of Hebei Medical University from February to June 2018 were enrolled in this investigation. The data including gender, age of onset, course of disease, site of first consulting department, time of the first visit and definite diagnosis, follow-up interval, and use of conventional disease modifying anti-rheumatic drugs (cDMARDs) and biological DMARDs (BioDMARDs) were collected and analyzed.
RESULTS:
In the cross-sectional study, 133 PsA patients were investigated. The mean age of onset was (47±11) years, the male to female ratio was 1.3:1, and mean disease duration was (16±8) years. Rheumatology department was the most common site of first hospital visit (37.6%, 50/133). Orthopedics department and dermatological department were visited by 24.1% (32/133) and 23.3% (31/133), respectively. Ratio of definite diagnosis was the highest in rheumatology department which was 78% (39/50). The ratio of definite diagnosis of dermatological department was the second highest, which was 19.4% (6/31). The mean definite diagnosed time was 7.6 months since the first visit of PsA patients, and diagnosed time was the shortest in rheumatology department, which had statistical significance. 37% PsA patients were treated appropriately in 3 months, 17.3% PsA patients were treated in 3-6 months and 40.2% patients with PsA visited their doctor more than once a year. 48.8% patients hadn't received standardized treatment before visit, and one third patients never received the therapy of DMARDs. Methotrexate was the most commonly used cDMARDs (58.3%), followed by leflunomide (20.5%) and BioDMARDs (19.7%), and biologicals were tumor necrosis factor antagonists.
CONCLUSION
In this multi-center study, the first visit department of PsA patients was widely distributed, and most patients were definitely diagnosed in Rheumatology Department. The time of their first visit and definite diagnosis were delayed due to multi factors. Nearly half of the patients did not receive standardized treatment.
Adult
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Antirheumatic Agents
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Arthritis, Psoriatic
;
Cross-Sectional Studies
;
Female
;
Humans
;
Male
;
Methotrexate
;
Middle Aged
;
Time Factors

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