Chinese herbal bath has long been used in the curative treatment of psoriasis vulgaris. However, there is no unified standard protocol for Chinese herbal bath. Many factors affect the curative effect of Chinese herbal bath, such as water temperature, bath concentration, and soaking time. Most studies involving Chinese herbal bath has described the bath generally, and few studies have investigated the factors that might contribute to the efficacy of Chinese herbal bath. Here we describe a protocol to evaluate the efficacy and safety of various bathwater temperatures and herbal concentrations on psoriasis vulgaris, and their effect on serum vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF-α), interleukin 23 (IL-23), and interleukin 17 (IL-17). These data could be useful for optimizing Chinese herbal bath treatments.In this randomized controlled trial, we planned to recruit 288 hospitalized atients with psoriasis vulgaris aged 18 to 65 years. All participants who meet the inclusion criteria will be randomly assigned to the observation group, the control group, or the basic treatment group. The observation group will be divided into 6 sub-groups according to water temperatures and bath concentrations, designated as observation groups 1 to 6. Thirty-six participants will be assigned to each group. The basic treatment group will be given co-qingdai capsule, po 2 g tid; compound glycyrrhizin tablet, po 75 mg tid; AA Skincare jojoba Oil, us.ext qd. The observation group will be given a Chinese herbal bath at the same time as the basic treatment. The control group will be given ozone hydrotherapy at the same time as the basic treatment. The entire treatment course will last for 2 weeks. The following parameters will be compared in each group, before and 2 weeks after treatment: the psoriasis area and severity index score (PASI), pruritus score, clinical efficacy, and dermatology life quality index score (DLQI); serum levels of serum VEGF, TNF-α, IL-23, and IL-17; and confocal laser scanning microscope images.This study will evaluate the efficacy and safety of various Chinese herbal bath conditions  on the treatment of psoriasis vulgaris, which will provide an important reference for the operation of Chinese herbal bath.ChiCTR1900027468 Through whole-genome analysis, most genes associated with psoriasis are immune-related. Psoriasis inflammation is mostly driven by innate and acquired immunity disorders. By promoting angiogenesis and the release of pro-inflammatory cytokines and chemokines, vascular endothelial growth factor (VEGF), tumor necrosis factor a (TNF-а), interleukin 23 (IL-23), and interleukin IL-17(IL-17) play important roles in the pathogenesis of psoriasis.,4 Because of its complex pathogenesis, at present, psoriasis cannot be cured completely. Psoriasis treatments mostly aim to control and stabilize the disease, decrease the development process, reduce clinical symptoms , reduce short- and long-term adverse reactions, control psoriasis-related complications, and improve the patients’ quality of life.Psoriasis affects about 2% of the global population, and psoriasis vulgaris accounts for about to 90% of the incidence of psoriasis. However, there is as yet no unified standard protocol for Chinese herbal bath, and few studies have investigated the factors affecting the efficacy of Chinese herbal bath, such as water temperatures, bath concentrations, and soaking time.Traditional Chinese Medicine (TCM) has unique advantages in the treatment of psoriasis, and increasing incorporation of TCM into clinics has greatly improved psoriasis outcomes.To address this, here we plan to use Chinese herbal bath to treat psoriasis vulgaris patients, for testing multiple water temperatures and herbal concentrations. Based on the study outcomes, we will assess the severity of the psoriasis vulgaris and serum VEGF, TNF-α, IL-17, and IL-23 levels. These data will help to optimize Chinese herbal bath protocols and provide insights into the therapeutic mechanisms of Chinese herbal bath in the treatment of psoriasis.22.1The study has been planned as a single-center, parallel-group, randomized controlled trial (RCT). The Chinese Ethics Committee of Registering Clinical Trials has approved this study. Patients meeting the inclusion criteria will first be screened. All participants will sign informed consent forms, and they will be randomly assigned to the observation group, the control group, or the basic treatment group. Randomization will be performed through IBM SPSS Statistics 22.0 software's random number generator. Figure 2.22.2.1The inclusion criteria are: inpatients; patients corresponding to diagnosis standards psoriasis vulgaris with Western Medicine; patients corresponding to diagnosis standards psoriasis vulgaris with the blood-heat syndrome of Traditional Chinese Medicine; patients corresponding to the progressive stage of psoriasis vulgaris; patients diagnosed with psoriasis vulgaris between 18 and 65 years old, regardless of gender and course of the disease; patients that have provided informed consent, and voluntarily accept and cooperate with treatment, examination, and observation.2.2.2The exclusion criteria are: pregnant or lactating women; patients allergic to drugs or drug components; comorbid psoriatic arthritis, pustular psoriasis, or erythrodermic psoriasis; patients who have taken steroids within the preceding 2 weeks and/or taken retinoids or topical steroids within the preceding week; patients with severe primary diseases, such as cardiovascular, cerebrovascular, liver, kidney, or hematopoietic system diseases; patients with active pulmonary tuberculosis, acute or chronic hepatitis, or other infectious diseases; psychotic patients, epileptic patients, or other patients without self-restraint; external injury or infection on the body surface; and female patients with menstruation during hospitalization.2.2.3 the necessary estimated loss rate is 10%, and the total sample size is 288 cases, with 36 cases per group. There will be 36 participants assigned to each group, including 36 cases in the basic treatment group, 36 cases in the control group, and 36 cases in each of the 6 observation groups.According to the calculation formula of sample size in clinical trials,2.2.4Randomized grouping will be done using IBM SPSS statistics (version 22.0) software's random number generator.2.2.5The random allocation form will be made in triplicate and kept in opaque envelopes. The project director, the pharmacy director, and the statistician will each keep one copy of the allocation form. At the end of the test, 3 random allocation forms will be simultaneously unsealed during a face-to-face meeting. If one or more of the seals are damaged, an explanation will be needed. Otherwise, the grouping information will be declared secret, or the test will be considered invalid.2.2.6Because the 3 groups’ intervention measures are not the same, blinding methods are not applicable.2.2.7The participants will be recruited from the Hospital of Chengdu University of Traditional Chinese Medicine and Chengdu Yinkang Psoriasis Hospital by an open recruitment method. Participants will be screened according to the inclusion and exclusion criteria. The recruiting members will be Professor Chen Mingling, associate chief physician Dai Li, associate chief physician Xiao JIANHUA, attending physician Yu Qianying, and attending physician Qin Yuesi.2.2.8The data will be collected by Liang Jiao and Shan Liu. The general information collected will include sex, age, height, weight, race, occupation, marital status, birthplace, home address, telephone number, disease season, past history, allergic history, and family history.2.32.3.1; manufactured by Tianning Pharmaceutical Co., Ltd., Shanxi Pharmaceutical Holding Group; National medicine permission number Z20010157; 0.5 g per granule; usage and dosage: po 2 g tid], glycyrrhizin tablets , AA Skincare jojoba oil .All of the included cases will be given the basic treatment which has three components: a co-Qingdai capsule [recommended according to expert consensus on the treatment of psoriasis vulgaris with Chinese patent medicine (2014)2.3.2The basic treatment group will be given only basic treatment.2.3.3The control group will be given ozone hydrotherapy at the same time as the basic treatment. The required tools are: a wooden bathtub, a disposable bathtub bag, cotton towels, slippers, and an ozone hydrotherapy instrument .The ozone water will be prepared as follows: the oxygen machine generates the oxygen that, via the ozone generator, generates a high ozone concentration (4 mg/L) in the bathwater. The participants will bath once per day, for 30 minutes.2.3.4The observation group will be given Chinese herbal bath at the same time as the basic treatment.The Chinese herbal bath prescription will be composed of: phellodendron (30 g), rhubarb (15 g), sophora flavescens (30 g), purslane (30 g), fructus kochiae scopariae (30 g), glycyrrhiza (30 g), mirabilite (20 g), alumen (10 g), and borneol (3 g). and the management standard of Chinese medicine decoction room, the decoction amount is 1 L per dose. Table All of the above Chinese herbs are provided by the Chinese medicine pharmacy of Chengdu Yinkang Psoriasis Hospital and decocted by the boiling machine of Chengdu Yinkang Psoriasis Hospital. According to the methods of the decoctum preparation and the standardization of decoction preparation in “Treatise on Exogenous Febrile Diseases,”2.3.5For bathing, the following equipment is needed: a wooden bathtub, a disposable tub bag, cotton towels, slippers, and a constant temperature heater . put the disposable tub bag in the bathtub, pour in the corresponding proportion of Chinese Medicine liquid and water, then add the constant temperature heater, setting the temperature and time. The patient will sit in the bath bucket, soak the torso and limb in the bathwater, and gently wipe their skin with a towel. The nurse will regularly check the situation in the bathroom and ask whether the patient has any discomfort, such as dizziness, dyspnea, palpitation, chest tightness, or other symptoms. If the patient reports any of the above discomforts, the herb bath will be stopped, and the nurse will assist the patients in returning to the ward, closely observe the condition, and ask the doctor to give treatment. After the Chinese herb bath is over, to avoid getting cold, the patients should thoroughly dry themselves with a towel. During the 2-week treatment period, the patient will take one herbal bath per day, with each bath lasting 30 minutes.Before the Chinese herb bath, the nurse will set the temperature of the bathroom to 20 to 22 °C,2.3.6Women are forbidden from taking Chinese herb bath during menstruation. The participants should not fast while participating in the Chinese herb bath trial and avoid using bath products outside of the test.2.3.7The treatment course will last 2 weeks, and the outcomes will be recorded before treatment and during the second week of treatment. After the 2 weeks of treatment, the patients will be followed up once per month for the next 6 months.2.4 scores will be evaluated as the primary outcome. The PASI is a reliable, reproducible, and responsive instrument. This index has good internal consistency, intra-observer reliability, and inter-observer reliability, and is considered as the gold standard for assessing the severity of cutaneous manifestations in psoriasis. Therefore, this index will be used as our primary outcome.Psoriasis area and severity index2.52.5.1The Guiding Principles for Clinical Research of New Traditional Chinese Medicine  is the general evaluation standard in China. According to the evaluation standard, the effective rate of treatment, pruritus score, and incidence of adverse reactions are taken as secondary outcomes.2.5.2 patients need to complete ten questions about the impact of the disease on their quality of life . The DLQI scores are calculated by summing the scores for each question. The maximum value is 30, and the minimum value is zero. The higher the scores, the greater the impact on the quality of life.According to the DLQI questionnaire,2.5.3Using the IBM SPSS Statistics (version 22.0) random number generator, 22 patients will be selected from each group to detect serum VEGF, TNF-α, IL-23, and IL-17 levels before and after the second week of treatment.2.5.4Patients in each group underwent in confocal laser scanning microscope before and after the second week of treatment.2.6 the safety of this study will be evaluated by adverse events, routine blood tests, and liver and kidney function tests.According to the safety assessment in randomized controlled clinical trials,2.7All data will be analyzed according to the intention to treat principle. The missing value will be dealt with by carrying forward the most recent observation to the end point.t test will be performed: the paired sample t test will be used for intra-group comparison, and the independent sample t test will be used for inter-group comparison. If the variance is uneven, the approximate t test will be used. If the sample is not normally distributed, the rank-sum test (non-parametric) will be applied. The Chi-square test will be used for counting data. P values less than .05 will be considered as statistically significant.This study will use the IBM SPSS Statistics (version 22.0) software for data management and analysis. Professionally-trained dermatologists will collect all data. Members of the research team will perform the data collection and statistical analyses. Quantitative indicators will be expressed as mean ± standard deviation. If the sample is normally distributed and the variance is uniform, the The Chinese Ethics Committee of Registering Clinical Trials , which does not have any competing interests, will be responsible for monitoring the data. The Department of Science Research of the hospital at Chengdu University of TCM, which is independent of the investigators, will perform data audits in the trial.3Psoriasis is a common chronic recurrent skin inflammatory disease. Psoriasis vulgaris plays a major role in the psoriasis. In the process of clinic, patients with psoriasis vulgaris are also the most common. The visiting time of patients is often in the progressive stage of psoriasis vulgaris, during this period, the original lesions gradually expand, or even fuse into pieces, new lesions continue to appear, which has the most serious impact on patients. With the gradual understanding of the pathogenesis of psoriasis and the continuous improvement of medical level, psoriasis has made great progress in treatment measures, but it is still in the stage of disease control and cannot be completely cured. Most patients need lifelong treatment. Long-term treatment, heavy economic burden, and easy recurrence have become the main factors affecting the quality of life of patients. Therefore, through the study of optimizing the treatment plan of psoriasis, reducing the economic burden of patients and delaying the time of recurrence, it is very important to formulate a reasonable treatment and follow-up plan, take targeted intervention measures and improve the quality of life of patients. The Chinese herb bath can achieve ideal curative effect by penetrating the drugs with warm effect into the skin or meridian points and directly into the meridians and blood vessels, acting on the focus site. After soaking in the bath of Chinese medicine liquid, the skin can remove pollutants such as exudates, crusts and scales, and has the effects of moisturizing and relieving itching, clearing heat and cooling blood, detoxification and convergence; Chinese medicine liquid can dilate the capillaries of patients and improve local microcirculation, promote metabolism, accelerate the repair of affected tissue, and promote the regression of skin lesions. In clinic, the use of Chinese herb bath, or Chinese herb bath combined with other therapies in the treatment of psoriasis is quite common, with high efficiency, definite curative effect, few adverse reactions and good patient compliance.This study is an in-depth study on the Chinese herb bath in the treatment of psoriasis vulgaris. The research results can help the clinic optimize the treatment scheme of Chinese herb bath in the psoriasis vulgaris. Through the study of the Chinese herb bath in the treatment of psoriasis vulgaris and the relationship between VEGF, TNF- α, IL-23, IL-17 and psoriasis, to lay a theoretical foundation for clinical judgment of psoriasis vulgaris.4Mingling Chen was the principal investigator of the study. Wenxia Lin and Qianying Yu contributed equally to this article, and both of them participated in the research design and the writing of the manuscript. Yuesi Qin, Li Dai, and Jianhua Xiao revised the original manuscript. Liang Jiao and Shan Liu involved in the recruitment of patients. Shengzhen Ye and Jiahao Zhang participated in data collection. All authors read and approved the final manuscript.Conceptualization: Wenxia Lin, Mingling Chen.Investigation: Liang Jiao, Shan Liu.Supervision: Li Dai, Jianhua Xiao.Writing – original draft: Qianying Yu, Yuesi Qin.Writing – review & editing: Shengzhen Ye, Jiahao Zhang.Mingling Chen orcid: 0000-0002-8879-0857.


To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed at restoring proteostasis, allowing cells to survive the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious, and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress, and this condition could be exploited from a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells. Proteins are key macromolecules that play fundamental roles in almost every cellular process, from gene expression to cell/tissue protection . The impCells use a complex network, called the proteostasis network (PN), in order to monitor protein homeostasis. PN includes molecular chaperones and proteolytic machinery. These gene families promptly cooperate to guarantee regular proteostasis. In this manner, PN coordinates protein synthesis with folding and, if necessary, it can trigger protein degradation ,6,7. TheMolecular chaperones supervise protein folding, a process that requires ATP hydrolysis and a high cost in terms of energy. In particular, the chaperones of the heat shock protein (HSP) family help protein folding and are fundamental when critical conditions such as heat stress, oxidative stress, or hypoxia emerge . These pChaperones function as the main players in the maintenance of proteostasis by facilitating the folding of proteins. They usually bind to the hydrophobic polypeptide segments exposed by unfolded or not-completely-folded proteins, thus avoiding their aggregation throughout the folding process . HSP70s Chaperones can do their duties either in cooperation with the ribosome, for example, the mammalian ribosome-associated complex (RAC) and some specialized HSP70s (HSP70L1) ,16, or, In general, proteins can be divided into proteins that fold easily and quickly after the interaction with the upstream chaperones, like HSP70s, and proteins that require more help during the process. The first group of proteins does not need downstream chaperones; instead, the second group of proteins is not able to complete the folding correctly and needs more specialized chaperones, like HSP90s or the chaperonins, to achieve the proper structure . These “The human PN has not yet been completely characterized in all its parts. However, investigations aimed at dissecting the network of proteins interacting with HSP90s have revealed the presence of E3 ligases (enzymes involved in the last step of ubiquitin-conjugation). This finding highlights the close relationship between the folding and protein degradation processes . A detaiImportantly, the chaperone systems have evolved several mechanisms to compensate when a single chaperone fails or is disabled. This aspect is also important from a therapeutic perspective when specific inhibitors against a chaperone are evaluated . For exaIn order to maintain the proteostasis, eukaryotic cells have evolved several systems monitoring quality control. These systems are different from the folding/re-folding actions of chaperones and are involved in the degradation of damaged and misfolded proteins. The most important system is represented by UPS. It works in cooperation with the lysosomal system ,28 and pThe 20S catalytic core is constituted by two heptameric rings of β-subunits and two heptameric rings of α-subunits. The α-subunits have a structural role, and the β-subunits have a catalytic role instead. In particular, β1 has a caspase-like activity, β2 has a trypsin-like activity, and β5 has a chymotrypsin-like activity ,43,44. AIn summary, even in the presence of UPS, protein misfolding can induce the creation of insoluble aggregates, particularly under stress situations. By contrast, autophagy can directly eliminate these aggregates via lysosomal degradation . The comDespite the presence of the chaperone systems, some errors occur during folding and many stressors such as heat, heavy metal ions, oxygen radicals, and mutations can hamper the correct folding. A misfolded or unfolded protein is not functional and can elicit a pathological condition derived from its aggregation ,61,62,63PERK is a serine/threonine kinase that has several substrates. The best characterized is the eukaryotic translation initiation factor-2 alpha (eIF2α). PERK is able to phosphorylate eIF2α at serine 51 ,71,76, tBiP/GRP78, a HSP70 family member localized into ER, is a master regulator of UPR in response to ER stress. It monitors the release and activation of the three sensors PERK, IRE1, and ATF6 ,87. PERKThe induction of proteotoxic stress through the use of small compounds/drugs achieves a therapeutic interest, particularly from an antitumor perspective . In ordeIt is well established that proteotoxic stress engages the mitochondrial pathway of caspase activation . However−DR5/− mice from taxol-induced inflammation [In the receptor-independent activation of caspase-8 following ER stress, a contribution of RIPK1 (receptor interacting serine/threonine kinase 1) has also been proposed. The contribution appears indirect and is sustained by the use of Ripk1-deficient murine cells. The involvement of Ripk-1 in ER stressor-induced apoptosis is still mysterious. It is independent of the kinase activity from cIAP1/2 -mediated ubiquitylation and does not involve the direct regulation of JNK/MAPK8 or CHOP . ER streammation . These sammation .A huge plethora of studies have indicated that cell death induced by proteotoxic stress can follow different routes. Certainly, the foremost investigated signaling pathway linking proteotoxic stress to apoptosis regards ER stress and the consequent UPR. A key element of this pathway is represented by ATF4 (activating transcription factor 4), a TF that belongs to the cAMP response element-binding protein (CREB)-2 family . As explATF4 can also trigger cell death independently from CHOP. It can promote the downregulation of the IAP family member XIAP (X-linked inhibitor of apoptosis) in a still-undefined manner. These proteins can bind and block caspase activities but can also, through a RING zinc finger domain with E3 ubiquitin ligase activity, promote ubiquitylation and the subsequent proteasomal degradation of their substrates, including caspases .CHOP supervises the expression of a collection of genes. Interestingly, some of these genes are shared with ATF4, thus suggesting the existence of a feed-forward mechanism to sustain proteotoxic-dependent gene expression . SimilarATF5 is another ATF/CREB family member under CHOP/ATF4 control . TranscrNOXA/PMAIP1 is a BCL-2 proapoptotic family member that plays important roles in different apoptotic responses. NOXA is the smallest of BH3-only proteins (54 residues), and its expression is dramatically upregulated after proteotoxic stress . InitialAdditional mechanisms are used by proteotoxic stress to engage the mitochondrial pathway of caspase activation. BIM/BCL2L11 and PUMA/BBC3 are other BH3-only proteins, of which upregulation was reported in several models of proteotoxic stress and, particularly, during ER stress. The ablation of these proteins influences the death response to proteotoxic stress ,93,94. BWhen proteotoxic stress advances, UPS becomes clogged by the accumulation of polyubiquitylated proteins. Blocking the proteasome affects the expression of unstable signaling proteins and, therefore, signaling pathways controlling cell survival and cell death are modulated. Two important UPS targets, controlling the survival/death switch, are the inhibitors of NF-kB, IkBɑ , and TP5As indirect consequences elicited by proteotoxic stress can favor cell death, the accumulation of ROS and the alterations of calcium homeostasis must be mentioned. These cofactors can be the deleterious corollaries of the progressive impairments in the clearance capacities normally operated by UPS and autophagy. Accumulation of unfolded proteins and aggregates impact ER and mitochondrial functions, thus leading to alterations in ROS and calcium levels that, in turn, engage further signaling events leading to cell death. How these events integrate with classic apoptotic signaling is not clear. In some studies, induction of oxidative stress can be observed in the initial phases of proteotoxic stress ,151,152.Necroptosis is a specific form of cell death activated through the serine/threonine kinases RIPK1 and RIPK3 and the pseudokinase MLKL . CompounFerroptosis is a specific form of iron-dependent cell death, characterized by the accumulation of lipid peroxides due to the failure of glutathione-dependent antioxidant defenses ,168. FewA final important point concerns the heterogenous response of cell populations to proteotoxic stress. It is well known that although exposed to the same intensity of proteotoxic stress, some cells die while others survive. Clearly, the availability of a pool of chaperones is a critical condition. Particularly, for ER stress, the ER resident chaperone BIP is a key factor during the switch from proteostasis to proteotoxicity . HSF1 isFor a detailed discussion on proteotoxic stress and cancer, we refer to previously published reviews, some of them cited thereafter. In this section, we would like to provide only a general overview of this topic.The protein synthesis process is intrinsically prone to errors. It has been estimated that in mammalian cells, more than 30% of newly synthesized proteins are degraded by the proteasome within minutes from their translation . These qA still poorly explored aspect of proteotoxic stress is its connection with cellular metabolism ,185. It In addition to the amplified levels of protein synthesis and the environmental conditions, genetic alterations accumulated in cancer are other sources of proteotoxic stress. Aneuploidy, copy number variations, and point mutations are common genetic alterations in cancers that can induce proteotoxic stress ,190,191.Cancer cells convive with proteotoxic stress by upregulating all the possible mechanisms that are able to maintain proteostasis ,203,204.Proteostasis is a fundamental task for every cell. The evolution has sculptured elaborate interconnected mechanisms to maintain proteostasis. Some of these mechanisms have been highly conserved through evolution and, with the appearance of eukaryotic cells, each subcellular compartment has evolved a dedicated set of strategies ,221. Pro


This is the first study showing the association of burnout and neuropathic low back pain, which is the most common cause of disability. Based on our results neuropathic low back pain and burnout have similar risk factors and consequences which raises the possibility of similar pathophysiology.Burnout is an increasingly prevalent syndrome mainly involving those working in human services. Although it is categorized as an occupational phenomenon and not as a medical condition, it seems to be strongly associated with several diseases such as pain syndromes. However, no studies examined the association between neuropathic low back pain and burnout. This questionnaire-based study was carried out between April 2019 and March 2020 in three main sites among teachers, social workers and healthcare workers. Demographic criteria included age, gender, marital status, number of children, type of work, years spent with work, work schedule, legal relation, secondary employment. Included diseases were diabetes, hypertension, ischemic heart disease, generalized pain (pain involving more than one area of the body) and depression. Low back pain was assessed by the painDETECT questionnaire, burnout was measured with the Maslach Burnout Inventory (MBI) and depression was measured by the Beck Depression Inventory. Dysfunctional attitudes were also recorded. Overall, 1500 questionnaires were successfully delivered and 1141 responses received (response rate of 76%). Three hundred social workers, 399 teachers, 339 paramedics, 35 doctors and 68 medical attendants have completed our survey. In a multivariate analysis including of all factors  neuropathic low back pain was associated with age > 62 (OR = 3.981,  Burnout is an increasingly prevalent syndrome resulting from situational, personal and professional stress (mainly driven by workplace stress) and can be characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment . The mosThe most important risk factors of burnout are gender, marital status, work environment, interpersonal and professional conflicts, emotional distress, and low social support .Although it is categorized as an occupational phenomenon and not as a medical condition, it seems to be strongly associated with diabetes, cardiovascular disorders, chronic musculoskeletal pain, headaches, changes in pain experiences, gastrointestinal issues, respiratory problems, severe injuries and mortality below the age of 45 years as well as with psychiatric complications such as insomnia, depressive symptoms and mental disorders based on a recent systematic review . The phyChronic pain is a devastating disease, one of the leading causes of disability, which can affect 10–20% of the population ,5. NeuroLower back and neck pain are the leading causes of disability in the jobholder population based on recent data . Lower bSimilar to burnout, emotional aspects also play an important role in the development of neuropathic pain . ImpaireDespite of the possible association of chronic pain syndromes and burnout, based on our knowledge and literature search, no study focused on the association between neuropathic low back pain and burnout.The aim of our prospective cross-sectional study was (a.) to detect the prevalence and risk factors of neuropathic pain, (b.) to examine the role of risk factors of burnout on neuropathic pain and (c.) to assess the connection between burnout and neuropathic pain among human service workers including educational, healthcare or social area.This questionnaire based cross-sectional study was carried out between April 2019 and March 2020, patients were recruited from three cities . The study was approved by the Ethical Committe of the University of Pecs (reference number: PTE/96773-2/2018).Paper based questionnaires were posted to teachers in the educational region of Kecskemét, Pécs and Komló (77 schools), to the social workers of Ágota Foundation  and to the healthcare workers employed in the hospitals of Komló, Kecskemét and Pécs (3 sites).Inclusion criteria were working with human services as a healthcare worker, social worker or teacher, being between 18 and 65 years of age and being employed at the time of the study apart from the type of employment .Exclusion criteria were being under 18 or over 65 years of age, having disability, having severe uncontrolled disease, being on permanent leave or refusing to participate in the study.Demographic criteria included age, gender, marital status, number of children, type of work, years spent with work, work schedule, legal relation, secondary employment.Included diseases were diabetes, hypertension, ischemic heart disease, generalized pain (pain involving more than one area of the body) and depression.Low back pain was assessed by the painDETECT questionnaire, which is a simple, patient-based, easy-to-use screening questionnaire developed by Freynhagen and his co-workers in cooperation with the German Research Network on Neuropathic Pain. It can determine the prevalence of neuropathic pain components both in individual low back pain patients and in heterogeneous cohorts of such patients ,10. We uBurnout was measured with the Maslach Burnout Inventory (MBI), which is an introspective psychological inventory consisting of 22 items pertaining to three dimensions of burnout: emotional exhaustion, depersonalization, and personal accomplishment . ResponsDepression was measured by the Beck Depression Inventory which is a 21-question multiple-choice self-report inventory, one of the most widely used psychometric tests for measuring the severity of depression. It is composed of relating symptoms-based items such as hopelessness, irritability, guilt or feelings of being punished, fatigue, weight loss, and lack of interest in sex ,15. EachThe Dysfunctional Attitude Scale (DAS) is a 40-item instrument that is designed to identify and measure cognitive distortions, particularly distortions that may relate to or cause depression ,17. EachStatistical analysis: Data were evaluated as means ± SD (standard deviation) the chi-square test, distribution ratios and the Pearson’s Rank-Order Correlation. Data were analyzed using descriptive statistics, linear regression, correlation, multivariate analysis of variance, and factor analysis. Analysis of variance (ANOVA) was used in neuropathic low back pain analysis. Logistic regression analysis was used to determine the significance of the included parameters as independent risk factors in the development of neuropathic low back pain. For all odds ratios, an exact confidence interval (CI) of 95% was constructed in our study. Logistic regression analyses were performed using the statistical package of SPSS 11.0 .Overall, 1500 questionnaires were successfully delivered and 1141 responses received (response rate of 76%). Three hundred social workers, 399 teachers, 339 paramedics, 35 doctors and 68 medical attendants have completed our survey.643 males (56.4%) and 498 females (43.6%) participated in our study. About one third of the examined workers was between 36–45 years of age (31.5%). 764 people (67%) were married or lived in a relationship. The number of childless workers was 65 (5.7%). 150 participants (13.1%) had secondary employment. The vast majority (44.2%) of our study population has been working for 11–30 years. Baseline data can be seen in Two hundred seventy-eight (24.4%) participants had hypertension, and sixty-six (5.8%) were diabetic. Ischemic heart disease can be detected in 161 (14.1%) workers. Two hundred twenty (19.3%) participants suffered from generalized pain (pain involving more than one area of the body). Thirty-nine (3.4%) persons had a history of depression .Low back pain occurred in 630 workers (55.2%): 264 (23.1%) had neuropathic low back pain , 366 workers (32.1%) had probable neuropathic pain  and 511 (44.8%) workers had nociceptive low back pain  .The prevalence of significant burnout among the study population was 81.4%. The mean burnout score was 57.6 (SD = 16.2); 212 workers had mild (18.6%), 884 had moderate (77.5%) and 45 had severe (3.9%) burnout .p = 0.035), having children ≥ 2 (p = 0.005), being a social worker (p = 0.03), and having a secondary employment (p = 0.014)  .p = 0.006), diabetes , history of depression (p = 0.014) and generalized pain (p = 0.044) based on ANOVA analysis  .Moderate and severe depression as well as dysfunctional attitudes were also associated with neuropathic low back pain (l cases) . The prep = 0.012) (p < 0.001).Severe burnout was also significantly associated with neuropathic low back pain (= 0.012) . There wp = 0.01), number of children ≥ 2 , job type  , burnout , current depression , and suffering from generalized pain .In a multivariate analysis including of all factors  neuropathic low back pain was associated with age > 62 , psychological , and occupational consequences (such as chronic pain syndromes which are amongst the leading causes of disability) ,19,20.The rate of low back pain was more than 50% in our population which is slightly above the estimated rates comparing to a previous study from Hungary . One in In our survey neuropathic pain was associated with age, there was a 3.98-fold increase over 62, and living in a larger family (having children ≥ 2) also has a 2.6-fold increase in developing neuropathic low back pain. Job type  and secondary employment were also strongly associated with this condition in a univariate analysis; being a social worker has a six-fold increase of risk alone. In a Canadian study neuropathic pain was associated with low income, unemployment, smoking, and being unmarried, which are slightly similar to our findings . Social We also found significant association among neuropathic low back pain, depression, diabetes and hypertension. Hypertension and cardiovascular diseases have been previously documented as being associated with neuropathic pain ,24,25. DDysfunctional attitudes are usually associated with depression; however, they are strongly related to burnout . PsycholWe also found a four-fold increase in the risk of developing neuropathic low back pain among those suffering from generalized pain, which underlines the involvement of pain perception pathways.Based on our results, neuropathic low back pain shared similar risk factors and consequences with burnout. Burnout was also a significant risk factor of neuropathic low back pain, workers suffering from burnout has an approximately 2.5-fold risk to suffer from neuropathic low back pain based on our results. The association can be bidirectional because burnout is mainly due to chronic occupational stress and work overload can result in the activation of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis , and this can be associated with low-grade inflammation, blood coagulation changes, depression of the immune system, sleep disorders, and adoption of poor health behaviors, such as overweight, smoking, excessive alcohol consumption and lack of physical activity ,28,29,30Secondly, neuropathic pain, which is caused by a lesion or malfunction of the somatosensory system is associated with imbalances between excitatory and inhibitory somatosensory signaling, alterations in ion channels and variability of pain processing pathways . ImagingIn summary, this is the first study showing the association of burnout and neuropathic low back pain, which is the most common cause of disability. Based on our results, neuropathic low back pain and burnout share similar risk factors and consequences, which raises the possibility of similar pathophysiology. We do not have a proper explanation to this phenomenon, but the activation of sympaticoadrenal system leading to katecholamine overload can probably be responsible for this association.Finally, our article has some limitations. Although it was a prospective cross-sectional study in nature including more than 1000 workers, it was not representative of burnout and neuropathic pain neither in the general nor in the human services population. As it was a paper-based survey, physical examination was not carried out (such as screening for neuropathic pain in pending cases for example with DN4). We had no detailed medical information about the previous diseases and medication of the included workers as well as about the duration of low back pain and its treatment modalities. History of neuropathic low back pain was also not recorded. The above-mentioned limitations may influence our findings. Finally, follow-ups were not carried out.


Participants aged 25–34 had the highest prevalence rates (21%). Participants who had cotinine ≥15 ng/mL had higher prevalence of OML as compared to those with <15 ng/mL . Most common lesions were nicotine stomatitis (33%) and leukoplakia (19%). Age, male sex, and higher cotinine levels were associated with increased prevalence of OML.Oral mucosal lesions (OML) can decrease oral health-related quality of life and some have the potential to become malignant. The aim of the present study was to report the prevalence of OML in relation to age, sex, and serum cotinine levels in a population with mixed ancestry from South Africa. This study is part of the Cape Town Vascular and Metabolic Health (VHM) study, conducted between 2014–2016. Trained dental examiners assessed the oral mucosa for the presence of OML according to WHO criteria. In total, 1976 individuals were included in the study, being 1496 females (75.7%) and 480 males (24.3%) with average age of 49.5 years (SD = 15.3). In total, 262 lesions were detected in 252 participants . Males had higher prevalence than females (14% vs. 9%,  Oral health plays a fundamental role in the overall health and well-being. Lack of attention to oral health is a serious concern, given that oral diseases are remarkably prevalent, affecting around 3.5 billion people around the world . Dental Oral lesions can decrease oral health-related quality of life due local irritation, discomfort, pain, and the potential to interfere with mastication, speech, swallowing, and oral hygiene . The etiCotinine constitutes the main nicotine metabolite in tobacco products and it presents a longer half-life when compared to nicotine , and is considered a dependable biomarker for tobacco exposure . StudiesWhile, most OML are benign and self-limiting, some can be potentially malignant. Leukoplakia, erythroplakia, and oral sub-mucous fibrosis are the most common pre-cancerous lesions . The impEpidemiological studies on oral lesions provide crucial information on their prevalence, extent and severity, providing the foundation for oral health policies . There iTo the best of our knowledge, there are no studies evaluating serum cotinine levels in relation to oral health status in the country. Cotinine is the main metabolite of nicotine, which is an addictive chemical found in tobacco products . Due to This cross-sectional study was conducted as part of the Cape Town Vascular and Metabolic Health (VHM) study, conducted from 2014 to 2016 in South Africa, as described previously . The excTrained and calibrated dental examiners comprehensively assessed the oral mucosa in each participant. The oral examination was undertaken using a portable dental chair, a portable overhead LED light, dental mirrors, and the handle of a periodontal probe for tissue retraction. All sections of the oral cavity were inspected systematically for any variation from normal in the following sequence, according to the criteria from the WHO: (1) Upper and lower labial mucosa and labial sulci, (2) buccal mucosa, (3) tongue, (4) floor of the mouth, (5) palate, and (6) gingiva and alveolar  The presIn the present study, 15 ng/mL was used as the cut-off value to differentiate smokers from non-smokers, based on previous studies ,7,8. A fp-value of 0.05 and below was considered statistically significant.Data were analyzed through the statistical package Stata 15.1 . Presence of oral mucosal lesions was presented as percentage prevalence. Age was categorized into groups , as well as serum cotinine levels (<15 ng/mL and ≥15 ng/mL). The Chi-square test and the Fisher test were used to compare the proportion of oral lesions in relation to sex, age group, and cotinine categories. A logistic regression was carried out to determine the probability of having at least one lesion of any type given sex, age group, and cotinine levels. A In total, 1976 individuals were included in the study, from which 1496 were females (75.7%) and 480 were males (24.3%). The sample had an average age of 49.5 years (SD = 15.3), ranging from 18 to 91 years. The average age was 47.3 for males and 50.2 years for females.p = 0.003, A total of 262 lesions were detected in 252 participants , the alveolar ridge, and gingiva (20.2%) and the buccal mucosa 14.5%, . The mosp < 0.001). Serum cotinine ≥15 ng/mL was observed in 59.7% of all men and in 45.6% of all women (p < 0.01).An association was observed between serum cotinine categories and total prevalence of oral lesions. Participants who had serum cotinine levels ≥15 ng/mL had higher prevalence of OML as compared to those with levels below 15 ng/mL ; the odds of having lesions in males were 2.5 times greater in comparison to females. Participants older than 54 years had lower prevalence of lesions in comparison to the younger age groups. Subjects with cotinine levels greater than 15 ng/mL had a higher chance of having lesions, in comparison to those who had levels below 15 ng/mL .The association between the prevalence of lesions and sex, age group, and cotinine levels remained significant in the regression analysis . Femalesn = 87, n = 48), abscess , candidiasis , ulcerations , and ANUG . In total, 21% of the oral lesions were classified as ‘other conditions’.Nicotine stomatitis was the most prevalent lesion  and the age groups with the highest prevalence were 25–34 years (30%), 35–44 years (25%), and 45–54 years (28%). Most nicotine stomatitis lesions were located in the palate , followed by alveolar ridge/gingiva , lips , sulci  and tongue .The overall prevalence of nicotine stomatitis was 4.4%. Sex was not associated with prevalence of this lesion  and females (p < 0.001), as well as for the age groups 25–34 (p = 0.009), 35–44 (p = 0.002), and 45–54 , with participants aged 25–34 presenting the highest prevalence  as compared to males  and alveolar ridge  were the most common locations for leukoplakia lesions, followed by palate , sulci , lips , and buccal mucosa . Tongue . This association was also statistically significant for the age group 35–44, with all leukoplakia lesions being present in participants with cotinine levels ≥15 ng/mL (p = 0.01). Cotinine categories were associated with the distribution of leukoplakia (n = 10), alveolar ridges/gingiva , tongue  and sulci . The prevalence of candidiasis was higher in subjects who presented serum cotinine levels 15 ng/mL and above, when compared to those with cotinine level below 15 ng/mL . The overall prevalence of candidiasis was 6% and it was not associated with sex or age group . Candidap < 0.001), with participants aged 45-54 presenting the highest prevalence (29%). In terms of location, 83% (n = 30) of the abscesses were located in the alveolar ridge/gingiva, followed by 8% (n = 3) in the buccal mucosa, 6% (n = 2) in the palate and 3% (n = 1) in the commissure.Prevalence of abscess (15%) was not associated with sex or cotinine levels. It was associated with age group (n = 5), sulci , floor of the mouth , and tongue .The prevalence of ulceration (3%) and ANUG (3%) were not associated with sex, age group, or cotinine categories. Ulcerations were mostly observed at the buccal mucosa , with the highest prevalence in the 35–44 age group (31%). The palate was the most frequent location , followed by alveolar ridge/gingiva , tongue , commissure , lips , and sulci .Lesions classified as “other conditions” were not associated with sex or cotinine levels. They were associated with age group  were associated with higher prevalence of OML. Nicotine stomatitis was the most prevalent condition, corresponding to one-third of all identified lesions.To our knowledge, this is the first epidemiological population study to present the prevalence of oral mucosal lesions in this South African sample of adults with mixed ethnic background. Comparison with previous studies is not possible as data are only available for HIV-related oral lesions ,18,19,20A variety of studies from other countries report prevalence of OML, ranging from 2 to 80% ,25,26,27The higher prevalence of oral lesions in male participants could be explained by higher serum cotinine levels. In the literature, there are studies reporting no association of OML with sex ,30, as wAge has been associated with an increased prevalence of OML ,34,35. HAlmost one fifth of oral lesions observed in this study were identified as leukoplakia, and the estimated risk for malignant transformation for these lesions range from 0.13 to 34% . Early sSmoking is a strong risk factor for NCDs, oral cancer, and OML , In the The high prevalence of non-diagnosed lesions can point to a lack of precise diagnostic criteria. Examiners were not capable of differentiating between 21% of the mucosal changes encountered. Future studies should include diagnostic tests and use digital resources to facilitate the interaction with a specialist in oral medicine during clinical examinations for diagnostic accuracy. The clinical examination took place during weekdays, which have resulted in selection bias, due to exclusion of males who worked.Although, patients with leukoplakia were referred to an appropriate health-care facility for further laboratory investigations to confirm the initial clinical diagnosis, and they were not followed-up. Hence, the initial tentative diagnosis was not confirmed through biopsy nor other diagnostic tests. An epidemiological study from Japan reported mass screening for leukoplakia in 3131 participants. The authors reported a positive predictive value of 0.73 and false positive ratio of 0.27 for diagnosing oral leukoplakia during the primary mass screening, which can be extrapolated to the results from the current study .This is the first study providing epidemiological data on oral lesions and cotinine levels for a population sample of mixed ethnic background from South Africa. Males, participants younger than 54 years, and higher cotinine levels were associated with a higher prevalence of lesions. The two most common lesions were nicotine stomatitis and leukoplakia, the latter has the potential to undergo malignant transformation. Programs aimed at reducing exposure to tobacco should be an integral part of reducing the burden of NCDs in this population group. Early screening and diagnosis of mucosal lesions should be a priority in primary care settings, as it can decrease morbidity and mortality related to oral cancer.


ABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2. However, there are variations in RF and genetic factors based on ethnic and geographic differences; it is clear that unified molecular pathways accounting for POAG pathogenesis remain uncertain, although inflammation and senescence likely play an important role. There are similar ethnic and geographic complexities in primary angle closure glaucoma (PACG), but several genes have been associated with this disorder, including MMP9, HGF, HSP70, MFRP, and eNOS. In exfoliation glaucoma (XFG), genes implicated include LOXL1, CACNA1A, POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. Despite tremendous progress, major gaps remain in resolving the genetic architecture for the various glaucoma subtypes across ancestries. Large scale carefully designed studies are required to advance understanding of genetic loci as RF in glaucoma pathophysiology and to improve diagnosis and treatment options.Glaucoma, the world’s leading cause of irreversible blindness, is a complex disease, with differential presentation as well as ethnic and geographic disparities. The multifactorial nature of glaucoma complicates the study of genetics and genetic involvement in the disease process. This review synthesizes the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, with the only treatable risk factor (RF) being the reduction of intraocular pressure (IOP). Genes associated with elevated IOP or POAG risk include:  Glaucoma is the world’s leading cause of irreversible blindness, implicated in approximately 12% of cases globally , the patImportantly, glaucoma may be classified in different specific subtypes with different pathophysiologic mechanisms, including primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and secondary exfoliation glaucoma (XFG), which have all been shown in the literature to be more prevalent in populations of different races ,9,10,11.In recent years, genetic and genomic studies have shown encouraging evidence for a possible genetic contribution to the pathogenesis of glaucoma. Starting with studies of single-gene variants, genetic analysis has expanded to whole exome sequencing (WES), genome-wide association studies (GWAS), and genetic/polygenic risk scoring (G/PRS) as methods to illuminate the possible genetic RFs underlying glaucoma ,29. ThesIn summary, glaucoma is a complex disease, with different types and presentations, and ethnic and geographic disparities among different populations. These features complicate the genetic study of glaucoma. It is crucial to understand the natural history among different ethnic groups, in order to identify genetic RFs that have the potential to transform the way that glaucoma is screened, diagnosed, and treated worldwide. Therefore, this review aims to synthesize the current literature on glaucoma and genetics, as stratified by glaucoma subtype and ethnicity.PubMed, Embase, Ovid, Scopus, and Trip searches were conducted through 1 December 2020 to evaluate all pertinent articles, abstracts, and ongoing research projects. Searched key words include: glaucoma, genetics, genome-wide association study, genetic/polygenic risk score, primary open-angle glaucoma, exfoliation syndrome, exfoliative glaucoma, primary angle-closure glaucoma, African descent, European, Asian, Middle Eastern, Latin American, Hispanic, and genes. The same key words were used in all search software. Articles were screened for relevance and analyzed based on inclusion criteria, population, and specific genes studied. Data was collected and organized using Microsoft Word (version 16.30), Microsoft Excel (version 16.30), and EndNote (X8.2).References from all relevant articles found were reviewed to ensure inclusion of all relevant articles. Primary open-angle glaucoma (POAG) is the most common cause of glaucoma worldwide, accounting for approximately 74% of all glaucoma cases . As the The major RF, and only treatable RF, for POAG is an elevated IOP while, other RFs including older age, family history , ethnicity (AD), thin central corneal thickness (CCT), and impaired ocular blood flow all may also play a role . InteresPrevious studies have demonstrated that POAG disproportionately impacts patients of AD when compared to patients of ED ,13,14, aIn order to identify the genetic RFs for POAG, researchers utilize genome-wide association studies (GWAS) to analyze groups of patients with POAG for common genetic variants. After these variants—single nucleotide polymorphisms (SNPs)—are identified, further analysis associates them with disease. GWAS are challenged by the fact that associated variants cannot be proven to be causative in the disease process . AdditioGiven these limitations, recent research has focused on reports of polygenic risk scores (PRS) . AlthougIn the case of POAG, most GWAS have been performed in populations of ED and Asian descent, leaving a gap in knowledge surrounding AD populations, which are disproportionately impacted by disease . This knABCA1, AFAP1, ARHGEF12, ATXN2, CAV1, CDKN2B-AS1, FOXC1, GAS7, GMDS, SIX1/SIX6, TMCO1, and TXNRD2 . In fact, when patients were in the top tertile for both IOP and VCDR, they were 7.77 times more likely to have POAG, 95%CI: 3.03–19.93, p = 2.0 × 10−5) . T. TACTBL2As opposed to Asian populations, the prevalence of PACG is low in Europe (0.42%) and North America (0.26%) ,126, andIn an Australian Caucasian population, SNPs in the MMP-9 gene have been associated with PACG but have not been replicated . SimilarMFRP to be associated with both cohorts, though they were not associated after they were adjusted for sex and age. Meanwhile, they found an association between an SNP of the CALCRL gene in the Australian population (p = 0.024), but no association for either population and SNPs in MTHFR [In 2012, Awadalla, et al. examined PACG among a cohort of Nepalese and Australian patients and matched controls. They found an association between SNPs in in MTHFR .SPATA13 gene as the causal gene for PACG in this family. Specifically a 9 base pair deletion was implicated in all of the patients who had PACG. When SPATA13 was then studied in a cohort of 189 unrelated individuals, the researchers found eight additional mutations associated with PACG. Importantly, this was the first study to identify SPATA13 as a gene that was associated with both PACG and any eye disease, though GWAS have implicated the gene product (protein SP-1277) with other disorders such as anorexia nervosa, thyroid cancer, and intellectual disability [More recently, in 2020, Waseem, et al. conducted a study of PACG in an ED family in the UK . They stsability .Across the ME there have been different reports of the prevalence of PACG. For example, in 2005 the Oman Eye Study reported the prevalence of PACG at 0.02% . MeanwhiCHAT (p = 0.02), EPDR1 (p < 0.001), FERMT2 (p < 0.001), and GLIS3 (p = 0.005), but not DPM2-FAM102A [In 2020, a study in Northeast Iran aimed to evaluate the five polymorphisms that had been previously identified by the 2016 multi-ethnic GWAS from Khor, et al. The researchers identified significant associations between PACG and the SNPs for -FAM102A .eNOS and HSP70 to be associated with PACG, as well as MMP9 [SMOC2 (G > A) polymorphism with PACG in a SA population [ACVR1 gene involved in the bone morphogenic protein (BMP) signaling pathway was associated with both PACG and PXG in a SA cohort [A variety of other single-gene variants have been associated with PACG in ME populations. For example, Pakistani populations have reported polymorphisms of  as MMP9 . The eNO as MMP9 . In 2017pulation . AdditioA cohort .SOD2 polymorphisms were associated with mean age of PACG onset, duration of onset, and mean visual acuity [Several studies have also identified polymorphisms that were not significantly associated with PACG in a SA population, but rather with clinical indices for PACG, suggesting that these SNPs could possibly be used as indicators for PACG severity. In 2013, l acuity , while al acuity .Similar to POAG, GSTM1 null polymorphism has been studied for association with PACG in ME patients. In 2015, it was determined that there were increased frequencies of GSTM1 null in Iranian patients with PCAG, leading the authors to suggest that GSTM1 null could be associated with a risk factor for PCAG incidence in Iranian populations . In factCOL18A1, which encodes collagen type XVIII, as a causative gene for angle closure in a pedigree with at least 10 individuals with PAC. COL18A1, however, has been associated with Knobloch syndrome, which itself is characterized by severe vision problems including high myopia and retinal detachment. COL18A1 was identified in two other cases of PACG in unrelated families, but these two individuals were parents and grandparents of KS-affected children [Finally, an interesting study from 2018 associated children . The prevalence of PACG in LAD and Caribbean populations is low (0.85%), but is still higher than the prevalence of PACG in ED populations ,126. SimCTRP5 S163R, were not present in the studied patients [The 2016 multi-ethnic GWAS from Khor, et al. is the only study to demonstrate a genetic association for LAD populations, as the studied population included cases and controls from South American countries in the analysis . Meanwhipatients .Ultimately, given the difficulties of replicating GWAS and PRS across ethnicities ,36, furtXFG is differentiated from POAG and PACG in that XFG occurs as a part of exfoliation (pseudoexfoliation) syndrome (XFS), which is an age-related disorder characterized by systemic deposition of fibrillar extracellular material throughout the body. In the eye, these depositions commonly occur in the anterior segment, leading to a form of open-angle glaucoma that typically progresses more rapidly than POAG and has significantly worse visual field damage and a higher severity of optic nerve damage ,171,172.LOXL1 (lysyl oxidase-like 1) gene on chromosome 15q24 . Additionally, this study confirmed the association between LOXL1 and XFS/XFG. This study was significant as it identified the first genetic locus outside of LOXL1 to be significantly associated with XFS/XFG [In 2015, a second locus,  XFS/XFG .LOXL1 and CACNA1A. In 2017, a GWAS using a global sample of 5570 XFS/XFG cases and 6279 controls identified five new variants: POMP, TMEM136, AGPAT1, RBMS3, and SEMA6A. This study also demonstrated that a rare LOXL1 missense variant may be protective against XFS/XFG [Genetic associations with XFS/XFG, however, are expanding beyond  XFS/XFG . LOXL1 protein expression leading to disease [Aside from genetics, it’s important to note that the widely varied prevalence of XFS/XFG among different population groups could also strengthen an argument for varied environmental exposures. In fact, geo-medical studies have shown that disease burden seems to increase as populations are more distant from the equator . The key disease . Still,  disease ,11,189.p = 0.0197), indicating a large disease burden in this population [XFS is most common in Greek and Nordic populations, with a prevalence as high as 10% in Iceland and 20% in Swedish people over the age of 60 ,191. In pulation .LOXL1 as genetic RFs for XFS/XFG, was performed in a Caucasian population [LOXL1 promoter region SNPs have also been associated with XFS/XFG [The 2007 study from Thorleifsson, et al., which established loci in pulation . In mostpulation . Meanwhipulation . In a US XFS/XFG .LOXL1 association is still present in patients with XFS from the Midwest United States [Importantly, ED populations are perhaps the strongest populations to demonstrate the possible importance of environmental factors of XFS/XFG. In the United States, several studies have demonstrated that individuals who live in northern regions of the country had an increased risk of XFS when compared to individuals living in middle and southern regions of the country. Generally, these studies found that risk of XFS corresponded with the average number of sunny days, indicating a possible role for altitude and UV exposure to pathogenesis of XFS and XFG ,195,196.d States . Additiod States .LOXL1 locus having similar genetic architecture in both populations [These findings about the possible role of environmental factors are supported by genetic characteristics described in an Australian Caucasian population. In 2007, Hewitt, et al. noted that the lifetime incidence of XFS in Caucasian Australians was nine times lower than that of Nordic populations, despite the ulations .Meanwhile, in 2010, the Reykjavik Eye Study found XFS also correlated with increased iris pigmentation, and noted a possible antioxidant protective effect, suggesting a possible oxidative stress mechanism for XFS . In populations of AD, the prevalence and distribution of XFS/XFG is widely varied. XFS is rare in African Americans ,200, butLOXL1 in an ancestral African population with XFG, specifically a black South African population. They confirmed the association between LOXL1 SNPS, specifically rs1048661 and rs3825942, and XFG [In 2010, Williams et al. conducted the first study of  and XFG . Additio and XFG . This fi and XFG .LOXL1 variants associated with XFS/XFG in South African XFS cases. They demonstrated that the relevant SNPs impacted a region containing a promoter and, therefore, disrupt the activity of the promoter. However, the identified region does not lead to increased LOXL1 promoter activity, so the pathogenetic role of these SNPs is unclear. They suggest that altered expression of LOXL1-AS1, the long non-coding RNA, leads to XFS pathogenesis via-dysregulated cellular stress response [In 2015, Hauser et al. determined a functional role for the response . These fresponse . HoweverA 2015 retrospective chart review of 73,946 inpatients at a Beijing hospital showed only 45 patients (75 eyes) identified, suggesting that XFS/XFG is uncommon in this specific urban Chinese population . SimilarLOXL1 polymorphisms confer similar risk of XFS/XFG in Chinese populations [LOXL1 SNPs have similarly been identified as risk alleles for XFS/XFG [TBC1D21 and ATXN2 [LOXL1 have shown no association [Despite the low prevalence of XFS/XFG, studies have shown that ulations ,212,213.ulations . In thes XFS/XFG ,215. Uygnd ATXN2 . Meanwhind ATXN2 , but othociation .LOXL1 genetic findings to a possible mechanism and explain variation in the LOXL1 expression phenotype. They argued that increased transcription of the risk sequence results in elevated levels of an irregularly spliced LOXL1 transcript leading to decreased levels of normal LOXL1 mRNA. They identified the transcription factor RXRalpha, and regulated coupling of alternative splicing and nonsense-mediated decay, as the keys to the mechanism of LOXL1 gene regulation [In 2017, Pasutto, et al. performed a GWAS on 771 German XFS/XFG patients and then independently tested the associated gene variants in Italian and Japanese data sets . The resgulation . Importantly, Pasutto, et al. did note as a limitation of the study, that the XFS/XFG risk alleles were identical in the German and Italian populations, but reversed in Japanese populations, with matches other studies in Asian populations compared to Caucasian studies ,222,223.LOXL1 variants and found 34 SNPs in LOXL1 but also TBC1D21 and PML, both also located on chromosome 15q24.1. Upon further analysis, they found a suggestive combinational effect between LOXL1 and TBC1D21 which seemed to be specific to Asian populations, and found only one TBC1D21 SNP to have a strong association while the PML SNPs were weaker [TLR4 gene in the pathogenesis of both POAG and XFG, but noted a strong association with NTG [Meanwhile, in Japan, a 2014 GWAS further explored the inversion of the risk allele in e weaker . Additiowith NTG .Prevalence of XFS/XFG in the Middle East is similarly varied. A retrospective chart review from Egypt in 2011 showed a 4.14% prevalence in 7738 patients who attended a general ophthalmology clinic. This indicates that XFG is relatively common in Upper Egypt . SimilarLOXL1 gene polymorphisms. In 2010, a Saudi Arabian study demonstrated similar findings to other non-African populations, showing associations between the G allele of both rs1048661 and rs3825942 SNPs with XFG [Similar to other populations, study of XFS in ME populations has focused on with XFG . Severalwith XFG ,229.LOXL1 was not significantly associated with XFS/XFG in the Turkish population [LOXL1 SNPs were only present in 35.3% of patients. Additionally, they demonstrated that the patients with the LOXL1 gene variants had no statistically significant differences in RNFL thickness and cup-disc ratio compared to patients without the SNPs, suggesting that LOXL1 mutations may not play a role in XFS/XFG severity [LOXL1 is not a gene for XFS and is rather a marker of the disease process that results in XFG.In a 2017 study from Turkey, however, researches demonstrated that rs1048661 of pulation . Additiopulation . Meanwhiseverity . These cACVR1 gene involved in the BMP signaling pathway was associated with both PACG and PXG in a Saudi cohort [Interestingly, Middle Eastern studies have also looked at other genes that may be associated with XFS/XFG. Similar to both POAG and PACG, GSTM gene polymorphisms have been studied with a variety of results. A 2010 study showed an association between GSTT1 and GTM1 genotypes with XFG in a cohort of female Pakistani patients . Additioi cohort . This waLittle is known about the prevalence of XFS/XFG in LAD populations . A 2007 LOXL1 polymorphisms with XFS/XFG in LAD populations. They performed a case-control study of a Mexican population and noted an elevated risk of XFS/XFG in this population when affected by LOXL1 variants [LOXL1 SNP was identified in this population, the T allele of SNP rs41435250, in 2013 [In 2012, Jaimes, et al. conducted the first study associating variants . Another in 2013 .Given the complex nature of glaucoma, and its non-Mendelian inheritance pattern, researchers have tried to further characterize glaucoma-associated genes using large-scale agnostic searches among mostly unrelated cases and controls that incorporate complex computational tools. In 2017, Danford et al. conducted a bioinformatics-based review of the “POAGome” . Using DisGeNET, an Integrative Biomedical Informatics Group database, they collected a list of 542 associated genes, and reviewed and analyzed possible pathways for disease development based on both specific ocular tissues and different phenotypes of disease. Ultimately, they suggested that there was no unified molecular pathway that could be the single responsible mechanism for POAG pathogenesis while noting that the inflammation and senescence in the TGF-β signaling pathway may play an important role in glaucoma development . UndoubtMeanwhile, it is similarly important to understand that the calculation of PRS presents several limitations that have yet to be overcome. For one, the actual application of risk scoring to broad-scale clinical use is still not widespread, indicating that the relevance is currently more abstract and requires work to reach the point of clinical implementation. Additionally, it’s important to again note the challenges associated with applying PRS across ethnic groups. According to Lewis and Vassos, current PRS analysis relies largely on the assumption that an individual’s genetic ancestry reflects the large GWAS where scores are calculated from—an issue compounded by the fact that the majority of these studies globally are reliant on ED populations . ImportaIn addition to the utility of PRS, there are several challenges in computing them. For example, according to Igo Jr. et al., the complexities of glaucoma and the definitions of its varying phenotypes present a challenge when determining the outcome of interest in the PRS. For example, in POAG, PRS may be calculated based on endophenotypes, IOP, VF loss, or other parameters alone or together . From thArtificial intelligence and mathematical modeling approaches, alongside deeper genotype-phenotype associations, may provide greater clarity of underlying RFs and mechanistic pathways for disease. For example, Guidoboni et al., have created mathematical models for ocular blood flow in order to understand underlying vascular RFs . SimilarLOXL1 expression [As for PACG and XFG, there is currently a lack of mathematical modeling and artificial intelligence applications for these disease presentations—perhaps given factors such as disease burden, population characteristics, and better-understood pathophysiologic properties. Particularly in the case of XFG, there seems to be a general consensus on the involvement of a limited number of genes, pointing to a mechanism involving pression . Finally, it’s important to note that the practice of genetic and genomic analysis is still evolving, with a variety of challenges to analysis including bioinformatics expertise. In 2019, Jeong et al. published a new web-based algorithm, called CRISPRBetaBinomial, to overcome these challenges and to make CRISPR analysis more easily accessible to researchers in addition to having greater sensitivity and fewer false negatives . While tGlaucoma is the worldwide leading cause of blindness, with increasing prevalence and a disease burden that varies by glaucoma subtype and ethnicity. Genetic and genomic studies have demonstrated the potential for genetic RFs in glaucoma; however, several challenges remain before their clinical application is realized.Generally, there remains a resource-allocation and distribution challenge that mirrors global development. Populations with better access to technologic advances, specifically ED and Asian populations, are largely progressing past the assessment of single-gene variants into GWAS, which allow for the creation of more detailed PRS and, possibly, a clinical tool. Genetic studies, however, have proven to have difficulty crossing ethnicities, a challenge demonstrated by POAG in populations of AD. AD populations are disproportionately affected by POAG and yet there is not substantial research on the genetics of these populations. This creates a knowledge gap that furthers the divide between disease burden and the resource allocation of the most affected populations.Meanwhile, other studies are challenged by the heterogeneity of populations. This is specifically true in the Middle East—where European, Asian, and African ancestry, along with consanguinity, muddies the water of analysis—and in Latin America, where a similar melting pot of ancestry seems to create a diversified genetic population. Additionally, genetic disparities between and within each population have made discernment of a common genetic pathway of glaucoma pathogenesis difficult. Therefore, genetic studies exploring endophenotypes within individual ethnic groups may elucidate common mechanistic pathways. LOXL1 does not track disease burden so much as its expression parallels environmental exposures. Undoubtedly, a future direction of study is to understand the genetic basis for disease burden in these populations. Genetic and genomic research has shown that common gene variants are RFs for POAG and have shown that IOP and cup-disc ratio are important endophenotypes for POAG, so PRSs show promise for clinical impact in these populations once genetic data is available. As for PACG, questions remain on what relevant endophenotypes may be and, given the disappointing state of PACG PRSs, much more genetic study is warranted to elucidate a genetic basis for disease. Meanwhile, further study is needed to determine if XFG is even a genetic disease or rather an environmental effect that is modulated by gene expression. It is also important to note alleles may flip in different populations and as described above In order for genetic analysis to expand and become useful tools in the clinic among these populations, large scale carefully designed studies are required; perhaps ones similar to the model of the UK Biobank or similar large long-term study. As more genetic data becomes available, the expansion of GWAS and PRS may eventually allow for the ability for earlier glaucoma detection and, possibly, genetic-based therapeutics. The application of artificial intelligence on determining individualized risk from glaucoma RFs that include genetic considerations may also further improve specificity of patient care.


Allergic rhinitis (AR) is a common allergic disorder worldwide. Western medicine is not optimistic about the therapeutic effect of this disease. However, moxibustion can enhance vital energy or immunity through a great number of clinical trials. Thus, the aim of this systematic review and meta-analysis is to systematically evaluate the effectiveness and safety of indirect moxibustion for treating AR.P < .1 and I2 > 50% are the thresholds for the tests. We will utilize the fixed effects model or the random effects model according to the size of heterogeneity.We will conduct a comprehensive literature search in Medline, PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure Database, WanFang Database, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database from inception to August 2020 without any language restriction. In addition, we will retrieve the unpublished studies and the references of initially included literature manually. Reviewers will identify studies, extract data, and assess the quality independently. The outcomes of interest include: total effective rate, total nasal symptom score, total non-nasal symptom score, rhinitis quality of life questionnaire, visual analog scale, laboratory indicators , and adverse events. Randomized clinical trials will be collected, methodological quality will be evaluated using the Cochrane risk-of-bias assessment tool, and the level of evidence will be rated using the Grading of Recommendations, Assessment, Development and Evaluation approach. Meta-analysis will be performed using RevMan 5.3.0 software. The heterogeneity test will be conducted between the studies, and Because the review is ongoing, no results can be reported.The results of this review will provide reliable evidence for effectiveness and safety of indirect moxibustion for treating AR.Ethical approval is not required for this study. This systematic review and meta-analysis will be disseminated online and on paper to help guide clinicians.CRD42019140944. An inflammatory reaction with eosinophilic infiltration may occur in later stages.–4 The occurrence of AR has seriously influenced people's quality of life. AR is often accompanied by asthma attacks. It is clinically diagnosed based on detailed medical history, specialized examination, and laboratory tests to assess serum levels of specific immunoglobulins .Allergic rhinitis (AR) is a prevalent non-infectious inflammatory disease, which is caused by allergic individuals exposed to allergens and mainly characterized by allergic inflammation of nasal mucosa. Epidemiological surveys showed that the prevalence of AR in American adults ranges from 10% to 30%.,8 Based on the AR and its impact on asthma (ARIA), the prevalence of AR is 40% to 50% in the general population of European countries and the USA and 4% to 38% in that of mainland China. Furthermore, AR is more likely to occur in individuals with atopy and family history of rhinitis, as well as in first-born children and immigrants.–12 Although the disease is frequent among children, it accounts for about one-third of the adult rhinitis cases.The widespread of AR has remarkably attracted scholars’ attention. In recent years, the incidence of AR has been on a sharp rise, currently affecting about 10% to 20% of the world's population. The most commonly used drugs include corticosteroids, antihistamines, mast cell stabilizers, etc. Although these methods can temporarily alleviate nasal symptoms, they cannot completely cure AR. Moreover, the mentioned methods have shown remarkable side effects, such as drowsiness, dry mouth, and cardiac toxicity caused by antihistamines, etc. Acupuncture, as a non-pharmacological method, was recommended for AR patients by the latest guidelines for clinical practice published in 2015 in the USA.,16 Non-pharmacological treatment, containing complementary and alternative medicine, for example, moxibustion, has shown significant clinical effects as well.Nowadays, the treatment methods for AR mainly rely on Western medicine. A previous research revealed that moxibustion has anti-allergic effects and can reduce the expression levels of signal transducer and activator of transcription 6 (STAT6), nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) in AR mice model. A number of clinical trials showed a remarkable efficiency of moxibustion in the treatment of AR.,21 Indirect moxibustion is performed when an ignited moxa cone is placed on an insulated material and not directly in contact with skin. At present, air and paper are used as buffer layers for modern indirect moxa devices. This method not only has the moxibustion functions of warming meridian and dispersing cold, activating blood circulation, eliminating blood stasis and dispersing, preventing and caring for diseases, but also has the therapeutic effect of mild firepower, which is easy to accept by patients and has been extensively applied in clinical practice.Moxibustion is based on the theory of traditional Chinese medicine (TCM), and it typically bakes acupoints with burning moxa wool. It is mainly extracted from mugmoxa leaves, stimulating specific acupoints or parts of the body surface through the heat generated by hanging moxibustion, as well as stimulating the meridians and vital energy to regulate the viscera, so as to treat diseases. However, to date, no systematic review or meta-analysis has concentrated on indirect moxibustion therapy for AR. The present systematic review was designed to assess the efficiency and safety of indirect moxibustion for treating AR patients. Intriguingly, several high-quality clinical trials have reported that Western medicine has serious adverse reactions, and its long-term application is prone to drug resistance, while indirect moxibustion has fewer adverse effects and higher safety. Hence, this systematic review and meta-analysis aimed to assess the quality of randomized controlled trials (RCTs), so as to evaluate the effectiveness and safety of indirect moxibustion for treating AR patients and better guide clinicians.Systematic reviews and meta-analyses could be advantageous for assessing clinical efficacy and developing clinical guidelines.22.1 The protocol was previously registered in PROSPERO 2019 CRD42019140944, and it could be found at http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42019140944.This systematic review and meta-analysis will be performed according to the guidelines of the Cochrane Handbook for Systematic Reviews and Meta-Analysis Protocol.Any changes in the full text will be described.2.22.2.1We will include all eligible RCTs.2.2.2) are eligible for inclusion. Patients’ age, gender, course of disease, syndrome type, and source of cases are not limited. Studies focused on AR combined with allergic asthma or allergic conjunctivitis and other allergic diseases will be excluded.Patients with all types of AR who were diagnosed with internationally recognized criteria  as the sole treatment or as a major part of a combination therapy with other interventions  will be included. Importantly, no restrictions are placed on the number of acupoints, the method of moxibustion, duration, and frequency. However, studies will be excluded if indirect moxibustion is used as an adjuvant therapy.2.2.4The comparators will include positive treatments , no therapy, placebo or sham moxibustion. The specific forms of choice include the following items:(1)Indirect moxibustion versus positive treatments;(2)Indirect moxibustion + positive treatments versus positive treatments;(3)Indirect moxibustion versus no therapy;(4)Indirect moxibustion versus placebo;(5)Indirect moxibustion versus sham moxibustion.2.2.52.2.5.1  will be used as primary outcomes.The total effective rate and total nasal symptom score2.2.5.2(1);Total non-nasal symptom score(2);Rhinitis quality of life questionnaire(3)Visual analog scale;(4)Laboratory indicators: serum levels of IgE, IgA, or IgG;(5)Adverse events.2.3Duplicate detection and republished literature; indirect moxibustion + other non-pharmacological treatment; experts’ experience or case reports; theoretical research or experimental research; unclear diagnostic criteria and efficacy evaluation criteria; conference papers and incomplete data of the results.2.4We will conduct a comprehensive literature search in Medline, PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure Database, WanFang Database, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database from inception to August 2020 without any language restriction. In addition, we will also retrieve the unpublished studies and the references of initially included literature manually. Searches will be re-run prior to the final analysis. The research will start following the PRISMA protocol. The main keywords include: “indirect moxibustion”, “allergic rhinitis”, and “RCT”. The search will be restricted to human subjects, while there is no restriction on any specific languages. The proposed search strategy for PubMed is presented in Table 2.5 The specific steps are as follows:We will include qualified trials according to Cochrane Collaborative System Evaluator's Handbook 5.2.0.(1)The literature will be obtained through comprehensive retrieval of the specific databases and imported into the document management software NoteExpress 3.0, and the repeated documents will be excluded from each database.(2)We will read the titles and abstracts preliminarily excluding the literature irrelevant to this study.(3)The selected clinical studies will be downloaded, and the full text will be screened.(4)The number of included RCTs will be determined by screening the literature of included studies according to inclusion and exclusion criteria.Three independent researchers  will follow the procedure strictly. If there is any disagreement, it will be resolved by the fourth researcher (JY). The flowchart of selection process is illustrated in Figure 2.6We will establish a normal data extraction table in line with PICOST. Before the formal data extraction, pre-extraction will be conducted twice to ensure the smooth progress of the formal extraction. Data extraction is carried out independently by 3 researchers  and cross-checked repeatedly. In case of disagreement, a tripartite discussion will be conducted to reach an agreement or a fourth investigator (JY) will assist in the determination. Meanwhile, intention-to-treat (ITT) analysis will be applied to the missing data. We will use Excel 2007 for data extraction. Relevant contents of data extraction include: title, author, publication time, average age, sample size, disease type, course of treatment, intervention measures, control measures, adverse reactions, outcome indicators, etc. When important data in the literature are missing or incomplete, the corresponding author will be contacted by phone or email.2.7 according to Cochrane Reviewer's Handbook 5.0. It includes 7 aspects: random sequence generation, allocation concealment, blinding of participants or doctors, blinding of outcome evaluator, incomplete outcome data, selective outcome reporting, and other bias. High (H), low (L), and unclear (U) will be selected to assess the degree of risk of bias in each item. The quality of the evaluation results included in the test will be cross-examined by 3 evaluators . If necessary, the corresponding author will be contacted to clarify the issues. Any disagreements will be resolved through discussion or consultation with a fourth reviewer (JY).The methodological quality of qualified trials will be evaluated by using the Cochrane risk assessment tool2.8 Two reviewers (TY and HF) will evaluate the level of evidence independently. In case of disagreement, a discussion will be conducted to reach an agreement or a fourth reviewer (JY) will assist in the determination.The quality of evidence of the included RCTs will be assessed by Grading of Recommendations, Assessment, Development and Evaluation approach using GRADEprofiler 3.6 software. RCTs start with high level of evidence. The level of evidence will be assessed as follows: high, moderate, low, and very low. If there are limitations on risk of bias, inconsistency, imprecision, indirectness, and publication bias, we will decrease 1 or 2 levels.2.92.9.1Meta-analysis will be performed using RevMan 5.3.0 software. The data are summarized using relative risk (RR) with 95% confidence intervals (CI) for binary outcomes or mean difference with 95% CI for continuous outcomes. If different measurement scales are used, standardized mean difference analyses will be carried out. If the missing data cannot be achieved by contacting the corresponding author, the existing data will be analyzed.2.9.22 value are used to assess the degree of heterogeneity. When P < .1, I2 > 50%, no heterogeneity is considered among the trials, and the fixed effects model will be used for statistical analysis; otherwise, the random effects model will be used. When the clinical heterogeneity between the 2 studies is large, only descriptive analysis will be undertaken.Forest plots will be constructed, and the heterogeneity between the qualified studies is tested. Chi-squared test and I2.9.3 If P > .05, the possibility of publication bias is small.When the number of included studies is > 10, the Egger test is used for potential publication bias.2.9.4If the necessary data are available, we will conduct subgroup analyses to assess heterogeneity according to the different control measures , period of treatment, and outcome measures.2.9.5The goal of sensitivity analysis is to identify the sources of heterogeneity and confounding factors. If the trials’ data are sufficient, sensitivity analysis will be conducted by using the STATA 14.0 software.3In the discussion part of the full text, we will summarize and analyze the research results of indirect moxibustion therapy for AR from the following aspects:(1)Indirect moxibustion intervention mechanism;(2)Main findings of indirect moxibustion effects;(3)Quality of evidence;(4)Discussion of heterogeneity;(5)Limitations and strength of the study; and(6)Conclusion. Topical intranasal glucocorticoids are the most commonly used therapy for moderate and severe AR in Western medicine. However, prolonged use of glucocorticoids can cause serious side effects, such as nasal dryness and nosebleed, and the incidence can be as high as 20%. Moreover, Western medicine is not effective for certain patients with moderate to severe AR. Although desensitization treatment could effectively improve the symptoms of AR, it has a number of disadvantages, including long course of disease, easy recurrence, and remarkable side effects. Hence, scholars should further concentrate on non-drug therapy to reduce the clinical symptoms and adverse reactions of AR.At present, AR is mainly treated with antihistamines and intranasal topical glucocorticoids in the nose. Nowadays, in view of the rare reports on the exact mechanism of indirect moxibustion for treating AR, it is suggested to intensify the clinical research on indirect moxibustion for AR in order to provide evidence-based medicine programs for clinicians better.Indirect moxibustion at 2 acupoints (CV 4 and CV 8) has an antioxidative capacity. It can significantly decrease the serum levels of total ROS and MDA, while increase the TAC level and catalase activity after moxibustion.This study has a number of limitations: firstly, due to the limitations of retrieval conditions, there is no way to ensure that all relevant RCTs can be included; secondly, there is a certain language bias in terms of searching only Chinese and English databases; thirdly, if we fail to contact the corresponding author, we may not be able to obtain the missing data; finally, in the process of indirect moxibustion treatment, the blind method is difficult to implement, which may also cause bias.4This is the first protocol for a systematic review designed to evaluate the effectiveness and safety of indirect moxibustion for AR. And this study will include comprehensive assessment of methodological quality and the level of evidence. Therefore, we speculate that our findings will provide reliable evidence-based medical evidence for indirect moxibustion treatment of AR. In addition, we expect that more research to be conducted in the future to elucidate the shortcomings of the present meta-analysis.Conceptualization: Ting Yuan, Yong Fu, Jun Xiong.Data curation: Ting Yuan, Hao Fan, Xue Wang, Jun Yang.Formal analysis: Ting Yuan, Xue Wang, Jun Yang.Investigation: Jun Xiong, HaiFeng Zhang.Methodology: Jun Xiong, Yong Fu, HaiFeng Zhang.Software: YunFeng Jiang, XiaoHong Zhou, LingLing Xu, Kai Liao.Supervision: Jun Xiong, Hao Fan.Writing – original draft: Ting Yuan, Yong Fu, Jun Xiong.Writing – review & editing: HaiFeng Zhang, Jun Yang, YunFeng Jiang, XiaoHong Zhou, Kai Liao, LingLing Xu.