Pterygium is an ocular surface disorder mainly caused by ultraviolet (UV) light exposure. This study explored the relationships between six cataract types with pterygium and UV exposure.We have previously studied cataracts in residents of three regions in China and Taiwan with different UV intensities. From that study, we identified 1,547 subjects with information on the presence or absence of pterygium. Pterygium severity was graded by corneal progress rate. Cataracts were graded by classification systems as three main types  and three subtypes  with high prevalence in middle-aged and elderly people. We calculated the cumulative ocular UV exposure (COUV) based on subject data and National Aeronautics and Space Administration data on UV intensities and used logistic regression to calculate odds ratios for the associations of COUV, cataract, and pterygium.We found an overall pterygium prevalence of 23.3%, with significant variation among the three regions. Four cataract types  were significantly associated with the presence of pterygium.There was a significant association between COUV and pterygium, indicating that COUV is associated with the risk of pterygium development and that pterygium is useful as an index of UV exposure. Furthermore, the type of cataract in eyes with pterygium may indicate the level of UV exposure. The ocular surface is exposed to various external factors, including three types of ultraviolet (UV) radiation produced by sunlight . UV-C light from the sun does not reach the surface of the Earth and accordingly not the human eye. Around 40% of UV-B is absorbed by the cornea on the ocular surface. UV-B is cytotoxic, and its absorption can result in cell death or abnormal cells by repetitive DNA damage and repair , 2. The UV-related eye diseases occur in the ocular parts of the keratoconjunctiva  and lens. Eye diseases related to acute UV exposure include UV keratitis and snow blindness. Chronic UV exposure can lead to disorders such as cataract , 5, pterPterygium is an ocular disease in which subconjunctival tissues abnormally proliferate and wing-shaped fibrovascular tissues invade the corneal surface. The disease has been reported to be associated with UV radiation –27 and eThe Han people are the largest ethnic group of China, Taiwan, and Singapore . StudiesIn the current study, we examined the relationship between pterygium and COUV in three geographical regions with different UV intensities, and between pterygium and cataract type in Han people.TM . Participants completed a questionnaire with demographic characteristics, previous diagnosis of diabetes mellitus (DM), work history (indoor or outdoor workers), time spent outdoors, and the frequency of wearing prescription glasses, sunglasses, or hats while outdoors. This study adhered to the tenets of the Declaration of Helsinki and was performed with the approval (No. I376) of the Ethics Review Committee of Kanazawa Medical University. All subjects provided written informed consent.Our previous work examined cataracts and UV exposure of residents in three regions of China and Taiwan with different UV intensities and annual temperatures , Table 1Pterygium was graded based on the corneal progress rate as developed by Miyata et al. , 46 S2 . Three gFor eyes with pterygium, cataract was classified into three main types: COR, NUC, and PSC, and three subtypes: retrodots (RD), waterclefts (WC), and fiber folds (FF) , 48. Allday) was determined byday, daily UV irradiance; protection factor of glasses, 0.9; Glt (use of glasses), always = 1, seldom = 0.5, no = 0; protection factor of hats, 0.2; and Hatt (hat use), always = 1, seldom = 0.5, no = 0.The COUV was calculated as an estimated cumulative value using the below formulas  and areaday ave) was calculated asThe mean daily ocular UV exposure (OUV6).The prevalence of pterygium and the correlations with COUV were considered after dividing the COUV values into five levels: < 5, 5 to < 10, 10 to < 15, 15 to < 20, and ≥ 20 . The Kruskal-Wallis test for comparison among three unpaired groups was used to assess differences in the average COUV between the regions, whereas Welch’s t-test for the mean of two groups was used to test the difference in COUV for eyes with/without pterygium. Logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) for risk factors for pterygium, cataract risk in eyes with pterygium, and cataract risk with increasing pterygium grade, controlling for the subject’s age, sex, work history, AL, and DM. Multiple regression analysis was also used to examine the associations between pterygium and some other factors. A p value of < 0.05 was considered statistically significant.Pterygium was found in 58.8%  of the subjects in Sanya, 11.8%  of participants in Taiyuan, and 5.3%  of subjects in Taichung, with an overall prevalence of 23.3%  . The preOf the 361 eyes with pterygium, outdoor workers accounted for 86.1% . There wThe adjusted risk of pterygium increased significantly with age , but was not significantly associated with sex . Outdoor6) in Sanya, 9.5 ± 5.1 (×106) in Taiyuan, and 7.4 ± 6.3 (×106) in Taichung; these values were not significantly different   .6). To verify the correlation between COUV and pterygium, COUV of all subjects was divided into five levels of 5 (×106) each: < 5, 5 to < 10, 10 to < 15, 15 to < 20, and ≥ 20 (×106). Logistic regression analysis showed that the risk of pterygium increased significantly with increasing COUV level   .For the 361 eyes with pterygium, the cataract risk for each additional grade of pterygium is shown in In this study, we found a significant statistical relationship between ocular UV exposure and risk of pterygium development in people from three central Asian regions with different UV intensities. After adjusting for age, sex, work history, axial length, and diabetes mellitus, NUC was the cataract type most likely to be associated with pterygium, followed by RD, COR with axle-shaped opacity (CEN-), COR with ring-shaped opacity, and PSC.Many epidemiological surveys have been conducted on the prevalence and risk factors of pterygium. In this study, we focused on the Han people living in the three regions in the “pterygium zone” within the latitudes 37° north and 37° south of the equator , 54. The6) as well. In a previous report, Australian residents who had spent the first 5 years of their lives in areas at latitudes less than 30° had an approximately 40-fold higher risk of pterygium than those at latitudes greater than 40°, and the risk of pterygium increased approximately 20-fold for those with the longest time spent outdoors in those early years [After controlling for time spent outdoors, age, and the use of sunglasses, eyeglasses, and hats, the average COUV was significantly higher for subjects with pterygium, and the risk of pterygium increased significantly with increasing COUV; thus, these results indicate a clear association between COUV and pterygium. On the other hand, pterygium was observed in eyes with low COUV levels  and ring-shaped opacity were significantly associated with pterygium. This result is equivalent to the finding by Modenese et al.  demonstrThis study showed that pterygium grade was not significantly associated with cataract risk and COUV. Factors other than UV exposure can be considered for the progression of pterygium; however, it is difficult to investigate these factors in this type of cross-sectional survey. Regarding the progression of pterygium, it is necessary to study this aspect using a longitudinal survey for each subject, which should be considered in the future. In this study, it was revealed that ocular UV exposure was associated only with the incidence of pterygium.There are very few reports on the relationship between pterygium and cataract. A recent study in two rural areas of China reported that the risk factors for pterygium included latitude, age-related cataract, sex , and age . In a clThe study has several limitations. First, we only investigated the right eyes of the subjects for the possibility that pterygium onset could be an objective indicator of high UV exposure and the relationship between pterygium and cataract from ocular UV exposure. There may be crosswise differences in eyes with pterygium due to occupational factors , 62, sucOur study found COUV to be a significant predictor of the risk of pterygium development. Thus, pterygium may be a useful indicator of ocular UV exposure in other eye diseases. Four cataract types  were associated with pterygium. These results support the existence of a relationship between ocular UV exposure and specific cataract type.S1 FigThe prevalence between right and left eyes were not significantly different (chi-square test). COR, cortical cataract; CEN-/+, absence or presence of the central opacity in the pupillary area; NUC, nuclear cataract; PSC, posterior subcapsular cataract; RD, retrodots; WC, waterclefts; FF, fiber folds.(TIF)Click here for additional data file.S2 FigGrade 1: mild, pterygium position up to one-third of the corneal diameter, Grade 2: moderate, pterygium position up to two-thirds of the corneal diameter, Grade 3: severe, pterygium position more than two-thirds of the corneal diameter.(TIF)Click here for additional data file.S1 TableSome cases overlap in cataract type classification.(TIF)Click here for additional data file.S2 TableSome cases overlap in cataract type classification.(TIF)Click here for additional data file.


The purpose of this study was to systematically review the existing literature to assess the clinical survival and success of PICN and ZLS indirect restorations as the clinical evidence for them remains lacking. PubMed, SCOPUS, Embase, Cochrane Library, Web of Science, LILACs, and SciElo databases were searched from 1 January 2000 to 1 February 2021. Clinical trials and cohort studies published in English were included while case studies, case series, and in vitro studies were excluded. Results were analyzed qualitatively and a meta-analysis using a random effects model was performed. A strength of recommendation taxonomy (SORT) analysis was conducted and risk of bias (RoB) was assessed using the Newcastle–Ottawa scale and Cochrane RoB tools. An electronic search through the databases yielded 2454 articles, of which 825 remained after duplicate removal. Five studies investigating PICN and four investigating ZLS indirect restorations remained after assessing for eligibility. The overall survival rate of PICN over 1 year was 99.6% and 99.2% over 2 years. The overall survival rate of ZLS over 1 year was 99%. The main mode of failure for both materials was catastrophic fracture. One study had a high RoB, four had a moderate RoB, and four had a low RoB. Both materials demonstrated moderate strength of recommendation at a level 2 evidence for all studies based on SORT analysis. PICN and ZLS show promising short-term clinical performance as full and partial coverage indirect restorations, but longer follow-up studies are required to confirm their long-term performance. The exponential development of computer-aided design/computer-aided manufacturing (CAD/CAM) in dentistry has led to an increased conversion to a digital workflow and an uptake in the use of CAD/CAM materials . Polymer1/2 to 1.4 MPam1/2 and 2.31 MPam1/2 to 4.7 MPam1/2, respectively [In vitro testing of PICN identified that PICN had superior mechanical properties compared to feldspathic ceramics (F.C.) that remain limited when compared to L.D. On the other hand, ZLS showed superior mechanical properties compared to L.D. and PICN. The three-point flexural strength of PICN and ZLS ranged from 124 MPa to 202.1 MPa ,11,12,13ectively ,17,18,19ectively ,18,21,22ectively ,16,18, rectively ,13,23, wectively . The elaectively , which iectively , indicatectively ,19 and Lectively . Althougectively , it doesectively . This isectively , but demectively . These aAlthough in vitro testing of ZLS and PICN may provide an initial insight of their mechanical and optical properties, but has inherent limitations given that they are performed under controlled conditions that might not replicate clinical presentation using tests that may not be standardized, resulting in differing results that are challenging to compare . FurtherThe study protocol was registered in the International Prospective Register of Systematic Reviews (CRD42020195749).All clinical (randomised and quasi) trials, as well as cohort studies, with a minimum follow up period of 6 months on adult patients were considered. Case studies, case series, and in vitro studies were excluded.Seven electronic databases  were searched to identify relevant articles for the review. The reference lists of the articles considered for full-text review were also screened by hand for any additional trials that may have been eligible for review. The search was restricted to include the articles published between 1 January 2000 and 10 June 2020. An updated search was conducted on 1 February 2021. The search was also limited to English language articles.The search strategy was peer-reviewed using the peer-review of electronic search strategies guideline (PRESS)  and mappStudy eligibility was performed individually and independently by two investigators (D.C. and A.S.). Any disagreements were resolved by a third investigator (K.A.). Records retrieved from the search strategy were initially screened through title and abstract and full-text publication were reviewed if necessary to discern if they were relevant to the study. After initial screening, full-text analysis was performed to assess for eligibility based on the eligibility criteria.Data extraction was performed individually and independently by 2 investigators (W.B. and J.H.) and tabulated in a Word document using pre-determined data extraction charts. Disagreements were resolved by a third investigator (K.A.).Data on variables which were extracted from included studies, if available, consisted of: author, year of publication, type of study, sample size (patient and number of restorations), clinical setting, age (mean and range), sex, restoration material and design, the reason for restoration, bonding/luting system, follow-up period, location (anterior or posterior), number and methods of failure, the method and type/criteria of clinical assessment, number of evaluators, definition of failure and success and survival, success and/or failure rates.Randomised controlled trials (RCT) were assessed for risk of bias using the revised Cochrane risk of bias tool . Cohort 2, with I2 < 25% being considered as low heterogeneity and <50% as moderate heterogeneity [A descriptive qualitative analysis of the included studies was conducted. Meta-analyses were performed to analyse the overall survival rates of PICN (five studies) and ZLS (four studies) restorations. Single-arm meta-analyses were performed using the fixed-effects model and presented as forest plots. A fixed effects model was used as the heterogeneity between the studies was low, and Open Meta-Analyst statistical software was used for this purpose . The surogeneity .An additional assessment was performed using the Strength of Recommendation Taxonomy (SORT) to evaluate the level of evidence of individual studies and the strength of recommendation .The initial search through all electronic databases yielded 2454 articles . After tOf the nine included studies, five investigated PICN ,40,43,44Studies investigating ZLS were published in a similar time frame from 2017 to 2020. The follow-up period for the studies ranged from 1 to 3 years, with two studies presenting only a 1 year follow-up period ,45. Of tThree of the five studies investigating PICN were limited to the posterior teeth only ,38,43, wThere was a large variety with regard to the type and design of the restorations placed in the studies investigating PICN. Two studies used a single-unit full-coverage crown ,44, one Three of the five studies investigating PICN used a dual cure resin cement ,43,44. OTwo of the four studies investigating ZLS used a dual cure resin cement to seat all their restorations ,45. UndeThe definition of survival varied amongst the studies which investigated PICN ,40,43,44All studies investigating PICN assessed restorations clinically at their respective follow-up periods, with one study using the modified California Dental Associated criteria (CDA) , three uDue to differences in the definition of survival, debonding was reclassed as absolute failures for the purpose maintaining consistency of reporting.n = 7/433), followed by abutment cracks or fractures (n = 2/433) and debonding of the restoration (n = 2/433). There was also a biological failure due to secondary decay with subsequent debonding of the restoration (n = 1/433). In terms of relative failures, the only reported method of failure was due to minor chipping of the restoration (n = 16/433).In studies investigating PICN, the most common method of absolute failure was due to a catastrophic fracture to the material (n = 5/230). This was followed by debonding (n = 2/230), and fracture of the abutment tooth (n = 1/230). The only reported relative failure was the loss of vitality of an abutment tooth (n = 1/230), which was subsequently endodontically treated.Similarly, in studies investigating ZLS, the most common method of absolute failure was also due to catastrophic bulk fractures of the material (p < 0.001) and 99.5% (p < 0.001) over 2 years demonstrated in p < 0.001) as demonstrated in 2 value of 0% [After quantitative analysis, the 1 year overall survival rate of PICN was determined to be 99.6% (ue of 0% .p < 0.001). A combination of conservative restorations including palatal veneers, veneerlays and occlusal tabletops using a “one-step no-prep” approach (subgroup 3) had a survival rate of 99.7%. In the 2 year follow up, single full coverage crowns had an overall survival rate of 96.5% (p < 0.001), while partial coverage restorations had an overall survival rate of 98.8% (p < 0.001) and the “one-step no-prep” approach had an overall survival rate of 99.7%. Heterogeneity was low (I2 = 0) between the studies in both the subgroups for 1 and 2 year survival. A similar analysis was not conducted for ZLS as all studies had a partial coverage restoration (inlay or onlay).A subgroup analysis of the survival of PICN restorations in relation to the design of the restorations was also conducted. Over a 1 year follow-up period, both single full coverage (subgroup 1) and partial coverage (subgroup 2) PICN crowns had an overall survival rate of 99.2% (An analysis on the success rate for both PICN and ZLS was planned but not completed as not all studies reported a success rate as well as inconsistent or obscure criteria for measuring success was reported. Therefore, it was deemed inappropriate to conduct a quantitative analysis with the remaining studies.The Newcastle–Ottawa scale was used to assess eight studies which were cohort studies ,43,44,45All nine included studies were graded as level 2 for evidence of individual studies and an overall moderate strength of recommendation for both PICN and ZLS due to a combination of short follow-up times, limited sample sizes, lack of independent evaluators, and clinical heterogeneity of the studies limited the level of evidence of all studies and the strength of recommendation of the two materials.The aim of this systematic review was to investigate the performance of two CAD/CAM materials, PICN and ZLS, as indirect restorations. Survival at 1 year for PICN and ZLS was >99% at 1 year, and >99% at 2 years for PICN. Among PICN restorations, full coverage restorations demonstrated higher survival than partial coverage. A quantitative analysis was not carried out for the success rates of each material due to limited reporting and varying definitions of success employed in the included studies. To the best of the authors’ knowledge, this is the first systematic review investigating the clinical survival and success of PICN and ZLS CAD/CAM materials. Previous reviews investigating the performance of indirect restorations were not able to discern the performance of individual CAD/CAM indirect restorations due to the heterogeneity of included studies assessing different materials with varying compositions, and instead reported overall survival rates with no meta-analysis specific to each material ,47.The most common methods of failure for both PICN and ZLS were catastrophic and bulk fractures of the material followed by debonding of the restoration. Similarly, reviews investigating ceramic, composite, and hybrid restorations ,49,50, aIn terms of survival, PICN appears to perform slightly worse than more established ceramic materials such as L.D. and monolithic zirconia. A systematic review by Pieger et al.  reveals The initial survival rate of ZLS appears to be promising and comparable to L.D. and zirconia ceramics; however, the results of the present study are limited to 1 year and a partial coverage design. In comparison to L.D., in which ZLS demonstrated better in vitro mechanical properties, both materials seem to be similar in terms of short-term survival ,17. A RCThe current systematic review has a number of limitations. The short follow-up periods ranging from 1 to 3 years within the included studies can only provide an insight into the short-term prognosis of the restorations and may not identify failures which may emerge in trials with longer follow-up periods. Furthermore, the limited sample size of the included studies without any reported power calculations leads to potential type I and type II statistical errors within the studies that are not accounted for. As well as this, five of the nine studies included in the review were also considered either at a high or medium risk of bias which may limit the robustness of the meta-analysis conducted within this study. A single arm meta-analysis was conducted as only two among the included nine studies had a comparison ,39. FurtIn terms of future investigations, longer follow-up periods are required to assess the long-term prognosis of both materials. Furthermore, a more consistent definition of survival and success, which is explicitly reported, is required to more reliably and accurately determine the survival and success rates of these restorations. Standard descriptive guidelines and methods of clinical reporting survival and success by Anusavice  should bBased on the current systematic review, PICN and ZLS demonstrated excellent clinical performance in the short term with a moderate strength of recommendation. Nonetheless, these findings need to be interpreted with caution as longer follow-up studies are required to support the long-term performance of PICN and ZLS indirect restorations.Further studies involving different restoration designs are required to support its use for the different indications. The current studies have mainly focused on partial coverage or full coverage crowns, but further investigations into survival and success of other restorations such as veneers or bridge designs both in the anterior and posterior regions would be beneficial. In particular, ZLS has demonstrated superior physical properties compared to LD and therefore it may be of interest to investigate whether they are more suited clinically as anterior or posterior bridges compared to LD. This may allow for more alternatives for a monolithic bridge design with good aesthetic properties. PICN has also been proposed for use as implant crowns given it has an elastic modulus similar to human dentine , and furAdditional parameters and patient-oriented treatment outcomes should also be investigated for both materials such as colour stability and resistance to wear, especially in challenging clinical presentations such as tooth wear. The colour stability of PICN over time may be of particular interest given that it also contains a resin component within the material . The inf


Patients with amnesic mild cognitive impairment (aMCI) are more likely to develop Alzheimer disease than corresponding age normal population. Because Alzheimer disease is irreversible, early intervention for aMCI patients seems important and urgent. We have designed a pilot multicenter, randomized, parallel controlled trial to assess the efficacy and safety of acupuncture on aMCI, explore the feasibility of acupuncture in the treatment of aMCI, so as to provide a reference for large-sample clinical trials in the next stage.We designed a pilot multicenter, randomized, parallel controlled trial. This trial aims to test the feasibility of carrying out a large-sample clinical trial. In this trial, 50 eligible patients with aMCI will be included and allocated to acupuncture group (n = 25) or sham acupuncture group (n = 25) at random. Subjects will accept treatment 2 times a week for 12 weeks continuously, with a total of 24 treatment sessions. We will select 6 acupoints . For the clinical outcomes, the primary outcome is Montreal cognitive assessment, which will be assessed from baseline to the end of this trial. And the secondary outcomes are Mini-mental State Examination, Delayed Story Recall, Clinical Dementia Rating scale, Global Deterioration Scale, Activity of Daily Life, Alzheimer Disease Assessment Scale-Cognitive Section, brain magnetic resonance imaging, brain functional magnetic resonance imaging, and event-related potential P300, which will be assessed before and after treatment. In addition, we will assess the safety outcomes from baseline to the end of this trial and feasibility outcome after treatment. We will evaluate neuropsychological assessment scale  at 3 months and 6 months after treatment.This pilot trial aims to explore the feasibility of the trial, verify essential information of its efficacy and safety. This pilot study will provide a preliminary basis for carrying out a larger clinical trial of acupuncture on aMCI in near future. As there is no effective method to cure AD, early prevention, early diagnosis, and early treatment are particularly important.With the world's population ages rapidly, Alzheimer disease (AD), the fourth main reason of death, will endanger more and more people's lives. World Health Organization predicts that the number of patients suffering from dementia will increase to 82 million in 2030 and 152 million by 2050. And AD is the commonest form of dementia. divided MCI into 2 types: amnestic mild cognitive impairment (aMCI) and non-amnestic mild cognitive impairment, both of which can be further subdivided into single-region and multi-region. At present, aMCI is the most studied one, and most aMCI patients would develop AD, with 10% to 15% developing AD within 1 year, 40% developing AD within 2 years, 20% to 53% developing AD within 3 years, and 55% developing AD within 4 to 5 years, while the incidence of AD in the corresponding age normal population is only about 1% to 2% per year.Mild cognitive impairment (MCI) is progressive memory disorder similar to AD, which emphasizes the state of illness. Cognitive impairment includes not only memory impairment, but also other impairments, such as executive function, attention, language ability, and so on. According to the existence of memory impairment, Petersen and NegashThe aMCI is considered to be the golden age to save memory impairment. In recent years, it has gradually become a research hotspot. Cognitive decline is the most prominent behavioral manifestation of aMCI patients. Unlike AD, aMCI patients retain a greater degree of cognitive ability to learn and use new skills, which makes them more suitable for early intervention. Because AD is irreversible, early intervention for aMCI patients seems important and urgent.At present, active intervention on MCI is an effective measure to delay the further decline of cognitive function. However, there is no consensus on which drugs or methods to intervene effectively, mostly in the experimental stage. Drug therapy for MCI includes cholinesterase inhibitors, estrogen replacement therapy, Ginkgo biloba preparations, non-steroidal anti-inflammatory drugs, and vitamin E. Current studies have shown that no drug has been found to be significantly beneficial for cognitive improvement or aMCI's transition to dementia. Most of the drugs belong to chemical preparations, which inevitably produce side effects on elderly patients. Non-drug treatment is mainly cognitive rehabilitation training, which is one of the methods to maintain the cognitive function of dementia patients, promote their maximum potential and make their condition relatively stable. The contents include: patient memory training, reality orientation, recalling and remembering the past, behavior management, and cognitive therapy, so as to improve the living quality of patients. But it has some shortcomings, such as limit efficacy, obvious cultural differences, poor compliance, and high treatment costs.,6 Functional magnetic resonance imaging (fMRI) study,8 of acupuncture treatment for elderly patients with MCI showed that acupuncture at Taixi acupoint can target activate the lesion brain area of MCI patients, namely the brain area closely related to cognition, memory, and emotion, and has a holistic regulatory effect on the related brain area.Recently, acupuncture becomes one of the most potential and widely recognized therapies to treat aMCI. It was showed that acupuncture combined with rehabilitation training can effectively improve the cognitive function of patients with MCI. A rigorously designed randomized controlled trial (RCT) aims to explore the efficacy and safety of acupuncture on aMCI is warranted. Compared with the previous RCTs, the methodological design of this trial is very strict and the trial has the following innovations: The sham needle device will be used for the first time in the treatment of aMCI patients by acupuncture; The influence of lifestyle factors on aMCI patients’ memory will be strictly excluded; Data will be managed by data management system in order to avoid the interference of human factors on the clinical research results. This pilot study will preliminarily assess the efficacy and safety of acupuncture on aMCI, and explore the feasibility of acupuncture in the treatment of aMCI, so as to provide a reference for large-sample clinical trials in the next stage.Despite some evidence of acupuncture for aMCI emerging, methodological quality is generally not high enough to produce convincing and suggestive results.22.1The trial is a pilot multicenter, randomized, parallel controlled clinical trial. The clinical study will be carried out at least 3 clinical trial centers, including the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen Bao’an Traditional Chinese Medicine Hospital, and Guangzhou Huangpi Hospital. Subjects will be allocated to the test group or the control group at random for 2 treatment per week in 12 weeks, with a total of 24 sessions. The test group will receive acupuncture and conventional therapy, and the contrast group will receive sham acupuncture and conventional therapy. During the whole duration of the trial, subjects will be required not take other drugs for MCI, such as cholinesterase inhibitors, estrogen replacement therapy, Ginkgo biloba preparations, non-steroidal anti-inflammatory drugs, and vitamin E. Assessments will be conducted at pre-therapy, posttherapy, and follow-ups at 3, 6 months after the end of treatment. The flow chart of the study is shown in Figure 2.2Prospective participants will be diagnosed by geriatric psychologists or neuroscientists, who meet all inclusion criteria and did not fulfill any exclusion criteria. Research assistant will tell them the details about the study and ask them for some information about the eligibility criteria. Qualified participants who have interest in taking part in the study will be arranged to conduct some evaluations on their state and safety. After signing informed consent, participants will be assigned to 2 groups with different treatments.2.3Participants will be widely recruited by publishing paper recruitment advertisements on the spot and electronic recruitment advertisements on the Internet. Participants who have interest in taking part in the research will be screened in relevant test units. Research assistant will offer a written informed consent form to participants or their carers and tell them all detailed information and potential risks of the study. And participants or their carers will be witnessed to sign the informed consent by research assistant.2.4:The diagnosis of aMCI in this study will be made by geriatric psychologists or neuroscientists, and the diagnostic criteria will be based on the relevant criteria in “The Diagnostic and Statistical Manual of Mental Disorders (5th Edition)”1.Patients themselves, family members, or insiders provide chief complaints of memory impairment. Patients or insiders report that cognitive function has declined over the past year compared with previous ones.2.The memory test  score is 1.5 standard deviations lower than those of the normal comparisons matched for age and education.3.The general cognitive grading scale is mild abnormality, that is, the Global Deterioration Scale (GDS) is assessed as grade 2 to 3 or the Clinical Dementia Rating Scale (CDR) is scored as 0.5.4.Daily living activities are intact or very slightly impaired, Activity of Daily Life (ADL) score = 20.5.Not fulfilling the diagnostic criteria of dementia.Patients who meet all of the above 5 criteria will be diagnosed as aMCI.2.5Participants fulfilling all the following 5 items will be included:1.Meeting the above aMCI diagnostic criteria.2.Informant Questionnaire on Cognitive Decline in the Elderly Scale score is ≥51 and ≤53.3.Aged 55 to 79 years, no gender limitation.4.Adequate visual and auditory discrimination for neuropsychological testing.5.Subjects participate voluntarily and sign informed consent.2.6Participants fulfilling any of the following fourteen items will be excluded:1.Education level <6 years.2.Hamilton Depression Scale score is ≥17, pseudo-dementia caused by depression and other emotional abnormalities.3.Patients with congenital mental retardation, patients with medical or neuropsychological state that can cause brain dysfunction, such as having a family history of dementia or having been diagnosed as dementia, psychosis, etc.4.Patients with a history of cerebrovascular diseases, including ischemic cerebrovascular diseases, hemorrhagic cerebrovascular diseases, and neurological disorders such as hemiplegia, aphasia, etc.5.Patients with secondary metabolic disorders caused by some endocrine, genetic and neurological diseases, patients with metabolic diseases induced by drugs.6.Critically ill patients, patients with other central nervous injury diseases or history, such as brain trauma, encephalitis, epilepsy, tumor, infection, severe liver and kidney dysfunction, blood system diseases, central nervous system demyelination diseases and degenerative diseases of the central nervous system, etc.7.Patients with a history of alcoholism and drug abuse, patients with long-term users of drugs that affect cognitive function, such as glucocorticoids, antipsychotics, sedatives and hypnotics, etc.8.,13 or diagnosed as sleep apnea syndrome by multiple physiological sleep tests (polysomnography).Patients who complain of snoring symptoms or whose family members state that they have snoring symptoms, with an Epworth sleepiness scale score ≥16,9.Having participated in other research programs in the past 3 months.10.Having received acupuncture treatment in the past 1 month.11.Allergic to needles or alcohol.12.Patients with syphilis or HIV positive.13.Patients with abnormal vitamin B12 or thyroid dysfunction.2.7Participants fulfilling the following item will be withdrawn:Occurrence of any serious adverse events (AEs): death or visceral function impairment caused by fainting during acupuncture treatment; stroke or accidental death during acupuncture treatment.2.8Fifty eligible participants will be randomly divided into 2 groups. Both groups will receive conventional treatment . On the basis of conventional treatment, the test group will be given acupuncture treatment, while the control group will be given sham acupuncture. They will be treated twice a week for 12 weeks. The time of each treatment wall be 30 minutes. Acupuncture venue is a separate closed-door treatment room. Only the acupuncturists and a subject will be present at the same time to ensure that different subjects will not guess the way of needling received by each other.Acupuncturists of the study have registered Chinese Medicine Practitioners in China, who have been working in the clinic for at least 3 years and have a wealth of clinical experience in acupuncture practice. All of the acupuncturists will accept training before the study, which include the acupoints location, acupuncture operation skills, and communication skills. After the acupuncturists pass training test, they will be allowed to take part in the treatment of the study.In the test group, needles for acupuncture will be standard stainless steel, sterile, and disposable , and electroacupuncture apparatus will be HANS-200E electroacupuncture apparatus. In the control group, needles for acupuncture will be placebo-needle with blunt-tip , and electroacupuncture apparatus will be HANS-200E sham electroacupuncture apparatus without electrical pulse. In each group, Park Sham Device (ACUPRIME company) will be used, and the acupoints are same. The methods of acupuncture and acupoints are demonstrated in Table 2.92.9.1Basic treatment mainly includes blood pressure management, blood glucose control, and other supportive treatment.2.9.2 doctors will adopt a one-to-one way to conduct cognitive rehabilitation training independently. The cognitive module in the system includes cognitive games with different contents and difficulty, which train the subjects’ attention , self-control, reaction speed, motor perception, and memory . Each training time is 30 minutes. Treatment will be performed 2 times a week for 12 weeks, with a total of 24 times.Through the Software System of Brain Function Information Management Platform,2.9.3Refer to Neal D. Barnard et al's “Diet and Lifestyle Guidelines for AD Prevention” published in Neurobiology of Aging.(1)Try to reduce the intake of saturated and trans fats. Dairy products, meat, and some oils  contain a lot of saturated fats. Snack cakes and fried foods contain a lot of trans fats.(2)Replace meat and dairy products with green leafy vegetables, legumes, fruits, and whole grains as staple foods of daily diet.(3)Vitamin E is taken through food rather than vitamin supplements, such as seeds, nuts, green leafy vegetables, and whole grains. The recommended dietary allowance of vitamin E is 15 mg a day.(4)A cumulative daily intake of 2.4 mg B12 is achieved through food or oral B12 tablets.(5)Avoid eating foods or herbal preparations, which contain iron and copper.(6)Avoid using utensils and cookers containing aluminum, and avoid eating foods containing antacids, baking powder, or other foods containing aluminum.(7)Insist on moderate aerobic exercise. Walk fast at least 3 times a week for 40 minutes each time.2.9.4Subjects in the group will accept acupuncture and conventional treatment. On the basis of in-depth study on aMCI and experience of acupuncture, Tongdu Tiaoshen Acupuncture, namely Baihui (GV20), Dazhui (GV14), and bilateral Ganshu (BL18), and bilateral Shenshu (BL23) will be used as therapeutic acupoints. Acupoint location is on the basis of the national standard of the People's Republic of China “Name and Location of Acupoints” . The base of Park Sham Device will be adhered to the skin of the acupoint. We will insert the needle into the tube and tap the needle handle to make the needle tip pierce the skin. Shenshu (BL23): continue to insert deep into the acupuncture point vertically; Baihui (GV20), Dazhui (GV14), Ganshu (BL18): remove the tube and base, remaining the tape and continue to insert the needle obliquely. We will insert the needles into the skin with the depth of 15 to 25 mm and manipulate the needle manually  until the participants states needling sensations (De-qi sensation). Then the needle handle will be rotated continuously for 2 minutes at a frequency of about 200 times per minute, with small amplitude, fast speed and uniform speed. The needles on BL18 and BL23 will be connected to a HANS-200E electroacupuncture apparatus, whose waveform is dilatational wave with alternating frequency of 2 Hz and 100 Hz. Needles will be retained for 30 minutes before removing.2.9.5Subjects in this group will accept sham acupuncture and conventional treatment. The needles will not insert into the skin, and acupoints are the same as test group. A non-invasive placebo control, namely sham blunt-tip needle, will be used in this trial. The base of Park Sham Device will be adhered to the skin of the acupoint. We will insert the sham needle into the tube and tap the needle tip to make the needle touch the acupoint skin but not pierce the skin. The needle on BL18 and BL23 will be connected to a HANS-200E sham electroacupuncture apparatus without electrical pulse. Needles will be also retained for 30 minutes before removing.2.102.10.1We will evaluate the neuropsychological assessment scale , brain cranial magnetic resonance imaging (MRI) and brain functional cranial fMRI, latency and amplitude of event-related potential (ERP) P300 before and after treatment. This incidence rate of acupuncture AEs will be counted. We will evaluate neuropsychological assessment scale  at 3 months and 6 months after treatment.2.10.22.10.2.1 The lower the score, the more significant the cognitive impairment.The MoCA contains 8 items: visuospatial and executive function, denominating, short-term memory, concentration, language, abstraction, delayed memory, and orientation. Total points range from 0 to 30. If participants have not been educated for more than 12 years, their scores will be increased by 1 point on their score (if <30). If the total score is less than 26, it represents cognitive decline.2.10.32.10.3.1The MMSE evaluates 10 domains of cognitive function which includes orientation, short-term memory, attention and calculation, delayed memory, language and ability to draw a complex polygon etc. Total points range from 0 to 30. The lower the scores, the more significant the cognitive impairment.2.10.3.2The Delayed Story Recall is to ask the subjects to listen to and retell the 2 stories first, at this time, no score will be given. After 30 minutes, the subjects retell the 2 stories, and then began to scoring. One point for each keyword, with a total point range from 0 to 40. The lower the score, the more serious the cognitive impairment.2.10.3.3 If CDR-GS is 0.5, it represents questionable dementia or MCI.,18 If CDR-SOB is 0.5 to 4.0, it represents MCI.,20 Higher score indicates more severe the cognitive impairment.The CDR includes 3 cognitive items and 3 functional items, namely, memory, orientation, discretion/ability to solve problems, social affairs, family/interest, and personal care. Each item is grated as 5 level, namely, 0 point represents no impairment, 0.5 point indicates questionable impairment, 1 point indicates mild impairment, 2 points indicates moderate impairment, and 3 points indicates severe impairment. And there are 2 methods of scoring for CDR, including global score (GS) and sum of boxes (SOB) score.2.10.3.4The GDS assesses the severity of cognitive decline over 7 stages, that is, stage 1 shows no cognitive impairment, stage 2 shows very mild cognitive impairment, stage 3 shows mild cognitive impairment, stage 4 shows moderate cognitive impairment, stage 5 shows moderate severe cognitive impairment, stage 6 shows severe cognitive impairment, stage 7 shows very severe cognitive impairment.2.10.3.5 The scale is divided into 4 grades: 1 = self-care; 2 = have some difficulties; 3 = need help; 4 = unable to complete. The total score ranged from 20 to 80. If the score of single item is 1, it is normal; if the score of single item is 2 to 4, it is functional decline. If the total score = 20 points, it indicates absolutely normal; if the total score is >20, it indicates different levels of functional decline. The higher the score, the worse the ability to live.The ADL assesses 20 domains of activities, which includes physical self-maintenance scale and instrumental activities daily of life. Physical self-maintenance scale includes 6 basic activities: toilet, feed, dressing, grooming, physical moving, and bath, and instrumental activities daily of life includes 8 instrumental activities: using telephone, going shopping, preparing food, doing housework, doing the laundry, transportation, taking medicine, ability to handle finances.2.10.3.6,24The ADAS-cog includes 12 cognitive domains, containing recall of word, recognizing word, constructional practice, orientation, denominating, commands, ideational practice, recall test commands, verbal ability, looking for words, comprehension, and concentration. The total scores ranges from 0 to 75. The higher the score, the poorer the cognitive impairment.2.10.3.7 Besides, atrophy of hippocampus and entorhinal cortex are reliable indicators of the transformation of aMCI to AD.,27 Other brain changes on MRI in patients with MCI include decreased cortical gray matter, enlarged ventricles, and increased white matter high signal intensity.MRI structural imaging can show different brain lesions, which is helpful for the etiological diagnosis and monitoring of the progress of MCI. The most common local brain changes in aMCI are atrophy of the hippocampus and the entorhinal cortex.2.10.3.8–30 Default mode network is a focus network for the study of cognitive function by using resting-state functional MRI. It includes the posterior cingulate/anterior cuneiform lobe, medial prefrontal cortex, hippocampus, angular gyrus, and ventral anterior cingulate gyrus, which are related to cognitive function, executive function, and situational memory. resting-state functional MRI in aMCI patients is mainly manifested as the gradual weakening of functional connections in the default mode network of brain regions, such as hippocampus and medial prefrontal lobe.Cerebral activation can be researched by Blood-Oxygen-Level-Dependent signal of fMRI. Blood-Oxygen-Level-Dependent signal would make differences when there are pathological changes associated with neurodegenerative disease.2.10.4–35 Component of P300 is the research hotspot of ERP and the numerous clinical P300 studies–42 show that the component can be used as an index of cognitive function. The prolonged latency and declining amplitude of P300 shows cognitive impairment.ERP are electric signals from the brain, which relate to miscellaneous cognitive function, like selective concentration, memory, or discretion.2.10.5The incidence rate of acupuncture's AEs during treatment will be counted. Clinical symptoms and related laboratory examination results of acupuncture's AEs will be recorded to judge their grades. Follow-up visits after AEs will be recorded.2.11We will evaluate vital signs, blood routine, urine routine, liver and kidney function, coagulation function, electrocardiogram, and clinical symptoms and related laboratory examination results of acupuncture's AEs at pre-therapy and posttherapy.2.12In order to evaluate the feasibility of carrying out RCTs with large samples in the next stage, we set the following indicators in this pilot trial. The feasibility outcomes are demonstrated in Table 2.13 in 2016, the sample size was estimated with MoCA as the main outcome. After 12 weeks of treatment, the difference of MoCA between pre-therapy and posttherapy in the conventional rehabilitation group (without acupuncture) was 2.83 ± 1.13, and that of MoCA between pre-therapy and posttherapy in acupuncture group was 1.33 ± 1.20. The test level was set at α = 0.05 and β = 0.1. By comparing the differences between 2 independent samples, PASS 2008 software was used to calculate that the required sample size of each group was 13 cases, and 26 cases in both groups.Based on the RCT report published by Jiang et alTo sum up, considering that the follow-up loss rate is 20%, the sample size should be 26/(1 – 0.2) = 33 cases. Considering that we have enough research capacity to fulfill the expected research tasks, we intend to expand the sample size to a total of 50 cases, 25 cases in each group.2.14The stratified random allocation operation of experimental group and control group will be completed by the researcher of the Clinical Research Center, South China Research Center for Acupuncture and Moxibustion, Guangzhou University of Chinese Medicine. The programming and randomized operation will be performed by PROC PLAN of SAS 9.2. The results of random allocation will be distributed through the central random allocation system in the internet.2.15Patients will be notified that they will be received acupuncture treatment or acupuncture-like simulation treatment, which is randomly allocated. And they will be required to close their eyes during treatment. Only the acupuncturists will be aware of the detailed grouping. Subjects and other investigators  will not know group assignments. All investigators will receive trial training before the study starts to ensure the success of the implementation of blind method.2.16All subjects will be tested for the success of blinding after the final treatment session. They will be asked to judge whether they have received real acupuncture or sham acupuncture. In the scale of 0 to100, 0 is “confirmed to be sham acupuncture”, 100 is “confirmed to be real acupuncture”. After scoring, the results will be collected and statistically analyzed by the research team. The blinding success assessment scale is shown in Figure 2.17If participants are considered to have undesirable effect after acupuncture treatment, they should discontinue treatment and tell acupuncturists. Acupuncturists will diagnose and cure the AE, and other investigator will contact them to fill in the AE form and AE record log. AEs may occur during acupuncture, such as fainting, hematoma, bent needle, stuck needle, broken needle, infection, etc. If any relevant AE occurs during the study, it will be dealt with immediately.Participants and acupuncturists should report all of the AEs . All detailed information of AEs  will be reported in the case report forms (CRFs). In case of serious AE, it will be reported to the lead unit and the state administration of traditional Chinese medicine within 24 hours. One week after symptomatic treatment, follow-up will be conducted through outpatient service, telephone, or visit. We will analyze the impact of all AEs after this trial finishes.2.18All data will be input into a pre-designed, password protected dataset by someone who will not know the group assignment. In order to protect the subjects’ privacy, we will adopt codes and initials to mark the subjects’ personal information. Specified investigators will monitor the quality of online CRFs completion. Only outcome evaluators can access CRFs and will carry out double-data entry with any amendment or transformation of written data in subjects’ CRFs documented and dated. The clinical supervisor will monitor the data and study progress at least once a day.2.19The statistical tests involved in this study will include unilateral and bilateral tests with a significance level of alpha = 0.05. Statistical analysis will be completed by SPSS 22.0 software .t test. Categorical variables, containing categorical baseline variables and incidence of AEs, will be analyzed by a chi-square (χ2) or Fisher exact test.Effect analysis will involve a population consisting of per-protocol subject analysis and intention-to-treat analysis. We will adopt a repeated measures design approach to compare the treatment outcomes  over time between 2 groups. The model will be built to distinguish the intervention effect and the time effect. Among-group differences at each assess time point will be further tested by student 2.20If the missing value is less than 5%, a full case analysis without calculating missing date will be adopted. If the missing value exceeds 5%, Little test will be adopted. If Little test showed that the full case data set is a random sample, the full cases without calculating missing date will be continued analyzing. If Little test showed that the full case data set is not a random sample, the point estimation and 95% confidence interval will be reported, with a worst- and best-case scenario imputation for the missing date. If the worst- and best-case analysis reach the same conclusion, we will not carry out multiple imputations. Or else, under the assumption of randomly missing value, multiple imputations will generate 10 estimated data sets. The pooled intervention effect and 95% confidence interval of the analysis of every data set after multiple imputation will constitute the results of the trial.2.21Before the experiment, all subjects participating in this study will receive the same training, detailed description of the study operation process, explanation of acupuncture related knowledge, and examination characteristics of ERP P300, MRI, and fMRI. All assessment will be conducted by a team led by a qualified professional evaluator. Researchers who participate in efficacy evaluation must have a certificate of medical practitioner and will not take part in the treatment of participants. All researchers will be trained and assessed by acupuncture physicians above the associate chief physician on standard operating procedure . In each research center, participants will be fixed as the same acupuncturist to perform the operation. Special independent supervisors will be set up in each research center. Each participant will be given a medication history book. The researchers will instruct participants to keep detailed records of all specific participant conditions during the study, including drug name, drug dosage, time of taking drug, and possible symptoms after taking drug. All data are entered into the data management system.3 and has been generally practiced in Western countries in recent years. Recently, despite some evidence of acupuncture for aMCI emerging, methodological quality is generally not high enough to produce convincing and suggestive results. We design a rigorous RCT, using the control group method to decline bias of test and ensure the dependability of the RCT. And the study is a significant RCT aimed to treat aMCI.Acupuncture therapy has been used in China for more than 2000 years According to our in-depth study on aMCI and experience of acupuncture, Tongdu Tiaoshen Acupuncture, namely Baihui (GV20), Dazhui (GV14), and bilateral Ganshu (BL18), and Shenshu (BL23) will be used as therapeutic acupoints. Secondly, we select the MoCA as the primary outcome. Multiple guidelines,47 suggest the MoCA as the primary outcome of aMCI, and many aMCI studies adopted the MoCA as an assessment outcome. Finally, we have set a control group to realistically examine recruitment, randomly allocation, complement of interventions, and blinding evaluation. Nowadays, placebo contrast for acupuncture contains non-acupoint, superficial, and sham acupuncture.–51 Some people think efficacy of acupuncture is controversial, as acupuncture takes effect primarily by a placebo result, or the controls of sham acupuncture maybe not absolutely non-effective.–54 In the study, control group will accept sham acupuncture, whose needles will not insert into the skin. In each group, Park Sham Device will be used, and the acupoints are same. The designs will help reduce non-specific influence in the sham acupuncture group. Besides, acupuncture venue is a separate closed-door treatment room. Only the acupuncturists and a subject will be present at the same time to ensure that different subjects will not guess the way of needling received by each other.This RCT has some improvement compared with previous trials. Firstly, it is a problem for the acupuncture investigators how to select the acupuncture points.Nevertheless, the study still faces some challenges. Firstly, the screening criteria for subjects in this study are very strict to ensure the homogeneity of subjects’ baseline and the validity of test results. Therefore, it may not be possible to recruit a large number of eligible subjects in a short period of time. We will summarize the experience after preliminary test, so as to expand the sample size and carry out the formal experiment in the next stage. Secondly, it is almost impossible to implement blind method for acupuncturists and it is inevitable that acupuncturists will know the treatment. Thirdly, in China, especially in Guangdong, many elderly people have received acupuncture treatment and know the feeling of being needled, so it is not easy to blind the subjects in the study. Some subjects may guess whether they are receiving real acupuncture treatment or not. To ensure the smooth implementation of blinding, participants in the 2 groups will use Park Sham Device when receiving acupuncture, and all participants are required to close their eyes during the whole course of treatment. In order to standardize the use of these false needle devices, all acupuncturists participating in the treatment will receive unified training and assessment before the start of the study, so as to ensure the consistency of the needle manipulation process and stimulation intensity. Fourthly, subjects will spend a lot of time on treatment because each treatment takes at least 1 hour and lasts for 12 weeks. Therefore, we anticipate that the compliance of subjects may not be high enough. In order to improve the compliance of subjects, we keep in touch with the subjects and at least 1 family member of the subjects. Let them realize the importance of intervening in aMCI by explaining the relationship between aMCI and AD in detail. In addition to the subjects, we will inform the family members of the research process in detail, so that the family members would urge the subjects to complete the treatment process. Meanwhile, we will give some compensation incentives to the participants.In order to reach our goals, we will try to make every step standard, such as selection of acupoints, manipulation of acupuncture, needle apparatus, and needle apparatus’ clinical experience. We look forward to that the study will offer strong positive proof for acupuncture on aMCI.3.1This trial was registered on 27 February 2019 . At present, the clinical study is underway. This trail started on July 2019 and the expectant finished date of this trial is June 2020.We would like to express gratitude to the staff of South China Research Center for Acupuncture and Moxibustion of Guangzhou University of Chinese Medicine, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen Bao’an Traditional Chinese Medicine Hospital and Guangzhou Huangpi Hospital.The trial was designed and developed by LZ and LML. The manuscript was drafted by JYZ and XK. The protocol was carefully revised and edited by CZT and NGX, SHX, LJX, YD, and SWW contributed to the discussion. All authors read and approved the final manuscript.Formal analysis: Liming Lu, Liang Zhang.Investigation: Nenggui Xu, Shengwen Wang.Methodology: Songhua Xiao.Project administration: Chunzhi Tang, Lingjun Xiao.Visualization: Yu Dong.Writing – original draft: Jiayu Zhang, Xu Kuang.Writing – review & editing: Xu Kuang.


The COVID-19 outbreak has caused challenges for healthcare systems worldwide. Recent data indicates that the psychological impact has differed with respect to occupation. In many countries, medical residents have been on the front line of this pandemic. However, data on the psychological impact of infectious disease outbreaks, and COVID-19 in particular, on medical residents are relatively lacking.The aim of our study was to assess the psychological impact of the COVID-19 pandemic on medical residents working on the front and second line.An electronic survey was sent to all medical residents in Qatar. Depression, anxiety and stress were assessed by the Depression, Anxiety and Stress Scale – 21 Items. Professional quality of life was measured by the Professional Quality of Life measure.Of the 640 medical residents contacted, 127 (20%) responded. A considerable proportion of residents reported symptoms of depression (42.5%), anxiety (41.7%) and stress (30.7%). Multivariate analysis of variance showed significant effects of seniority in residency, with junior residents having poorer outcomes. In addition, there was a statistically significant interaction effect with moderate effect sizes between gender and working on the front line, as well as gender, working on the front line and seniority, on mental health outcomes.The COVID-19 pandemic may have a negative impact on junior residents’ mental health. Preventive measures to reduce stress levels and easy access to professional mental health services are crucial. This pandemic has strikingly changed the lives and outlook of residents in a very short time. For instance, the ‘normal’ daily, weekly, monthly and annual schedules planned by the residency programmes, which were to be in effect at this time, have been heavily affected; for example, deployment of medical residents as primary care doctors in screening facilities; shifting supervision, didactics and educational conferences online; and lack of clinical exposure because of curtailing office visits.4 However, data on the psychological effects of infectious disease outbreaks, and COVID-19 in particular, on medical residents are relatively lacking even though the psychological aftermath of the 2003 SARS and COVID-19 outbreaks seem to differ with respect to occupation.7 A PubMed search on 31 July 2020 for ‘(covid-19 OR coronavirus) AND ’ identified 194 results. Out of 50 articles that specifically targeted medical residents or residency programmes, nine cross-sectional studies earmarked the mental health outcomes of the COVID-19 pandemic on medical residents.16 Although South Korean orthopaedic residents have reported a decrease in their quality of life during the pandemic, data on the impact of COVID-19 on medical residents’ mental health outcomes remains scarce, according to our literature search.10 Although a nationwide study among otolaryngology residents and attending physicians in the USA indicated a higher level of resident burnout, medical residents in China had a lower risk of psychological problems than other physicians and nurses.15 Working on the front line and directly engaging in the diagnosis, treatment and care of patients with COVID-19 may also be a key factor. In Wuhan, China, the epicentre of the original outbreak, front-line staff were found to have higher psychological burden than second-line staff.6 On the other hand, front-line medical residents in Romania had lower levels of burnout than second-line medical residents.13 It is also unclear how seniority in residency affects mental health outcomes during the COVID-19 pandemic.11 To address this gap, we aimed to assess levels of symptoms of depression, anxiety and stress, and professional quality of life, among medical residents with the Hamad Medical Corporation (HMC) in Qatar.Medical residents are doctors in training and account for the majority of patient contacts with doctors within teaching hospitals, and they are, consequently, at risk of exposure to communicable disease.17We conducted a cross-sectional study among medical residents from all specialties in Qatar. All residency programmes in the country are with HMC, an institution accredited by the Accreditation Council for Graduate Medical Education-International (ACGME-I). A resident is a physician enrolled in an ACGME-accredited residency programme, usually after graduation from the medical school. The residency programme is designed to prepare resident physicians to practice independently in a primary specialty.The survey took place from 17 May to 16 June 2020. During this period, the total confirmed cases of COVID-19 in Qatar exceeded 80 000, with 80 deaths. HMC, the main public healthcare system in Qatar, is the largest provider of tertiary health services in the country, accounting for more than 90% of the care delivered, with only few and relatively small private healthcare systems.In our questionnaire we did not include information about how to seek help. However, HMC residency programmes have mentorship programmes and access to counselling through a variety of channels; for example, graduate medical education, trainee council, trainee psychology services and routine mental health services. Even before the pandemic started, and more so after it occurred, the residents have been especially encouraged to get support.The study was approved by the Hamad Medical Corporation Institutional Review Board , and all study participants provided electronic consent.The survey was built with Qualtrics software . An email was sent to the professional email addresses of all medical residents in the country. To improve the participation rates, reminder emails were sent at 1, 2 and 3 weeks after the initial email.18To measure the mental health outcomes, we used two scales. The Depression, Anxiety and Stress Scale – 21-Items (DASS-21) quantitatively measures distress along the three axes of symptoms of depression, anxiety and stress. Higher scores in any of the axes indicate higher levels of distress/symptoms. The suggested cut-off scores for detecting symptoms of major depression, anxiety and stress are 4, 3 and 7, respectively.19 It measures compassion satisfaction (a low score (<23) signifies a poor level of professional satisfaction) and compassion fatigue. The latter is broken down into two parts: burnout (higher score (>41) indicating higher risk for burnout) and secondary traumatic stress (a score >43 indicating a frightening experience at work).19The Professional Quality of Life measure (ProQOL) is the most commonly used measure of the positive and negative effects of working with people who have experienced extremely stressful events.All statistical analyses were done with IBM SPSS software version 25 for Windows. For descriptive statistics, we calculated absolute and relative frequencies for categorical variables, and means and s.d. for continuous variables. We used t-test for independent samples to compare the different DASS-21 and ProQOL scores between groups.2. The defined significance level was α = 0.05.To assess the differences in mental health outcomes between groups , we constructed a three-way multivariate analyses of variance (MANOVA), using DASS-21 depression, anxiety and stress scores as dependent variables, with ‘residency seniority’ , working on the front or second line, and gender as independent variables. A medical resident working on the front line is one who is directly engaged in the diagnosis, treatment and care of patients with COVID-19. Second-line medical residents do not face and address patients with COVID-19. Preliminary assumptions for MANOVA  were tested. Pillai's trace test was used because the DASS-21 scores violated the normality assumption. The effect size was assessed with partial ηOut of 640 medical residents contacted, 127 (20%) responded to the survey. The participants could not skip individual items, therefore there were no item-level missing data.A considerable proportion of residents had symptoms of depression (42.5%), anxiety (41.7%) and stress (30.7%). Overall, most (93.7%) participants had high levels of compassion satisfaction, all had low-to-moderate levels of burnout and virtually all (99.2%) had secondary traumatic stress.v. 5.5, P = 0.046), but depression and anxiety scores were not significantly different. No difference in mental health outcomes was noted between junior and senior male residents.The mean scores on the ProQOL for compassion satisfaction, burnout and secondary traumatic stress for all respondents were 36.4 ± 8.3, 25.3 ± 6.5 and 22.6 ± 7.0, respectively. Independent t-test comparisons did not show any statistical differences between gender, junior versus senior residents or front-line versus second-line residents.The three-way MANOVA analysis examining mental health outcomes  as dependent variables, with seniority in residency, working on the front line and gender as independent variables, showed that the mental health outcomes were significantly affected by seniority in residency, with junior residents having poorer outcomes. In addition, there was a statistically significant interaction effect with moderate effect sizes between gender and working on the front line, as well as gender, working on the front line and seniority, on the mental health outcomes .Table 3Post-hoc power analysis, meaning the retrospective power derived from our data-set, showed an observed power of 0.604.Univariate tests of between-participant effects  showed sρ = 0.71, P ≤ 0.01). Moreover, there was a very strong negative correlation between burnout and compassion satisfaction .Spearman correlations between mental health outcomes  showed aThis cross-sectional survey enrolled 127 respondents and revealed a high prevalence of mental health symptoms among the residents during the COVID-19 pandemic in Qatar. Overall, 42.5%, 41.7% and 30.7% all participants reported symptoms of depression, anxiety and stress, respectively. In contrast, the residents demonstrated high compassion satisfaction, moderate-to-low burnout and secondary traumatic stress, all of which translate into high professional quality of life. Multivariate analysis showed significant effects of seniority in residency, with junior residents having poorer outcomes. In addition, there was a statistically significant interaction effect on mental health outcomes, with moderate effect sizes between gender and working on the front line, as well as gender, working on the front line and seniority. Univariate analysis showed that the effect of gender on the depression score depended on working on the front line versus second line, and vice versa. Moreover, the effect of gender on all scores depended on working on the front line and seniority, with junior female front-line residents and male junior second-line residents exhibiting the poorest outcomes. Together, our findings present concerns about the psychological well-being of the junior residents during the COVID-19 pandemic.20 During the COVID-19 pandemic in Wuhan, China, a survey among healthcare workers showed a high prevalence of depression (50.4%), anxiety (44.6%) and distress (71.5%).6 Similarly, 90% of the neurosurgery residents across different programmes believed that this pandemic had influenced their mental health and social life.9 In a national study among otolaryngology residents and attending physicians in the USA, the prevalence of depression, anxiety, distress and burnout among the medical residents were 10.6%, 47.9%, 60.2% and 21.8%, respectively. The authors also found that the residents had increased burnout relative to attending physicians.12 In terms of association with gender, previous studies have found a higher level of depression, anxiety, distress and burnout in women, which are probably explained by a combination of biological and social factors.12 In our study, female gender was not independently associated with any of the mental health outcomes. Nonetheless, our study demonstrated an interaction effect between gender and working on the front line, as well as an interaction between gender, working on the front line and seniority, which showed a moderate but significant effect on mental health outcomes. This probably means that female medical residents might be at a higher risk of detrimental psychological effects when they are junior residents and/or working on the front line, but are probably less affected as they gain experience (become senior residents) or as long as they are not deployed to COVID-19 sites. Possible explanations might include increased experiences of fear related to COVID-19 among women, but these fear experiences are probably attenuated by their medical experience.21In this study, a significant proportion of participants experienced symptoms of depression, anxiety and psychological symptoms. In a previous study during the acute SARS outbreak, 89% of healthcare workers who were in high-risk situations reported more negative psychological effects  than the control group.13 Internal medicine and psychiatry residents in Michigan, USA, have stated a lack of adequate personal protective equipment, physical and emotional exhaustion and overwhelming fear of catching the virus and infecting their loved ones, as potential grounds for burnout in front-line medical residents.22 They also suggested that the psychiatry residents, for example, who are not working on the front line may develop higher vicarious traumatisation, as suggested by a study in Wuhan illustrating that second-line nurses had significantly higher level of vicarious traumatisation than front-line nurses.23 Possible explanations for the lower propensity of developing burnout and vicarious traumatisation among the medical residents in Qatar are high levels of personal accomplishment and satisfaction with medicine, and a low level of depersonalisation, as illustrated in a cross-sectional study in 2017 among medical residents in the HMC.24 On the other hand, we do not have a direct comparison using scales used in this study. As part of ACGME-I accreditation, the well-being of the residents is monitored and HMC did not receive any citations regarding this in their 2018 site visit. Nonetheless, in general, medical residents experience exceptional stress during their training programmes because of long working hours, heavy workload, poor work environment, lack of social support, problems of relocation and difficult patients and families.24In contrast with previous findings, our study showed that residents did not report high levels of burnout, whereas the prevalence of burnout among the Romanian residents was as high as 76% during the COVID-19 pandemic.25 A recent study in Wuhan showed that working on the front line was an independent risk factor for worse mental health outcomes such as depression, anxiety, distress and insomnia.6 In our study, the male junior second-line residents and female junior front-line residents had the highest levels of psychological symptoms. A possible explanation could be that the junior residents have less clinical and infection control knowledge and experience, and consequently, are less prepared to face the current pandemic crisis.25 In Singapore, front-line medical residents had lower stress levels than second-line residents, because of the higher degree of psychological preparedness among front-line residents and anticipatory anxiety among second-line residents, despite the fact that second-line residents seem further away from the crisis.11 Furthermore, following the deployment of the residents to high-risk areas, second-line residents may have faced longer working hours, extra responsibilities and less supervision.Several studies have compared front-line and second-line healthcare workers, with the majority showing poorer mental health outcomes for those in high-risk environments.6 Nonetheless, a study in Singapore found no difference between the junior and senior residents in terms of psychological responses to the pandemic.11 On the other hand, the junior residents and second-line residents in Qatar were at increased risk for symptoms of depression, anxiety and stress. Consequently, their mental health may require special attention, bearing in mind that they are particularly vulnerable. In a recent paper, the leaders of the American Heart Association wrote that ‘residents and fellows — whether due to lack of experience, poor preparation or lack of training — are particularly vulnerable’. Therefore, they are the ones most in need of protection and mental health support during moments like this. They went on to state ‘Protect medical trainees on the COVID-19 front lines or do not send them in’.26 In France, a collaborative and helping crisis department has been set up for every medical resident in need. This department connects the residents in training with the psychiatry residents 24 hours a day, to address their mental health needs.8 It is also important for healthcare leaders to develop and implement support measures based on the needs and desires of the healthcare workers. For instance, in a survey among New York medical residents and other healthcare workers on potential wellness resources, self-guided counselling with access to a therapist, individual counselling and therapy, and an online clinician support group gathered the most interest.16Our findings indicate worse mental health outcomes among junior residents. This is in accordance with the findings from a study in Wuhan, which indicated that healthcare workers with junior titles may be at higher risk of more severe mental health outcomes in terms of depression, anxiety, insomnia and distress.27 Besides, our response rate is comparable with rates of 20% and 27.4% from national studies in USA and South Korea, respectively.14 This means that extrapolating our findings to the entire population of medical residents might be difficult. The observed power of 60.4% was also rather low, thus indicating the possibility of a type 2 error. Moreover, we did not include a control group and therefore are unable to definitely conclude that these symptoms in the medical residents differ from those of the general population. Last, but not least, we have not investigated secondary stressors, such as familial and social stressors, between the front-line and second-line residents, which may affect the residents’ longer-term mental health.28This study has several strengths, chief among them that the survey was sent to all medical residents in Qatar, and used validated, widely used questionnaires in the field. However, a few limitations need to be acknowledged. Indeed, we had a low response rate of 20% and the possibility of non-response bias cannot be ruled out. Indeed, it is possible that the nonrespondents were either too stressed to respond or were in good health and therefore not interested in this survey.In conclusion, our findings indicate that medical residents, and in particular the junior residents, display high levels of depressive, anxiety and stress symptoms during the COVID-19 pandemic. Contrary to preconceived ideas, these symptoms are not limited to frontline healthcare workers. Medical residents may require particular attention during a pandemic. This includes wellness resources such as individual counselling with a therapist, or a support group with the other residents. The reassuring professional quality-of-life scores in our study may indicate that the residents may benefit from engagement, opportunities for continuous education and other opportunities to grow in their position. Nonetheless, further studies are needed to capture the longitudinal picture during the ongoing COVID-19 pandemic, for it is important that institutions continue their efforts regarding the mental wellness of their medical residents.


Meanwhile, we also address the potential challenges on the lncRNAs-mediated epigenetic study to further understand the molecular mechanism of the neurodegenerative diseases.Emerging evidence addresses the link between the aberrant epigenetic regulation of gene expression and numerous diseases including neurological disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). LncRNAs, a class of ncRNAs, have length of 200 nt or more, some of which crucially regulate a variety of biological processes such as epigenetic-mediated chromatin remodeling, mRNA stability, X-chromosome inactivation and imprinting. Aberrant regulation of the lncRNAs contributes to pathogenesis of many diseases, such as the neurological disorders at the transcriptional and post-transcriptional levels. In this review, we highlight the latest research progress on the contributions of some lncRNAs to the pathogenesis of neurodegenerative diseases  Epigenetics literally refers to regulation of gene expression due to external modifications to DNA and histones without altering DNA sequence. Caused by a variety of factors inside/outside of organisms, such as hormones, metabolism, diet, temperature, light, drugs, air pollution, age and so on, epigenetic changes could alter growth, development, reproduction and aging, and even contribute to pathogenesis of diseases such as neurological disorders. Significant efforts have been made in study of the epigenetic basis of neurodegenerative diseases , such asN6-methyladenosine (m6A) have been identified and characterized as important epigenetic markers involved in regulation of gene expression in complicated mechanisms -mediated modifications . Of the chanisms . In a brBased on the length with 200 nt as cutoff value , ncRNAs It has been estimated that there are more than 50,000 of lncRNAs in the human genome . Based oStructurally, majority lncRNAs are very similar to but different from mRNAs. In terms of the similarity, they are transcribed from RNA polymerase II (POLII) from genomic sites in a chromatin-like state; usually 5-capped, spliced, and polyglandular. However, there is still a general trend to distinguish lncRNAs from mRNAs: lncRNAs tends to be shorter than mRNAs, with fewer but longer exons, failing to translate due to lacking in open reading frame, relatively low expression level and poor conservation of primary sequences .via binding to transcription factors  by β-position APP cleaving enzyme 1 (BACE1) and γ secretase. Indeed, dysregulation of BACE1 leads to overproduction of Aβ, contributing to pathogenesis of AD . Basical2O2 oxidative stress. Bioinformatic analysis predicted a binding site between miR-124 and XIST as well as between miR-124 and BACE1. Expression of XIST was negatively correlated with miR-124 but positively with BACE1. Consistently, knockdown of XIST upregulated expression of miR-124 but downregulated the expression of BACE1 in N2a cells. The direct interactions between XIST and miR-124, as well as BACE1 and miR-124 were further confirmed by using luciferase reporter assay  to bind miR181c-5p, as enhancer of hyperphosphorylation of tau protein by activating P25/P35/GSK3β signaling pathway , indicating the potential anti-inflammatory effect of MALAT1 on MS . StimulaLncRNA MEG3  plays important roles in cell proliferation, learning, and memory . The expvia inhibiting miR-137. KREMEN1 belongs to the dickkopf (Dkk) family of Wnt antagonists. Wnt-independent way plays a role in promoting apoptosis in cells  accounts for up to 90% of ALS cases and the other 10% have a strong genetic component also called as familial ALS (FALS). Mutations in more than 20 genes contribute to FALS . TDP-43,d to ALS ; Table 3Transcriptomic profiling conducted in 30 patients with SALS and 30 matched normal persons, led to identification of 293 of lncRNAs differentially expressed (DE) in the SALS patients. Of the DE lnc-RNAs, 183 out of 293 (62.5%) were upregulated, while 184 out of 293 (62.8%) belong to antisense RNAs and 81 out of 293 (27.7%) were reported as real DE lincRNAs , suggestvia direct protein-protein interactions  . Both TDractions . The freractions . More deractions . Given tractions .via interaction with proteins related to ALS pathogenesis, such as TDP-43 or FUS. The expression of the MALAT1 was significantly upregulated in the cortex of sporadic FTD patients and binds to TDP-43 that interacts with several other lncRNAs, including lnc-BDNFOS and lnc-TFEB α (in SHSY5Y cells) and lnc-Myolinc (in muscle cells) (via direct interaction with hsr ω. Upregulated expression of hsr ω is detected in both human FTD patients and cellular model of TDP-43 overexpression (Other lncRNAs are involved in ALS mostly e cells) . The exppression . The ALSin vitro n (G4C2) repeats in 5′UTR of the C9ORF72 gene has been acknowledged as one of the most common genetic factors in ALS . Three tHuntington’s disease is a neurodegenerative disease characterized by autosomal dominant inheritance, cognitive impairment, dance motor disorder and mental disorder. Selective loss of intermediate spinous neurons in caudate nucleus and putamen is a typical pathological feature of HD . The abnPrevious studies have confirmed the contribution of ncRNAs to HD pathogenesis. 12 of ncRNAs were identified and characterized in the brains of HD mice, eight of which are human homologs. Of the identified ncRNAs, MEG3, NEAT1 and XIST showed a sustained and significant increase in HD cells and animal models. Knockdown of MEG3 and NEAT1 in HD cell model resulted in a significant decrease in the aggregation of mutant HT protein and a downregulation of endogenous Tp53 expression . Upregul2O2 oxidative stress, revealing the functional correlation of NEAT1 and neuroprotective mechanism in the pathogenesis of HD  positively regulate BACE1 mRNA levels in the brain of HD patients. It is worth of noting that knocking down of BACE1-AS,could reduce the stable mRNA level of the justice gene . Anothervia epigenetically regulating expression of genes crucially involved in the pathogenesis at both transcriptional and posttranscriptional levels. In the nucleus, lncRNAs can inhibit or promote gene expression through act either in cis or in trans  genetically, epigenetically, molecularly, and biochemically. Understanding the interaction networks and orchestration of all the ncRNAs and target genes could help us identify the biomarkers for diagnosis and therapy.in vitro but could recapitulate key features brain development. Thus, candidate lncRNAs identified in animal models should be further validated in human organoids even human tissues.Antisense oligonucleotides (ASOs) have been confirmed to target lncRNAs in the nucleus more effectively than siRNAs. Furthermore, ASOs based study in disease animal models as well as the clinical trials have been conducted for some disease such as cancer. For example, specific ASO can act on specific lncRNA to alleviate the production of A β in the AD animal model . MoreoveTo sum up, further study on lncRNAs in CNSNDs will contribute to further understanding of brain function and the pathogenesis as well as the development of the promising therapeutic strategies for the CNSNDs.SX designed the topic and conceived the structure of the manuscript. SZ, XY, YM, DS, HY, and DW collected the articles, and made the tables and figures. SZ wrote the manuscript. SX, MW, and JB revised the manuscript. All authors contributed to the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.