Acupuncture has been recommended for the treatment of tension-type headache (TTH). However inconsistent findings on the efficacy of acupuncture impacts on the uptake of this effective therapy for TTH. This systematic review aims to 1) Evaluate the efficacy of acupuncture for TTH; and 2) Clarify the factors contributing to conflicting findings through conducting a meta-analysis and meta-regression of randomized controlled trials.Comprehensive literature search will be performed on PubMed, EMBASE, CINAHL, ProQuest, Cochrane Central Register of Controlled Trials, Acubriefs, ScienceDirect, Scopus, AMED, and 4 leading Chinese databases of the China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Data, and CBM (SinoMed). We will include Randomized controlled Trials or controlled trials of patients with TTH that compared acupuncture with sham interventions. The primary outcome is the number of days on headache (within 4 weeks) at the end of the treatment and follow-ups. Secondary outcomes include intensity of pain, frequency of attack, and the adverse effects resulting from the intervention. We will use pre-defined sub-group analysis and meta-regression to explore the influential factors of acupuncture effects. Heterogeneity assessment will be performed before carrying out meta-analysis, whereas the subgroup analyses and meta-regression will be used in verifying the possible factors of heterogeneity when significant heterogeneity detected.Review Manager 5.3 software will be used for meta-analysis. The synthesis will be performed by generating forest plots. Meta-regression will be used to understand influential factors for acupuncture in patients with TTH.By utilizing techniques of meta-regression, this study will provide evidence toward to a more focused understanding of influential factors for acupuncture in patients with TTH. This systematic review will provide quality evidence for the optimization of acupuncture therapeutic regimen. It will facilitate the development of clinical practice guideline on acupuncture for TTH. The headache is mild to moderate in intensity, and the pain is usually bilateral, nonpulsatile, generally markedly persistent. It is a significant cause of distress and disruption to life, resulting in marked reductions in quality of life and engagement in social and family activities. However, the exact aetiology and pathophysiology of TTH remain unclear and the treatment strategies for TTH remain unspecific.–4Tension-type Headache (TTH) is found to be the most common type of primary headache and the second most prevalent chronic disorders. It is an invasive stimulation technique using thin needles on specific acupoints on the skin of the body. Based on Chinese medicine (CM) theory, it corrects imbalances in the flow of qi. One recent Cochrane review confirmed that acupuncture is effective for treating frequent episodic or chronic tension-type headaches. As a valuable non-pharmacological option for patients suffering from frequent episodic or chronic TTH, acupuncture has been recommended as a prophylactic treatment due to its effectiveness and safety profile. However, consensus on whether real acupuncture is superior to sham acupuncture has not been fully reached. Heterogeneity in trials might have contributed to the conflicting findings.Acupuncture, one of the most widely used complementary therapies has been reported to be effective for pain management. In that study, we analyzed sources of heterogeneity and explored factors that have been considered to have direct impact on the quality of acupuncture trial. Those may include stimulation modes, needle retention time, and treatment frequency. However, the conclusion is limited due to a small number of trials. Among the 5 trials included, only 2 studies provided detailed information to enable us to compare the treatment protocol. In this proposed systematic review, we aim to evaluate the efficacy of acupuncture for TTH, and clarify the factors contributing to conflicting findings through conducting a meta-analysis and meta-regression of randomized controlled trials (RCTs) by comparing the effects of real and sham acupuncture on TTH. Specifically, this review will investigate the effect of major contributing factors that have been reported or considered to have direct impact on the quality of acupuncture trials.This systematic review is an update of our published study in 2013.22.1The protocol has been registered in the International Prospective Register of Systematic Reviews with registration number CRD42019134067.2.2 The meta-analysis will be performed in accordance with the recommendations of Cochrane Handbook for Systematic Reviews of Interventions.The systematic review will follow the items of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol.2.32.3.1Included studies(1)Are randomized or quasi-randomized controlled trials (RCTs or quasi-RCTs);(2)Have adult patients;(3)–14 or the Ad Hoc committee on the Classification of Headache Ad Hoc 1962;With TTH diagnosed according to International Headache Society criteria of the International Classification of Headache Disorders (4)Reported headache days as an outcome measurement;(5)Employed invasive acupuncture needling;(6)Needled acupoints, Ashi point; and(7)Compare against sham interventions:Studies will be excluded if:(1)Point injections are used because it is difficult to differentiate if the efficacy is from medication or acupuncture itself;(2)Dry needling is employed because its theory and practice is not in accordance with traditional acupuncture; or(3)Results about patients with TTH were not reported separately from those with other types of headache, such as migraine.2.3.2–14 or Ad hoc committee's criteria if studies conducted before 1988. Studies including patients with headaches of various types  unless separate results are presented for patients with TTH will not be included.Adult patients must have been diagnosed with TTH according to the International Headache Society diagnostic criteria2.3.3 or the Streitberger needle.In this review, acupuncture is limited to needle insertion type, that is , invasive methods, such as manual acupuncture, electro-acupuncture. Points needled include acupoints, Ashi point, trigger/tender points, and auricular acupoints. Interventions such as point injection, and dry-needling, laser acupuncture, acupoint catgut embedding will be excluded because its theory and practice is not in accordance with traditional acupuncture. Control intervention in this study is specified as sham control, acupuncture. Sham acupuncture refers to interventions mimicking “real” or “true” acupuncture treatment procedure, not in accordance with traditional acupuncture treatment process. Two types of conventional sham control are acceptable in this study, that is , using superficial needle insertion with real needles on non-acupuncture points, or, applying non-penetrating placebo acupuncture devices, such as the Park sham acupuncture device2.3.42.3.4.1 at the end of the treatment and follow-ups.Headache days (within 4 weeks)2.3.4.21)Intensity of pain ,2)Frequency of attack 3)Adverse effects resulting from the intervention2.42.4.1Thirteen major databases will be searched, consisting of 9 English databases  and 4 leading Chinese databases ) from the inception to December of 2019. An updated search will be performed prior to the data analysis.2.4.2As shown in Table 2.52.5.1The screening process will use EndNote X9 literature management software  for management and deduplication. Two reviewers will read the titles and abstracts to exclude irrelevant trials. Full text will be obtained for the determination of the potential eligible studies against the inclusion and exclusion criteria. The entire screening processes will be performed independently and in duplicate. Disagreements will be solved by discussion and consult with a third reviewer. Authors will be contacted for insufficient information and missing data. Reasons for the excluded studies will be recorded, and the selection process will be presented in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram Fig. .2.5.2The 2 reviewers will extract data from eligible trials independently by using a standard pre-defined data extraction form, which covers the following components:1)Study characteristics: authors, year of publication, study design, sample size, interventions and controls, methods randomisation blinding, and allocation concealment;2)Outcome data: mean and standard deviation/standard error will be extracted for continuous outcomes, whereas the number of events and total population will be extracted for dichotomous outcomes;3)Patients characteristics: age (mean age) or age range, sex , ethnic population, numbers of randomized treated, analyzed and their withdrawals of data, and primary and secondary outcomes at all reported time points;4)Acupuncture treatment characteristics: number of needles, total number of treatments, frequency of treatments, timing of treatments, point selected, needle retention time, mode of stimulation, achievement of De-qi, manipulation technique on needles, rational on point selection, feature of sham control stimulation styles, and repot of background or training information of practitioners, which are in line with the Standards for Reporting Interventions in Controlled Trials of Acupuncture criteria.Other information including protocols of treatment and selection criteria will be also extracted for study comparisons.2.5.3,20 will be used, which involves 7 specific domains ofFor the assessment of study quality, the Gordon H. Guyatt's revision of Cochrane risk of bias tool for the assessment1)Random sequence generation,2)Allocation concealment,3)Blinding of patients and caregivers,4)Blinding of outcome assessment,5)Blinding of patients and caregivers,6)Selective outcome reporting, and7)Other bias.Methodological quality will be considered as “low risk” of bias, “high risk” of bias or “unclear risk” of bias.2.5.4 and funnel plots will be used to assess the publication bias if there are at least 10 trials included in meta-analysis. A P < .05 indicates a significant publication bias.Egger test2.6www.cochrane.org) will be used for meta-analysis. The synthesis will be performed by generating a forest plot for meta-regression. A random-effect model will be used if significant heterogeneity (I2≥50%) among the trials is detected. For continuous data, weight or standard mean difference will be used. When different scales are used for assessing 1 outcome measure, standard mean difference will be calculated.RevMan 5.3 (Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) software provided by Cochrane collaboration Type of acupuncture 2)Needle retention (needle retention vs no-retention)3)Frequency of treatment (twice a week or more vs once a week)4)Point selection (semi-standardized vs formula treatment)5)Number for study center (multicenter vs single site)6)CM diagnosis guided treatment .7)Design of sham acupuncture (having sham points on the head vs not on the head).The post-hoc subgroup analyses and meta-regression for other independent variables will also be considered subject to other necessary variables.2.6.3Sensitivity analysis will be performed to evaluate the robustness of the pooled results, by excluding studies with “high risk” and “unclear risk” of bias.2.6.4 the Grading of Recommendations Assessment, Development, and Evaluation will be used as a tool for assessing the strength of the body of evidence. In this evaluation system, the strength of evidence can be divided into 4 levels as “high”, “moderate”, “low”, or “very low” by the outcome.The quality of evidence will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach2.7The results of this meta-analysis and meta-regression will be disseminated in a peer reviewed journal. Ethics approval is not required in this study as no individualized data will be involved.3 1 Cochrane review published in 2009 and an update version on 2016. In contrast to the published reviews, our previously review use subgroup analyses to explore the contributing factors to the inconsistent findings. Due to a relatively small number of eligible clinical trials and limited evidence, we were not able to provide conclusive recommendations on the contributing factors.Several systematic reviews discussed effectiveness and efficacy of acupuncture for TTH, including a 2008 systematic review,In this proposed study, we will include more trials and use meta-regression. Those strategies will provide quality evidence towards a more focused understanding of influential factors for acupuncture in patients with TTH. Our findings will facilitate the development of clinical practice guideline of acupuncture for TTH and contribute to the optimized acupuncture treatment regimen for the enhanced therapeutic effects.Xinyu Hao, Yang Shi, Ying Li, and Zhen Zheng conceived the systematic review. Xinyu Hao and Yang Shi contributed equally as first co-authors and wrote the final draft. All the authors helped to write the article and approved the publication of the protocol.Conceptualization: Xinyu Hao, Yang Shi, Ying Li, Zhen Zheng.Data curation: Xinyu Hao, Jun Zhu, Jing Wang, Qianhua Zheng.Formal analysis: Xinyu Hao. Yang Shi.Methodology: Xinyu Hao, Charlie Changli Xue.Supervision: Zhen Zheng, Ying Li.Writing – original draft: Xinyu Hao, Yang Shi.Writing – review & editing: Xinyu Hao, Yang Shi.


Pneumonia is a common respiratory disease. In severe cases, it can induce cardiovascular disease and even life-threatening. In particular, pneumonia caused by the new coronavirus (SARS-CoV-2) that broke out at the end of 2019 has seriously affected the health of people in all countries. In recent years, it has been treated with the combination of traditional Chinese medicine (TCM) (such as Reduning injection) and Western medicine, and its mortality has decreased significantly. But their efficacy has not been scientifically and systematically assessed. Accordingly, it is essential to provide a systematized review program to estimate the efficacy and safety of Reduning injection combined with Western medicine to treat pneumonia.The following databases are retrieved from start to September 2020: Pubmed, Cochrane Library, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, the Chongqing VIP Chinese Science and Technology Periodical Database (VIP) databases, Chinese Biomedical Literature Database (CBM), and other databases, which are absorbed into clinical RCTs of pneumonia using western medicine alone or plus Reduning injections. The selection of studies, data extraction, and assessment of risk of bias will be performed independently by 2 reviewers. At the same time, Review Manager V.5.3.5 (Rev Man V.5.3.5) was used for bias risk assessment and data synthesis.The efficacy and safety of Reduning injection combined with western medicine in the treatment of pneumonia were evaluated in terms of overall effective rate, the patient's antipyretic time, antitussive time, rales disappearing time, X-ray recovery time, and the incidence of adverse reactions.This study provides reliable evidence-based support for the clinical application of Reduning injection combined with western medicine for pneumonia.Ethical approval is not required in this secondary research evidence, and we will publish the results of this study in a journal or relevant conferences.DOI 10.17605/OSF.IO/VS75Y. There are 50% of intensive care units (ICUs) patients all over the world, who have acute pulmonary infections.,4 The cause of pneumonia is more common with viral infection and bacterial infection. The new coronavirus pneumonia (COVID-19) that broke out at the end of 2019 is caused by the new coronavirus (SARS-CoV-2).–8 As an acute respiratory infectious disease, COVID-19 has been included in Category B infectious diseases as stipulated in the Law of the People's Republic of China on the Prevention and Control of Infectious Diseases, which is listed as Category A infectious diseases.–8Respiratory infections are a chief reason of infectious disease death all over the world.,9–11 TCM injection is the main type of TCM for syndrome differentiation of TCM therapy, but its effect is relatively slow.,11 Although Western medicine routine treatment has quick effect and remarkable effect, it also has shortcomings such as drug resistance and is not suitable for long-term use. Reduning injection has achieved a certain effect in clinical treatment of acute bronchitis and upper respiratory tract infection.,9–11 In the course of the outbreak of COVID-19, Reduning injection is widely used to treat severe patients with COVID-19 in China, which is also recommended for use in the Guideline on Diagnosis and Treatment of Coronavirus Disease 2019 (Revised 7th version) officially issued by National Health Commission of the People's Republic of China.–8 Western medicine routine treatment mainly uses antibiotics –21 and antiviral drugs (interferon and ribavirin).–25 However, the evaluation of their efficacy is not scientific and systematic.In recent years, it has been treated with the combination of TCM (such as Reduning injection) and Western medicine, and its mortality has decreased significantly.Accordingly, it is essential to provide a systematized review program to estimate efficacy and safety of Reduning injection combined with Western medicine to treat pneumonia.22.1This protocol of systematic review and meta-analysis has been drafted under the guidance of the preferred reporting items for systematic reviews and meta-analyses protocols (PRISMA-P). Moreover, it has been registered on open science framework (OSF) on September 8, 2020. (Registration number: DOI 10.17605/OSF.IO/VS75Y).Any changes in the standard protocol will be described further.2.2Since this study is a secondary analysis of existing literature, ethical approval is not required. We will provide a systematical view and evidence of Reduning injection combined with western medicine for pneumonia, which will benefit clinical practice and further research. Also, we will publish our study in a peer-reviewed journal or distributed at related conferences.2.32.3.1We are eligible for a RCTs of Reduning injection combined with Western medicine to treat pneumonia.2.3.2According to the international or Chinese official published diagnostic criteria for pneumonia, patients with a definite diagnosis of pneumonia are included with no restriction on nationality, region, race, gender, age, course of disease, or type of pneumonia.2.3.3The experimental intervention group is treated with Reduning injection combined with Western medicine. The control group is treated with conventional Western medicine. Conventional Western medicine treatment is mainly based on antibiotics  and antiviral drugs (interferon and ribavirin). We excluded RCTs comparing simple Reduning injection with Western medicine.2.3.42.3.4.1 Recovery: the body temperature returned to normal, and respiratory tract symptoms such as cough and sputum were completely or basically relieved. The X-ray chest radiographs showed that the lung shadow was small or not expanding, and leukocyte or neutrophil examination was close to normal. Significant effect: the body temperature was basically normal, and the respiratory symptoms such as cough and sputum had improved. There was no enlargement of lung shadows in the X-ray chest radiographs and no increase in blood leukocytes or neutrophils. Invalid: fever persisted, and respiratory tract symptoms such as cough and sputum did not change or worsened. The X-ray chest radiograph showed enlarged or new lung shadows, and the white blood cells are elevated or persistently lower than normal.Overall effective rate = (number of cured + number of marked effect) / total number of people. The evaluation criteria of efficacy are:2.3.4.2Include the patient's antipyretic time, antitussive time, rales disappearing time, X-ray recovery time, and the incidence of adverse reactions 2.41.If the paper is repeatedly published, the one with the most complete data shall be included;2.Articles with missing data and we are still unable to obtain data after contacting the author;3.Articles with obvious data errors;4. The included literature was evaluated as low, medium, and high quality according to the following criteria: ① If randomization or allocation-hiding assessments were high risk, the study was rated as low quality regardless of other risks; ② When the randomization and allocation of hidden assessment is low risk, and all other quality assessment are assessed as low risk or clear, the study is rated as high quality; ③ If the research is neither in line with high quality, nor in line with low quality standards, it is considered to be of medium quality research.Low-quality literature will be excluded, and low-quality reference standard is the standard in Jiaguo Zhaos paper.2.52.5.1These databases will be retrieved from start to May 2020: Pubmed, Cochrane Library, EMBASE, Web of Science, CNKI, Wanfang database, VIP databases, and CBM. In order to comprehensively obtain RCTs of Reduning injection combined with Western medicine for pneumonia, we searched baidu academic, Google academic, as well as the International Clinical Trials Registry Platform (ICTRP), Chinese Clinical Trial Registry and Clinical Trials to obtain grey literature and relevant data that have not been publicly published. These are only trials report including English and Chinese.2.5.2Table 2.5.3This research screening will be performed by 2 independent reviewers. Read titles, abstracts and full-texts of research, and evaluate whether it meets the requirements according to the inclusion criteria. The third reviewer will decide several studies with different opinions. The research screening process is defined for a systematic review and meta-analysis flow diagram Fig. .2.6Referring to the method of research selection in version 5.0 of the Cochrane collaboration Network system Evaluator Manual, according to the PRISMA flow chart, the 2 researchers used the EndNote X9 document management software to independently screen and check the literature according to the above inclusion and exclusion criteria, and check each other, if there were different opinions, negotiate with a third party to resolve the differences. At the same time, Excel 2013 was used to extract relevant information, including: ① basic information of the included study, including research title, author name, and publication year, etc.; ② baseline characteristics of the included study, including sample size, patient age, sex ratio, and course of disease of the treatment group and control group; ③ intervention methods, intervention time, frequency, dose and route of the treatment group and control group; ④ the key elements of bias risk assessment; ⑤ the outcome indicators concerned and the relevant measurement data.2.7The assessment of risk of bias will be carried out independently by 2 reviewers via the Cochrane Collaboration's “Risk of bias” tool. According to these criteria , study bias is classified into the following levels: unclear, low, and high risk. If the assessment of bias causes controversy, it will be necessary to discuss it with the third reviewer. The RevMan V.5.3.5 is applied to study graphic representations of potential bias within and throughout research.2.82.8.12 test, I2 value of forest and plot is measured to evaluate heterogeneity. I2 ≥ 50% is regarded as a measure of severe heterogeneity, and I2 < 50% is considered that there is no heterogeneity. Therefore, the conclusion is drawn as appropriate. If there is no clinical and methodological heterogeneity, the random effect model will be evaluated by merger analysis. If the heterogeneity is oversized, a descriptive analysis will be conducted. Based on sample size of the clinical study, including measurement, intervention methods and the length of treatment, we will conduct a systematized review of the literature through meta-analysis. A meta-analysis including multiple homogeneity studies will be performed by Rev Man V.5.3.5. When I2 < 50%, the fixed effect model will be chosen; When I2 ≥ 50%, the sources of heterogeneity are analyzed, and subgroup analysis may be performed. If there is statistical heterogeneity between studies but no clinical heterogeneity, a random effect model will be selected to analyze. Otherwise, we will exclude the research from meta-analysis.Statistical analysis is performed by a 95% CIs. Odds ratio (OR) and relative risk (RR) are usually applied to dichotomy result data. For continuous results, if the measurement method and measurement unit are the same, the weighted mean difference (WMD) shall be used; if the measurement method or measurement unit is different, the standard mean difference (SMD) shall be used for statistical analysis. Based on the Cochrane Handbook, χ2.8.2When data for some research results are insufficient or missing, we will contact the corresponding author via e-mail or phone to supplement their content. Articles that do not provide data or are unable to calculate the given information will be excluded.2.8.3The units of each outcome from different studies will be converted to the International System of Units before statistical analysis.2.8.4Funnel plots and statistic tests will be used to detect overall estimated reporting bias. Eggers and Beggs test are used to quantitatively assess potential publication bias.2.8.5Subgroup analysis will be carried out to evaluate heterogeneity. The various types , severity of pneumonia , age of patients , and course of treatment may have an effect on heterogeneity.2.8.6Sensitivity analysis will be applied to test the robustness of key decisions made during the review process. The sensitivity analysis of all indicators is carried out through one-to-one elimination method to verify the stability of the obtained results by Rev Man V.5.3.5.2.8.7The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) will be used to assess the quality of evidence. It contains 5 domains . And the quality of evidence will be rated as high, moderate, low, and very low.3–4 At the same time, patients with pneumonia may have varying degrees of fever, cough, shortness of breath, and irritability, whose lungs exist wet rales and have solid tissue changes. In addition, their X-ray film shows a flaky shadow and serum IgM antibody is strongly positive.–4 In recent years, it has been treated with the combination of TCM (such as Reduning injection) and Western medicine, and its mortality has decreased significantly. Reduning injection is mainly composed of Artemisia annua, honeysuckle, and Gardenia jasminoides Ellis. It is mainly used in the upper respiratory tract infection (exogenous wind heat syndrome) caused by high fever, slight evil wind cold, head and body pain, cough, phlegm yellow, and other diseases.,9–11 Previous pharmacological studies have shown that paraquat modulates AMPK/MAPK/NF-κB signaling to reduce acute pulmonary injury. In the treatment of COVID-19, Reduning injection may be associated with anti-inflammatory and immunoregulation effects of the active ingredients via multiple targets and pathways.–8,29 Western medicine routine treatment is mainly based on antibiotics and antiviral drugs, such as penicillin, ceftriaxone sodium, amoxicillin, amoxicillin and clavulanate, erythromycin, azithromycin, minocycline, doxycycline, clarithromycin, levofloxacin, interferon, ribavirin, oseltamivir, ganciclovir, and so on.–25 There are many Western medicines used in clinical. Therefore, the systematic review assesses efficacy and safety of Reduning injection combined with Western medicine to treat pneumonia and provide evidence to clinicians.The main pathogenic characteristics of pneumonia are acute onset, severe symptoms, and many complications, which can easily cause circulatory system failure and seriously threaten peoples health.However, this systematic review has some limitations. For example, diagnose criteria, dosage, duration of Reduning Injection, and no blind method in the trials may result in insignificant heterogeneity. Research published in English and Chinese are retrieved. There is no related research in other languages.Data curation: Chenggang Cao, Zelong Zhen.Funding acquisition: Tao Xu.Investigation: Tao Xu.Resources: Chenggang Cao.Software: Zelong Zhen, Shengnan Kuang.Writing – original draft: Chenggang Cao, Zelong Zhen.Writing – review & editing: Tao Xu.


We conducted a meta-analysis to summarize all available evidence from randomized controlled trial studies regarding the clinical efficacy and safety of spironolactone in patients with resistant hypertension (RH) and provided a quantitative assessment.A systematic search of PubMed, Web of Science, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) databases through December 8, 2019, was performed. Randomized controlled trials randomized controlled trials meeting inclusion criteria were included to assess the effect of the addition of spironolactone on office blood pressure (BP), 24-hour ambulatory BP or adverse events in RH patients.P < .001; office DBP WMD = −5.73, 95% CI = −8.13 to −3.33, P < .001) and 24-hour ambulatory BP . Compared with alternative drugs, spironolactone treatment in RH patients significantly decreased 24-hour ambulatory BP .Twelve trials, which enrolled a total of 1655 patients, were included in this meta-analysis. In comparison with placebo, spironolactone significantly reduced office BP (office SBP, weighted mean difference [WMD] = −20.14, 95% CI = −31.17 to −9.12, This meta-analysis fully evaluated the antihypertensive effect of spironolactone compared with placebo, alternative drugs, renal nerve denervation and no treatment. Spironolactone can result in a substantial BP reduction in patients with RH at 3 months. The inability to reach standard BP levels (below 140/90 mm Hg) despite the concurrent use of 3 or more antihypertensive agents of different classes that include at least one kind of diuretic is defined as resistant hypertension (RH). The etiology of RH is poorly understood, but it is associated with diabetes, chronic kidney disease (CKD), and obesity. To improve BP control in patients with RH, lifestyle modification should be recommended. Despite the ineffectiveness of the first 3 recommended drugs, including calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), and thiazide diuretics, adherence should be carefully assessed to exclude pseudo resistance. New treatment strategies must be developed to improve BP control.Patients with hypertension are at higher the risk of cardiovascular disease and stroke.,5 However, some recent observational studies have demonstrated that the addition of spironolactone to triple-drug therapy was the most effective add-on drug for patients with RH. As a mineralocorticoid receptor antagonist, spironolactone has a promising effect on lowering BP in hypertensive patients. The adverse effects of spironolactone, including gynecomastia, breast discomfort, and biochemical abnormalities, are relatively. Although some randomized controlled trials (RCTs) have demonstrated the efficacy of spironolactone as a fourth-line therapy for patients with RH, there are no available high-quality, large-scale clinical trials to evaluate the efficacy and safety of spironolactone for RH.Currently, the most suitable fourth drug to add to the 3 commonly prescribed antihypertension drugs is not well established.We conducted a meta-analysis to summarize all available evidence from RCT studies regarding the clinical efficacy and safety of spironolactone in patients with RH, and we conducted a quantitative assessment. The results of this study were merged with updated available evidence to fully assess the influence of spironolactone on BP compared with placebo and other active interventions. To our knowledge, this was the first study that included data describing BP changes over time.2 guidelines, to elaborate the effect of spironolactone on RH.This meta-analysis was performed, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)2.1Two reviewers systematically searched 5 electronic databases, including PubMed, the Web of Science, the Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI), until December 8, 2019. The search terms were “spironolactone” and “resistant hypertension” matched with “Randomized Controlled Trial” or “Clinical Trial” OR “Controlled Clinical Trial.” The language was not limited. Our meta-analysis selected only the most recent publication when the same study had been published in different journals or in different years. If different studies were performed and published by the same researchers, all studies were selected for the meta-analysis.2.2Two reviewers independently examined the titles and abstracts of all obtained articles. Eligible studies met the following inclusion criteria:(1)RCT design;(2)patients with RH ;(3)office, home or ambulatory BP monitoring;(4)a follow-up of at least 4 weeks; and(5)a clear description of relevant outcomes.Articles that were not RCTs, including letters, practice guidelines, conference theses, commentaries, and editorials, were excluded, but relevant articles from the reference lists were retrieved to identify potential studies.2.3Relevant data were collected independently by 2 reviewers, and the third reviewer was responsible for resolving discrepancies through discussion. The standardized predefined form used included 4 parts:(1)basic information: title, first author, the year of publication, and corresponding address;(2)study characteristics: the type of intervention and control, daily dosage of intervention, study design, inclusion and exclusion criteria, and RH definition;(3)the characteristics of participants: sample size, sex distribution, mean age and race; and(4)results of the study: outcome measures of BP and heart rate. When there were missing data, errors or ambiguous information in the included studies, we contacted the original authors of the study. If the author failed to answer the questions, insufficient information was neglected, or the study was excluded. Different opinions between reviewers were resolved by communication with other reviewers.We assessed the quality of the involved RCTs by using the Cochrane Collaboration tool. Two reviewers who performed data extraction separately evaluated the risk of bias in the involved studies. Disagreements in scoring were resolved by discussion among the reviewers. Several sources of bias are evaluated in the Cochrane Collaboration tool, including random sequence generation; allocation concealment; the blinding of participants, personnel, and outcome assessment; incomplete outcome data; selective reporting; and anything else, ideally prespecified, and others.2.4P > .10, there was no obvious heterogeneity). A random-effects model was utilized when heterogeneity was obvious; otherwise, a fixed-effects model was used. The risk ratio and weighted mean difference (WMD) were used to represent binary variables and continuous variables, respectively, with a 95% confidence interval (CI). A funnel plot was used to detect publication bias and meta-regression analysis was used to evaluate the factor of effect on heterogeneity.All statistical analyses were performed using Cochrane Program Review Manager Version 5.3 . We used the I2 test and chi-squared test to evaluate the heterogeneity of the included RCTs to estimate the discrepancy across studies . In the GRADE system, the quality of evidence will be classified into very low, low, moderate, or high judgment.2.6Ethical approval was not required.33.1Overall, 1988 studies were identified by searching databases . After removing duplicates, 1208 remained and were evaluated. By assessing abstracts and full texts, 77 studies were eligible and then further examined thoroughly. Finally, 12 studies met our inclusion criteria, and 65 were excluded for the following reasons: 35 were not RCTs, 23 had incomplete data, and 7 were the same studies at different stages. The literature search processing and reasons for exclusion are listed in Figure –13 that selected patients with CKD, heart failure and obstructive sleep apnea and those on dialysis. Two RCTs,15 enrolled participants with type 2 diabetes mellitus and 2 RCTs,17 were conducted in patients with true RH.The main characteristics of the included RCTs are listed in Table 3.2,16–19 were open label and did not provide clear information on the accurate assessment of the risk of bias; therefore, they were evaluated as having an unclear risk of bias. The details for the blinding of outcome assessment in 1 study were inaccessible; therefore, the study was evaluated as having a high risk of bias. The results of the quality evaluation of the eligible RCTs are shown in Figures According to the Cochrane risk of bias tool, most items of the included studies are given in Figures 3.3P < .001). Compared with no treatment, spironolactone also significantly reduced SBP . However, there was no significant difference between spironolactone and alternative drugs or renal nerve denervation (RND) in the effect on office SBP. Relatively high heterogeneity was shown in comparison with the placebo group, which might be related to the background therapy, the dose of spironolactone, the duration of the intervention and demographic characteristics in each study.  . There was no significant difference between spironolactone and RND in the reduction in 24-hour ambulatory SBP. However, in comparison with alternative drugs, spironolactone showed a significant difference in the reduction in 24-hour ambulatory SBP , with relatively obvious heterogeneity . Apart from comparison with the placebo group, the data analysis did not show any significant difference between spironolactone and the other control groups. Significant heterogeneity was present between spironolactone and placebo because of the dose of spironolactone, the duration of intervention and demographic characteristics  and blank groups . There was no significant difference between spironolactone and RND in the reduction in 24-hour ambulatory DBP. However, in comparison with alternative drugs, spironolactone showed a significant difference in the reduction in 24-hour ambulatory DBP  without heterogeneity  was better than that of less than 3 months  or longer than 3 months on SBP .  was better than that of less than 3 months  or longer than 3 months on DBP   without heterogeneity. However, the spironolactone group did not show any increased risk of elevated serum potassium levels compared with the other-treatment control groups, such as those who received alternative drugs, no treatment, or RND  that evaluated the effectiveness of spironolactone (12.5–50 mg/d) on RH with a control treatment—ramipril in 1 trial, bisoprolol in 1 trial, clonidine in 1 trial and an alternative treatment  in 1 trial. The follow-up periods ranged from 8 to 12 weeks. Although there were no significant differences in the effects of spironolactone vs alternative drugs on office SBP and DBP, the results of 24-hour ambulatory BP still demonstrated that spironolactone had a better antihypertensive effect. ABPM has the advantage of less bias than office BP and provides a complete picture of BP values throughout the day. Some studies have supported the concept that ABPM is less vulnerable to other factors effects since it is assessed in a patient's daily life. Based on our results, spironolactone had a better antihypertensive effect than other drugs, and its effects were not worse than those of RND, making it more suitable for many Chinese individuals.This meta-analysis also included 2 trials (with 165 patients) that evaluated the effectiveness of spironolactone and RND. Subgroup meta-analysis showed that spironolactone had the same antihypertensive effect as RND. In renal RND, patients undergo splanchnic sympathectomy for the treatment of severe hypertension. The excess risk associated with RH is importantly linked to the development of CKD, which is known to be a major cardiovascular risk factor. Several studies initially reported that this intervention substantially reduced the elevated BP of RH patients, but this conclusion has not been supported by the results of this meta-analysis. The antihypertensive efficacy and overall validity of RND did not show a difference compared with spironolactone. In addition, many Chinese people tend to reject invasive treatment strategies. Our subgroup meta-analysis showed that spironolactone significantly increased the concentration of serum potassium compared with placebo. When compared with the other interventions, there was no significant difference in the serum potassium concentration with the use of spironolactone. The mild degree of the elevation of serum potassium with the administration of spironolactone may indicate the safety of the intervention. Although we did not have direct data to assess the incidence of adverse events, hyperkalemia still occurred in ∼3% of patients receiving spironolactone in another study. Therefore, it is necessary to pay attention to serious adverse events caused by spironolactone.Our study showed a significant benefit of spironolactone use in lowering BP in patients with RH, and the most frequent adverse events, such as hyperkalemia and gynecomastia/mastodynia, should be considered.4.1Several limitations of this study should be mentioned. First, unexplained high heterogeneity might affect the results of the subgroup meta-analysis, although we used strict inclusion criteria to ensure the inclusion of high-quality RCTs. Second, we included several trials with small sample sizes, which may have resulted in a risk of bias in this meta-analysis. Third, original data could not be accessed for every study, which might influence the results, although this is a limitation inherent to all study-level meta-analysis. Fourth, we did not evaluate the incidence of hyperkalemia due to a lack of data in multiple studies. In the future, the occurrence of other long-term complications in patients who use spironolactone should be analyzed. Fifth, the prevalence of primary aldosteronism (PA) is very high in RH patients. However, several studies did not evaluate the influence of spironolactone on PA. Therefore, we did not fully evaluate the safety of using spironolactone.4.2The finding that a 3-month duration of spironolactone intervention had the best effect was newly discovered through our meta-analysis, but the specific mechanism is not clear. Our later research will further explore the specific mechanism of the drug to provide theoretical support for the clinical application of spironolactone.5This meta-analysis fully evaluated the antihypertensive effect of spironolactone compared with placebo, alternative drugs, RND and no treatment. Spironolactone can result in a substantial BP reduction in patients with RH at 3 months. Additionally, more large and long-term randomized controlled trials, including data that evaluate the incidence of hyperkalemia and long-term adverse events, are needed.XXXX.


We report the fabrication of nanofeatured polymeric films using nanosphere lithography and ultraviolet (UV) soft-mold roller embossing and show an illuminative example of their application to solar cells. To prepare the nanofeatured template, polystyrene nanocolloids of two distinct sizes (900 and 300 nm) were overlaid on silicon substrates using a spin coater. A lab-made soft-mold roller embossing device equipped with a UV light source was adopted. A casting method was employed to replicate the nanofeatured template onto polydimethylsiloxane, which was used as the soft mold. During the embossing procedure, the roller was driven by a step motor and compressed the UV-curable resin against the glass substrate to form the nanofeatured layer, which was subsequently cured by UV radiation. Polymer films with nanoscaled features were thus obtained. The influence of distinct processing variables on the reproducibility of the nanofeatured films was explored. The empirical outcomes demonstrate that UV soft-mold roller embossing offers a simple yet potent way of producing nanofeatured films. Nanotechnology confines the understanding of the basic physics, chemistry, biology, and technology of nanoscaled objects, and has considerably improved various technical and industrial sectors including information, medicine, and energy, etc. . Amidst To fabricate nanofeatured films, several fabrication methods were proposed, including laser ablation, photolithography, micro-jet manufacture, and hot embossing, etc. . Amidst Nanocolloid lithography ,11 is a In this study, we report the fabrication of nanofeatured films using nanocolloid lithography and UV soft mold roller embossing, and show an illustrative example of their application to solar cells. To prepare the nanofeatured template, polystyrene nanospheres (900 and 300 nm) were overlaid on a silicon substrate employing a spin coater. A soft-mold roller embossing device equipped with a UV exposure source previously built in our lab was adopted. A casting method was also employed to replicate the nanofeatured template onto polydimethylsiloxane, which was used as the soft mold. During the embossing procedure, the roller was driven by a step motor and compressed the UV-curable resin against the glass substrate to form the nanofeatured layer, which was subsequently cured by UV radiation. Polymer films with nanofeatured surfaces were obtained. The replicability and the surface roughness of embossed films were characterized. Additionally, the influence of distinct processing variables on duplicated film quality was evaluated.Commercially available polystyrene colloidal nanospheres with two distinct sizes (900 and 300 nm) were acquired from micro-Particles GmbH. Ethanol was purchased from Sigma-Aldrich, St. Louis, MO, USA. The polydimethylsiloxane (PDMS) pre-polymer solution (Model SYLGARD 184) and cross-linker were purchased from Dow Corning, Midland, MI, USA. Dispersant (Model DS-UPS-Aw series) was obtained from Golden Innovation Business Co, Taipei, Taiwan, while ultraviolet curable epoxy resin (Model FL171-10) was acquired from Everwide Chemical Co, Taipei, Taiwan. In addition, hexane was purchased from JT-Baker, Phillipsburg, NJ, USA.v/v) was used, while the ratio of surfactant solution to 300 nm nanosphere in a ratio of 1:2 (w/w) was adopted.To self-assemble the colloidal array, 300 nm nanosphere latex was overlaid on a silicon substrate (6.5 cm by 11.5 cm) employing a spin coater . Some test trials were completed so as to identify the optimum processing conditions. As shown in The spin coating of the 900 nm colloid array followed the same scheme for that of the 300 nm, except that a multi-stage spin coating was utilized, for example, the substrate was subject to a spin speed of 500 rpm for 30 s followed by a spin speed of 1500 rpm for 30 s and a spin speed of 2000 rpm for 60 s. w/w), while the ratio of PDMS to hexane was either 2:1, 1:1, 1:2, or 1:5 (w/w). After curing, the PDMS mold was exfoliated from the template. The mold with a nanocavity array was placed into acetonitrile and subject to sonication for 30 min to remove the residual PS spheres stuck on the mold. A soft mold (a dimension of 1 × 1 cm2 and a thickness of 0.5 cm) with nanocavities was thus obtained.The soft mold was obtained by pouring the polydimethylsiloxane (PDMS) pre-polymer solution (Dow Corning SYLGARD 184) onto the nanosphere arrays, which acted as a template. The ratio of PDMS pre-polymer solution to cross-linker was 10:1  were adopted for the roller embossing procedure. The distance of 0 mm denotes a mild contact while a negative distance indicates interference between the roller stamp and glass substrate. Furthermore, the distance between the roller stamp and the liquid photopolymer container below the roller could also be altered via the Z-stage.In the embossing procedure, the UV curable epoxy resin with a refractive index 1.45 at a wavelength of 365 nm and a viscosity of 320 to 470 cps at 25 °C was first kept in the container. As the roller stamp rotated, the stamp (soft mold) came into contact with the UV-curable resin, and the liquid photopolymer was squeezed into the nanocavities of the mold on the roller. Once the roller was in contact with the glass substrate, a polymer film with nanofeatures was then formed on the substrate post-UV radiation. After being peeled off of the glass substrate, nanofeatured films were obtained.The influence of weight percentage of dispersant on the centrifuged 300 nm colloidal array is shown in The influence of weight percentage of dispersant on the centrifuged 900 nm colloidal array is shown in With a combination of proper processing conditions, namely a dispersant content of 7%, a spin speed of 3000 rpm, and a spin time of 30 s for the 300 nm nanocolloids, and a dispersant content of 7% and spin conditions of 500 rpm for 30 s followed by 1500 rpm for 30 s, and 2000 rpm for 60 s for the 900 nm nanocolloids, nanosphere arrays of 300 and 900 nm with good dimensional uniformity could be obtained. The arrays were characterized by an atomic force microscope (AFM), and The influence of PDMS to hexane ratio on nanocavity replication on the soft mold was examined. The average surface roughnesses (Ra) for 300 and 900 nm soft molds in B were 17The influence of distinct processing variables, including table moving speed, distance between the roller stamp and the glass substrate, and UV dose, on the formation of the surface nanostructures were evaluated. The influence of the roller stamp/glass substrate distance was examined and shown in The influence of various UV doses on film quality was also evaluated. The experimental result in By adopting the optimum conditions, 300 and 900 nm nanofeatured films were successfully embossed. The average surface roughnesses (Ra) for 300 and 900 nm nanofeatured films . This paper adopted nanosphere lithography and UV roller embossing technology for the manufacturing of polymer films with nanofeatures. The influence of various spin coating parameters on the assembly of nanocolloid arrays was explored. Furthermore, the effects of distinct processing variables on the replicability of nanofeatures onto the polymeric films were also evaluated. By adopting the appropriate processing conditions, polymer films with arrays of 900 and 300 nm nanostructures were satisfactorily manufactured. The hydrophobicity of embossed films was enhanced with the nanofeatures. In addition, all polymeric films with nanofeatures exhibit greater energy conversion efficiency of solar cells than the flat films. The 300 nm featured films also show higher conversion efficiency than the 900 nm films. The empirical outcomes in this work demonstrate that UV soft mold roller embossing offers an effective way of producing nanofeatured films employing low pressure at room temperature. This method will offer considerable advantages with regard to a shorter processing time and enhanced part quality.


Rhodococcus equi-related pulmonary malakoplakia is a rare condition with few reported cases; hereby, we present a case associated with advanced human immunodeficiency virus (HIV) infection, and thus far to our knowledge, the first report in Mexico. It is estimated that approximately 10% of the infections occur in immunocompetent patients, whereas the rest are immune deficient, targeting virtually any organ. Histologically, malakoplakia is characterized by the buildup of infiltrated inflammatory tissue as a consequence of the gathering of histiocytes embedded with concentric inclusions. The diagnosis relies on the cultures and the susceptibility testing as well as the pathologic findings compatible with the disease. Case Presentation. We present a 25-year-old male patient with persistent nonproductive cough for over a year and with weight loss, who comes to the emergency department with recent fever, swollen and tender lymph nodes, and hemoptysis. The patient gets diagnosed and treated for Rhodococcus equi-related pulmonary malakoplakia. Rhodococcus in HIV is fundamental for the diagnosis and optimal treatment, which although unknown, a combination of antibiotics with intracellular penetration, on-time resection, and a proper immune reconstitution represents the best approach. Prognosis varies with mortality rates from 34% to 54%. Knowing the involvement of  Malakoplakia is a rare condition, histologically characterized by the buildup of infiltrated inflammatory tissue as a consequence of the gathering of histiocytes embedded with concentric inclusions known as Michaelis–Gutmann bodies, as well as the abnormal proliferation of macrophages within, forming a plaque known as xanthogranulomatous inflammation.It is mostly appreciated as an infectious process that results in an acquired lysosomal impairment and a flawed elimination of ingested pathogens . The resMycobacterium tuberculosis, Pasteurella multocida, Escherichia coli, Tropheryma whipplei, cytomegalovirus (CMV), and human simplex virus 2 (HSV2), the most commonly associated pathogen is thought to be Rhodococcus ssp. [Although malakoplakia pseudotumor has been seen as a result of different kinds of infection such as cus ssp. .Rhodococcus equi previously known as Corynebacterium equi was first isolated in 1923, and not until 1967, it was reported in human beings for the first time. The microorganism is most commonly seen in a variety of land and water animals including, but not limited to, cattle, swine, reptiles, and birds. It can be found in any continent except for Antarctica, and it has the capacity to proliferate in freshwater, marine environments, and within the gastrointestinal system of arthropods. The means by which the infection can be acquired by humans is through inhaling the bacteria or direct inoculation to an open wound or a permeable mucosa that comes in contact with it, predominantly in immunocompromised hosts [ed hosts .Rhodococcus come from animal models, where several mechanisms of pathogenicity mediated by proteins of variable virulence have been found even within species and depending upon the host and its immunological status. In vitro observations have identified the presence of IL4 and INF-y and the formation on granulomas as part of the mechanism [The vast majority of studies made in regards to echanism .A 25-year-old male patient from Tabasco, a tropical southern state in Mexico, presented with persistent nonproductive cough and weight loss of more than 10% its normal weight as chief complaints. He mentioned having the symptoms for a year, denying fever, shortness of breath, or other constitutional symptoms.He allegedly started with whitish sputum, later mild hemoptysis (specks of blood) together with fever quantified above 102.2°F and resting dyspnea occurred until he reached for medical attention in a local hospital where a chest X-ray was taken, showing a total left atelectasis. The patient was later transferred to the National Institute of Respiratory Diseases (INER), a specialized referral center in Mexico city.Additional medical history included MSM practices, occasionally with no protection. The patient denied the use of alcohol, illicit drugs, or nicotine, and he denied having followed the adult immunization schedule. He mentioned having no contact with domesticated or undomesticated animals whatsoever.On admission, physical examination revealed a temperature of 102.7°F, a heart rate of 120 beats per minute, and a respiratory rate of 30 breathes per minute. The patient presented oral candidiasis and had multiple purple lesions with elevated borders affecting the skin and palate, with bilateral cervical nontender, indurated swollen lymph nodes. A hyperdynamic precordium was identified, with asymmetric chest expansion, diminished respiratory sounds, and fremitus as well as a flat sound on percussion.μL (lymphocytes 300/μL), and platelets 183,000. Liver and renal function test appeared within normal rage, creatinine 0.6 mg/dl, AST 35 UI/L, ALT p26 UI/L, LDH 241 UI/L, ALP 93 UI/L, procalcitonin 0.84 μg/L, and arterial blood gasses: pH 7.45, PCO2-26.4, PO2-51.6, HCO3-18, EB-(−)4.2, AG-21.1, SAT-82.7%, FiO2-27, and Lac-0.9.His complete blood count on admission presented a normocytic-normochromic anemia of Hb10.4 g/dL , Hct32.1%, leucocytes 6.500/μL (2%) and a viral load of 126,916 copies/ml (log5.1) and tested negative for hepatitis B and C screening.The patient tested positive for HIV , as well as for HHV8, with CD4 of 7 cells/The CT scan showed bilateral pleural effusion  with an Rhodococcus equi using a Biomerieux in vitro diagnostic technique. The antibiogram showed the microorganism to be TMP/SMX resistant, quinolone sensible, rifampicin sensible, and vancomycin sensible. The rest of the cultures were negative for other bacteria, mycobacteria, and fungus. Bronchioloalveolar lavage cultures turned positive for Rhodococcus equi too.Blood cultures on admission turned positive for Gram-positive, catalase-positive, CAMP-positive coccobacillus compatible with The histopathological report of the transbronchial biopsy  shows a Besides, several skin and cervical lymph node biopsies were done resulting in Kaposi sarcoma, for which the patient received management with liposomal doxorubicin.Two weeks after admission, the patient started HAART with the EFV/TDF/TFC regimen.A combination with vancomycin 1 gr IV b.i.d and rifampicin 600 mg PO q.d. antibiotic scheme was used for 3 weeks and then was changed to ciprofloxacin 750 mg PO b.i.d. and rifampicin for 3 months more, given the chosen scheme. At the time of this report, the patient showed a fine recovery from the malakoplakia with full radiologic and symptomatic remission and a viral control at 6 months with considerable adherence to treatment. Thus far, no other intervention was required and the patient referred going back to his normal lifestyle.Even though there are few reported cases, therefore lack of research, it is estimated that approximately 10% of the infections occur in immunocompetent patients, whereas the rest are immune deficient, mainly patients with HIV .Therefore, the majority of infections has something to do with patients with defects in cell-mediated immunity, with a history of contact with farm animals .The key features depend mainly upon the immune state of the host, as well as the inoculum that the subject comes in contact with, as well as the risk factors involved. Symptoms can vary from those resembling cavitary pneumonia with hilar lymphadenopathy to that of intraluminal mass , which iWhen the infection occurs in the lungs, 40% of the cases in immunocompromised hosts , the disThe diagnosis, however, relies on the cultures and the susceptibility testing as well as the pathologic findings compatible with the disease, typically necrotic with dense histiocytic infiltrates with an eosinophilic, granular cytoplasm and intrahistiocytic coccobacilli. Serologic assays have not been clinically validated and are not commercially available .Radiographic presentation of the infection most of the times appear to be cavitary upper lobe pneumonia, frequently misdiagnosed as pulmonary tuberculosis , 7. LessRhodococcus equi infections in these people, showing that the main independent predictor factors of mortality were the absence of highly active antiretroviral therapy (HAART), extensive pulmonary disease (multilobar infiltrates), and the inappropriate choice of antibiotic treatment [Given the advent of the HIV epidemic, studies have been made regarding reatment . A summaet al. supported in 2002 that effective HAART therapy and a short course of antibiotic therapy including levofloxacin can resolve Rhodococcus equi pneumonia without surgery in spite of a slow immune reconstitution [The treatment for this condition varies in some of the articles published and recommendations. Nonetheless, it is of great importance to accurately establish the most efficient treatment in each case, with sensitivity profiles, in order to prevent and bypass all complication foreseen, given that the prognosis of this condition might worsen very easily. Generally, for the optimal treatment, although unknown, it is a combination of antibiotics with intracellular penetration, and sometimes prolong schemes with quinolones, rifampin, macrolides, tetracycline, or a combination for systemic disease, with adequate on-time surgical resection, as CD4 T helpers type 1 cells, are needed and frequently underperformed on HIV-infected individuals , 18. OthRhodococcus-associated malakoplakia in all unresolved pneumonia cases with nonneoplastic lung tumoral mass since the course of the disease in immunocompromised patients could be fatal.Given the low incidence of this disease, the clinician requires high skills and acuity for suspecting Specific goals in achieving healing and a successful treatment include three main aspects: (1) combined and prolonged use of sensitivity-proven antibiotics of intracellular penetration, (2) precise surgical evaluation for on-time resection for patients who do not respond adequately to antibiotic therapy, and (3) efficient immune reconstitution with the adequate use of antiretroviral therapy.In this case, our patient had a satisfactory recovery under a treatment based on rifampicin and ciprofloxacin over a period of 6 months, plus an optimal virologic control with HAART.Rhodococcus-associated pulmonary malakoplakia in an uwnusual presentation of an uncommonly reported disease; this evidence serves for the record in advance HIV infection. Up to this point, according to the literature revised, this is the first reported case in Mexico and one of the few around the world.More information and research are needed in this topic since this paper is just limited to the current literature and based on the findings on one single patient.


Headache is a common reason to visit the emergency department (ED). Tension-type headache (TTH) is the commonest headache. The diagnosis of TTH implies a mild condition, with no need for special tests. We evaluated the use of the International Classification of Headache Disorders (ICHD) criteria for TTH in the ED. We performed a cross-sectional study including all ED patients with a definite TTH diagnosis in their discharge report for 2.5 years. We evaluated whether the ICHD criteria for TTH were referenced and met. We analysed discrepancies concerning anamnesis or prior history and reclassified patients. A total of 211 out of 2132 patients fulfilled the criteria (9.9%). Only five patients fulfilled TTH criteria. Criteria A-D were referenced in 60–84% of patients and met in 16–74% of these patients. Anamnesis was discrepant in 87.5% as was prior history in 20.8%. After re-reclassification, 21 patients fulfilled the criteria for TTH (five) or probable TTH (16). In 106 patients, another headache was diagnosed, with migraine in 40 (18.9%), secondary headache in 64 (30.3%), and a life-threatening disorder in 13 (6.1%). In our sample, TTH was overdiagnosed. Only a minority of patients fulfilled the ICHD criteria. Inconsistencies in prior medical history or anamnesis were frequent. The prevalence of TTH is estimated to be between 30 and 70% of the general population according to different studies2. The diagnostic criteria proposed by the International Classification of Headache Disorders (ICHD) have remained unaltered since the first edition in 19886. The criteria are based on bilateral, oppressive and mild pain, without typical migraine features and with no better explanation6. Given the mild nature of the disorder, few patients seek assistance, and in headache unit-based series, it is not a frequent diagnosis, accounting for 16% of all diagnoses7. On the other hand, it is not uncommon for migraine patients to be erroneously diagnosed with TTH8.Tension-type headache (TTH) is the most common primary headache disorder10 particularly when other series are performed by neurologists or using ICHD criteria diagnosis, TTH represents only 1–6% of total headache patients15. In the ED setting, secondary headache detection represents the main priority. TTH is particularly threatening, as its typical phenotype is relatively unspecific, and many secondary headaches may mimic it.Headache is one of the main reasons for consultation in the emergency department (ED). It seems remarkable that in some ED-based series, TTH diagnosis accounts for up to 25–33% of all headache visits;16. However, we hypothesize that TTH is probably overdiagnosed in the ED setting, which might represent a risk for patients with nondetected secondary headaches. Establishing TTH diagnosis might be dangerous, as it implies that the patient has a harmless disorder.The use and knowledge of the ICHD criteria in the ED setting may be difficult. Most clinicians use red flag lists to rule out secondary headaches6 criteria for tension-type headache and the percentage of patients presenting each of the different criteria. The second objective was to analyse the presence of data in the discharge reports that contradicted TTH diagnosis, such as relevant prior medical data, atypical symptoms or abnormal findings in the examination. The third objective was to analyse whether patients could be re-classified as having other headache disorders by using the ICHD-3 criteria.In this study, the first objective was to analyse the percentage of patients who fulfilled the ICHD17.This is an observational study with a cross-sectional design. Our study population included patients who visited the emergency department due to headache. The study was performed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelinesThe study took place at the ED of the Clínico San Carlos University Hospital, Madrid (Spain), a third-level hospital with a reference population of 700.000 people. The study period was between January 2012 and July 2014.The inclusion criteria were as follows: 1) patients visiting the ED because of headache and 2) patients with a definite diagnosis of “tension-type headache” in the ED discharge report. We excluded patients with 1) some degree of uncertainty in the diagnosis, such as “possible” or “probable”; 2) another headache diagnosed at the same time; and 3) no available information in the patient chart.We screened all the patients who visited the ED during the study period because of headache by using the ED database, which codifies patients by initial reason for consultation. We reviewed the digitalized reports and gathered the information from the discharge reports. We did not review any additional sources, and we did not evaluate any patients. The rationale for this was that we aimed to see if with the information present in the ED reports, TTH diagnosis was appropriate or not.The included demographic variables were sex; age; and relevant prior medical history, including current or past cancer, pathology of the immune system, and prior headache history. Clinical variables included headache description, with special attention to the presence of any red flag, neurological examination and abnormal focal signs, vital signs and general examination.6 .For the first objective, we reviewed the ICHD criteria for TTH6 Table . We analsymptoms highly suggestive of another headache disorder, including pulsating quality, presence of both photophobia and phonophobia, worsening with exercise, cervical topography, neuralgiform pain, or highly localized pain.Presence of abnormal neurological symptoms or signs, such as aphasia, dysarthria, sensory disturbances, paresis, visual symptoms, vertigo, instability, and papilledema.Presence of red flags related to the headache description, such as thunderclap onset, severe intensity (>9/10), progressive worsening, recent onset, worsening with Valsalva manoeuvre, precipitation by exercise, and refractoriness to appropriate treatment.Presence of Systemic symptoms, such as fever, chest pain, abdominal pain, arthralgia, diarrhoea, urethral syndrome, and localized ocular pain.Close temporal relation with an event able to produce headache, including cranial trauma, high blood pressure, lumbar puncture, and cranial surgery.For the second objective, we analysed discrepancies concerning both anamnesis and prior medical history. Anamnesis discrepancies were classified into five groups:prior medical history included prior headache disorders, cancer affecting encephalic structures, sinus disease, ophthalmological diseases able to produce ocular pain, sleep apnoea syndrome, and any other intra- or extracranial conditions able to produce headache.Discrepancies in For the third objective, two headache specialists  independently reviewed each case and analysed the information present in the discharge reports. With that information, when possible, patients were re-assessed according to ICHD-3 (77). In case of discrepancies, a third headache specialist (JPE) solved the disputes.We also evaluated the management of patients. We determined the total duration of the emergency department stay, from when the patient was admitted to discharge. We analysed whether patients had been examined, specifically reviewing whether fundoscopy had been done. Complementary exam referrals were also addressed, including lumbar puncture, cranial tomography (CT), X-ray, and laboratory exams. Management at discharge was reviewed, inspecting if any treatment had been prescribed and if patients were referred to the neurological department. We compared whether patients who had undergone neurological exams or complementary exams had a longer stay and if they were more often diagnosed correctly.The local ethics committee board approved the study. The study was performed according to the principles of the Declaration of Helsinki. Informed consent was obtained from all the participants.Qualitative variables are presented as frequencies and percentages. Quantitative variables are presented as the means and standard deviations (sds) or medians and interquartile ranges (IQRs) in the case of a nonnormal distribution. Normality was tested by using the Kolmogorov-Smirnov test. The first three endpoints did not include statistical analysis and were based on descriptive qualitative data. As we analysed only patients with a definite TTH diagnosis, we only determined the positive predictive value of TTH diagnosis. In the analysis of the management of patients, for the comparison of qualitative variables, we used the chi squared test. When comparing two continuous variables, we used Student’s t test if a normal distribution was shown in the Kolmogorov-Smirnov test, and we used the Kruskal-Wallis test if the data were not normally distributed. We considered a p-value as significant if it was lower than 0.05 and specified degrees of freedom (df). In case of missing data, we performed complete-case analysis. We did not anticipate any sample size a priori but included all possible patients during the study period.The Clinical Research Ethics Committee of Hospital Clínico San Carlos approved the study. Informed consent forms were obtained from the participants.All authors gave their consent for publication.During the study period, 2132 patients visited the ED because of headache. The inclusion/exclusion criteria were satisfied by 211 patients , and these patients were included in the study. The median age of the patients was 42.6 years [30.9–57.3], and 75.6% were female.Only five patients fulfilled all ICHD criteria for TTH (2.4% of the included patients). The frequencies at which each criterion was referenced were as follows: criterion A was referenced in 81% of patients and fulfilled in 16% of patients, criterion B was referenced in 84% of patients and fulfilled in 74% of patients, criterion C was mentioned in 72% of patients and fulfilled in 43% of patients, and criterion D was referenced in 60% of patients and fulfilled in 56% of patients. Figure There was at least one discrepancy in regard to anamnesis in 184 patients (87.2%). Symptoms suggestive of another headache disorder were present in 131 subjects (62.1%); 87 patients (41.2%) described other neurological symptoms; red flags were identified in 55 patients (26.1%); 57 subjects (27.0%) also reported systemic symptoms; and in 31 patients (14.6%), an event able to produce headache was described.Concerning events related to headache onset, in 12 patients, traumatic injury to the head had occurred in the prior 7 days and was mentioned by patients; in 11 patients, an acute increase in blood pressure (BP) over 180/140 was documented, with cessation of headache after proper BP management; in three patients, headache started after dental manipulation with no prior history of headache; in two patients, headache began after the use of corticosteroids or amisulpride and olanzapine; in two patients, headache started after lumbar puncture; and in one patient, an intracranial aneurism was embolized the same day the headache started.Regarding prior medical history, 44 patients (20.85%) had some condition able to produce headache. In 17 patients, a prior history of migraine was present. Those patients referred to an unchanged headache phenotype that was resistant to treatment; nine patients had acute sinusitis, four patients had painful ophthalmological conditions , three patients had cerebral and arteriovenous malformation, two patients had a recent history of subarachnoid haemorrhage, two patients had a history of intracranial cerebrospinal fluid (CSF) hypotension, one patient had cerebellar haemangioblastoma, one patient had Erdheim-Chester disease, one patient had a history of temporal arteritis, one patient had a history of occipital neuralgia, one patient had sleep apnoea, one patient had intracranial aneurism and one patient had polycythaemia vera with hyperviscosity syndrome.After reviewing all the discharge reports, only 21 patients  fulfilled the ICHD-3 criteria for tension-type headache (five) or probable tension-type headache (16). The positive predictive value of TTH diagnosis was 0.099. In 106 patients, another ICHD-3 diagnosis was met (50.2% of patients). In 64 patients, a secondary headache was the final diagnosis (30.3%), with 13 having high-risk secondary headaches (6.1%). Figure The total duration of the ED visits, from admission to discharge, had a median length of 3.59 hours [IQR: 2.5–5.1], with a range between 0.35 and 19.10 hours. Neurological examination was described in the reports of 90.5% of patients and was abnormal in 6.8% of these patients. When the neurological exam was done, the duration of the ED visit was 4.0 hours vs. 3.9 hours when it was not done . Fundoscopy was performed in 10.9% of patients, and the results were normal in all cases.The diagnosis was more often appropriate in patients who underwent fundoscopy .Regarding complementary exams, laboratory exams were performed in 32.6% of patients. Laboratory exams including erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) were performed in 48.6% of patients older than 65 years old. Cranial CT was performed in 11.3% of patients, and cervical or sinus X-ray was performed in 12.7% of patients. Only 2 CT exams were abnormal, one exhibiting a vascular malformation and the other with acute inflammation of the frontal sinuses. Figure When complementary exams were performed, the mean duration of the stay increased from 3.28 to 4.94 hours . Requests for complementary exams were not associated with a higher probability of proper diagnosis . At discharge, 21.3% of patients were referred for a neurological examination. In 90% of the discharge reports, some acute medications were prescribed.The present study was performed in the emergency department setting. We systematically analysed a series of patients with definite TTH diagnosis according to whether the diagnostic criteria were mentioned and fulfilled in the discharge report. We screened the reports for the presence of data that would contradict TTH diagnosis, and finally, we tried to reclassify patients based on the information provided in the reports.The main findings of our study were that only a minority of patients, only 2.4% of the whole sample, fulfilled the ICHD criteria for TTH. In over 80% of patients, a discrepancy was found in the anamnesis, and in one-fifth of patients, prior medical history made TTH diagnosis unlikely. Finally, when we tried to reclassify patients, migraine diagnosis was two-times more frequent than TTH diagnosis. In almost 40% of patients, the information was not sufficient for a diagnosis, so in the best possible scenario, only half of patients with TTH diagnosis would have this condition, leading to a total percentage of 4.9% of the whole sample.6, the most frequently mentioned criterion was duration, followed by number of episodes and phenotype. The most surprising data were that criterion A, describing the number of episodes, was mentioned in 81% of cases, but it was only fulfilled in 16% of cases. This fact may reflect the idea that many patients visit the emergency department due to recent-onset headaches. New onset headache and progressive worsening are two of the main red flags18. In patients with primary headaches, a previous history of similar unchanged attacks might constitute a green flag.Concerning the ICHD criteria3, attempt to differentiate TTH from the other main primary headache, migraine. The criteria include positive, negative and exclusion criteria. The positive criteria describe the typical characteristics of TTH: bilateral, pressing, and relatively mild. The negative criteria rule out the presence of typical migraine features, such as nausea, vomiting, photophobia and phonophobia or worsening as a result of activity. Finally, as in every ICHD diagnosis, the condition should not be better described by any other diagnosis. In the literature, some series have diagnosed TTH in 53% of patients with nausea19. Other series included patients who were diagnosed with TTH who had pulsating (23.8%) and hemicranial headaches (20.1%)20.The ICHD Criteria for TTH, unchanged since the first edition8. Misdiagnosis might be related to the classification of patients based on pain phenotype; however, headache diagnosis should be performed by integrating prior medical history, headache anamnesis, presence of other symptoms and neurological examination, not solely by headache phenotype21.The typical TTH phenotype is probably the most unspecific, and many conditions might have similar features, such as migraine, hemicrania continua, primary cough headache, primary exercise headache, primary headache associated with sexual activity, external-pressure headache, hypnic headache, new daily persistent headache and the vast majority of secondary headache disorders6. Some of these names may suggest a psychogenic cause. Currently, we consider stress and affective disorders a cause of worsening or a trigger rather than the cause of headache23.The confusion surrounding TTH diagnosis might be partly influenced by the many names that have been used to describe this condition: tension headache, muscle contraction headache, psychomyogenic headache, stress headache, ordinary headache, essential headache, idiopathic headache, or psychogenic headache18.Medical attention at the emergency department usually prioritizes the detection of life-threatening conditions. The frequent saturation, rush and wide variety of conditions complicate the thorough and meticulous anamnesis that headache disorders require. In our sample, 30% of patients had a secondary headache, and 5% of patients had a secondary headache with potential morbimortality. In a previous series, up to 10% of patients diagnosed with TTH had an abnormal examination18. Some rules16 and lists of red flags have been proposed to detect secondary headaches24. CT and lumbar puncture, although frequently requested26, do not always rule out many entities, such as cerebral venous sinus thrombosis, intracranial space-occupying lesions, or cerebrospinal fluid pressure disorders.One of the biggest needs in the headache field is the development of reliable biomarkers. Unlike other painful syndromes, such as chest or abdominal pain, we still base our diagnosis on anamnesis and neurological examination18 therefore, all ED physicians should be trained in headache medicine. In our sample, just a minority of patients underwent fundoscopy, and in many cases, even plain X-ray was requested. The use of lab tests was not properly selected for elderly patients, as less than half of the patients had an ESR or CRP exam.Headache is one of the leading reasons for consultation, accounting for 2.3% of all ED visits;27. In those cases, it is important to note that declaring a primary headache disorder without certainty might implicate the end of the diagnostic work-up and a higher risk of complications. In case of doubt, final diagnosis should be “possible” or “headache not otherwise specified”24.Sometimes an accurate diagnosis cannot be made; in our study, up to 38% of patients had an unspecific diagnosis, with this figure reaching 38–45% in the literature13.The consequences of inaccurate diagnosis are the risk of morbimortality among patients, inappropriate use of diagnostic resources, and the potential cost of establishing the proper diagnosis. Treatment of different secondary headaches differs widely, and in many conditions, prognosis is correlated with a prompt and proper treatment, as in the case of temporal arteritis, cerebral venous sinus thrombosis, or central nervous system infections29, it is seldom treated in headache outpatient clinics30, and some authors even suggest that patients diagnosed with TTH suffer from improperly diagnosed migraines in at least one-third of the cases32. Research on TTH and knowledge about its pathophysiology are also scarcer than those of other primary headaches, such as cluster headache or migraine33.Although tension-type headache is supposed to be the most prevalent primary headache disorder22, and when patients complain of stress or mood disorders, TTH diagnosis is often made. It is well known that primary headache disorders are associated with significant personal, societal and familiar burdens30.In many cases, TTH has been related to psychosocial factors2 in the general population, but in the ED setting, it is important to clarify whether the headache that motivated the consult has changed, worsened progressively, resisted treatment or had new features. With regard to prior medical history, in our sample, one-fifth of the patients had conditions able to produce headaches, and 8% of the subjects were migraineurs. It is well known that chronic migraine exhibits a less typical phenotype, and some of the episodes might resemble TTH episodes34. In the diagnosis of chronic migraine, only 8 out of the minimum 15 headaches per month are needed to fulfil the migraine without or with aura criteria6.The pre-test probability of having TTH is 60–70%The main limitations of the present study are the participation of a single centre, which might affect the generalizability of the results. Because of the design of the study, some data could have been asked and evaluated but not written; however, from a legal perspective, non-written data did not “occur”. The re-classification was performed without evaluating patients; therefore, there was potential for misclassification, and we used the current ICHD instead of the two editions valid during the study period (ICHD-2 and ICHD-3 beta). We did not follow up with patients to confirm the final diagnosis. The strengths of the study are the thorough review of every patient chart, the participation of headache experts and the three different analyses performed.In our sample, TTH was overdiagnosed in an emergency department, as only 2.4% of the patients fulfilled all ICHD criteria for TTH. Inconsistencies in prior medical history or anamnesis were present in the discharge reports in one-fifth and four-fifths of patients, respectively. Our analysis of medical records allowed us to reclassify these patients as having other primary or secondary headaches. Efforts to improve knowledge on headache disorders and ICHD are needed among ED physicians.Supplementary material 1.


Coriandrum sativum seed extract (CSSE) can ameliorate memory impairment in senescence-accelerated mouse-prone 8 (SAMP8) mice. Sixteen 10-week-old male SAMP8 mice were divided into two groups, which were orally administrated water (SAMP8(−)) or CSSE ). Eight 10-week-old male Institute of Cancer Research (ICR) mice were used as a normal control group and were also orally administrated water. The mean escape time in the Barnes maze test of SAMP8(−) mice was significantly longer than that of ICR mice. However, SAMP8(+) mice showed a shorter mean escape time compared to that of SAMP8(−) mice. Neurofilament messenger (m)RNA levels significantly decreased in the frontal lobe of SAMP8(−) mice when compared with ICR mice, but significantly increased in SAMP8(+) mice relative to SAMP8(−) mice. In addition, mRNA levels of inducible nitric oxide synthase (iNOS) and neuronal (n)NOS significantly increased in the frontal lobe of SAMP8(−) mice, but only the mRNA level of nNOS significantly decreased in SAMP8(+) mice. These results indicated that continuous oral administration of CSSE for 12 weeks could ameliorate aging-induced memory declines in the senescence-accelerated SAMP8 mouse model.The purpose of this study was to investigate whether or not  In 2017, the global population aged 60 years or over was 962 million and is expected to double by 2050 . The maiCoriandrum sativum (CS) is utilized not only as a medicinal herb belonging to the Apiaceae (Umbellifera) family in Iran and Egypt, but also as an edible vegetable in Asian countries, such as Japan and Taiwan [d Taiwan . All pard Taiwan . Severald Taiwan , hypolipd Taiwan , and antd Taiwan  and sedad Taiwan . On the d Taiwan . The repd Taiwan ,17. Mored Taiwan . Thus, Cd Taiwan .Therefore, it was hypothesized that seeds of CS might also have a similar effect as leaves that could ameliorate degenerative brain diseases by decreasing oxidative stress caused by ageing. In this study, the senescence-accelerated mouse-prone 8 (SAMP8), which is a naturally occurring mouse line that displays a phenotype of accelerated aging, was used to explore this hypothesis.A total of 8 10-week-old male Institute of Cancer Research (ICR) mice  and 16 10-week-old male SAMP8 mice  were used in this study. Mice were individually housed in temperature-controlled cages at 24 ± 1 °C and 55% humidity with a 12-h light-dark cycle. Mice were allowed free access to a standard rodent diet  and water during the entire experimental period. All procedures were approved by the Institutional Animal Care and Use Committee of Yokohama University of Pharmacy (2017-010).Coriandrum sativum seed extract (CSSE)  at random. The administration method for CSSE was according to Sukura et al. [After acclimation for 1 week, SAMP8 mice were divided into two groups with (SAMP8(+) group) and without (SAMP8(−) group) oral administration of a et al. . As in oDuring the 12-week experimental period, the BW of each mouse was measured twice a week. Furthermore, the senescence of SAMP8 mice was evaluated according to a grading system comprising the following seven items in three categories: behaviors (reactivity and passivity), skin and hair , and spine (lordokyphosis) ,21,22. “Two weeks before the end of the experiment, spatial learning and memory were evaluated using a Barnes maze test. The instrument  has a diameter of 455 mm, a height of 920 mm, and 20 holes with diameters of 25 mm, located 30 mm from the edge of the platform. The escape box has a width of 130 mm, a depth of 95 mm, and a height of 50 mm. The brightness of the maze was evenly set to 750 Lx. The maze was surrounded by partitions with three visible patterns on them, such as triangle, double-circle, and star patterns. After each mouse finished the test, the platform was cleaned with a 10% ethanol solution. To avoid visible and olfactory trails in the maze, the platform was turned once a day. The entire process was recorded by a digital hi-vision camera .th week, a repetitive learning test was performed. A mouse was placed in a cylinder (starter tube) with a diameter of 38 mm, a height of 73 mm, and a gray color. After 20 s, the starter tube was removed, and the mouse was given 2 min to search for the escape box. The escape time, i.e., the time to find the correct hole for the escape box, was measured. If the mouse did not find the escape box within 2 min, it was guided by a glass beaker and entered the escape box. After that, the mouse was kept in the escape box for 60 s before being returned to its cage. The test was executed four times a day for 4 days. If the mouse did not immediately enter the escape box after it had found the correct hole, 10 s was added to its time. The rate of change of the escape time was calculated on days 1, 2, and 4.In the 10A probe trail was executed 2 weeks after the spatial memory test, which was also the day before sacrifice. The escape box was removed, and the test mouse was placed in the cylinder for 20 s. After 20 s had passed, the cylinder was removed, and the mouse was given 2 min to search for the target hole. The mouse was returned to its cage after the test. In the probe trial, the Barnes maze was divided into four zones. The mouse was placed in the maze within 60 s, and the time to discover each zone was recorded. The correct rate was calculated using the following formula:Zone 4 (time in seconds or travel distance)/Zone (1+2+3+4) (time in seconds or travel distance).g for 15 min at 4 °C) to obtain plasma samples. Furthermore, brain tissues were rapidly excised and the frontal lobe and hippocampus were removed. All samples were stored at −80 °C for further measurements as described here.All mice were sacrificed at the end of week 12 of the experiment. Blood samples were collected in heparin-containing tubes and centrifuged  was used to determine the activities of superoxide dismutase (SOD) in plasma as measured by the inhibition of formazan dye formation.Total RNA in the frontal lobe and hippocampus was extracted by the addition of POLYTRON PT 1300 D  with Isogen , according to the manufacturer’s instructions, with minor modifications as described in a previous study . The RNAp < 0.05 or p < 0.01 levels. Results were analyzed using Stat View 5.0 statistical software .All values are expressed as mean ± standard error of the mean (SEM). Statistical significance was assessed using a one-way analysis of variance (ANOVA), followed by Fisher’s protected least significant difference (PLSD) test, and was accepted at the Changes in the final BW and appearance in each group are shown in As shown in The performance on the probe trial is shown in SOD activity in each group is shown as As shown in SAMP8 mice have been widely used in aging research to study such phenotypes as immune dysfunction, osteoporosis, and brain atrophy. It has been verified that SAMP8 mouse exhibit moderate to severe degrees of activity loss, hair loss, and lordokyphosis, and also aging-associated behavioral impairments, including learning and memory difficulties ,21,22,23As shown in When SAMP8 mice were supplemented with CSSE (SAMP8(+) mice), BW reductions and appearance changes were also seen . TreatmeAs shown as the result of the spatial memory test, mice in the SAMP8(−) group had longer escape times than ICR mice on days 1, 2, and 4, but the escape time was significantly shortened after CSSE supplementation . AccordiMemory retention is affected by synaptic plasticity, which is related to a variety of proteins, such as apoE, and NF-L ,33,34,35The damage of hippocampus and frontal lobes is the risk factor of AD, since these two parts of the brain contribute to episodic memory performance. In this study, the NF-L mRNA levels in the frontal lobe and hippocampus were significantly lower in SAMP8 mice without treatment a. TogethIn this study, mice in the SAMP8(−) group showed significantly higher mRNA levels of nNOS in the frontal lobe compared to ICR mice a. OverprOn the other hand, in this study, changes in related biomarkers were found in the frontal lobe, but not in the hippocampus. The brain is divided into areas that are each responsible for different areas of functioning. The frontal lobes are involved in executive function, memory, and social behavior, while the hippocampus is mainly associated with memory, particularly long-term memory, which plays an important role in spatial navigation. Miyamoto et al. indicated that significant hippocampus-related memory impairment was observed in SAMP8 mice after 12 months (48 weeks old) of age [Patel et al. indicated that CSSE is nontoxic at up to 3000 mg/kg BW and can be considered safe for consumption . PreviouCoriandrum sativum seed extract and their effects on memory impairment in SAMP8 mice.There are some limitations in this study. First, only using Barnes maze test is not sufficient to validate the behavioral outcome in this study. More animal behavior trials are necessary. However, although many behavioral tests for evaluating the anti-amnesia have been reported, most of these tests must be considered other factors, such as stress, smell, anxiety, and fear. In most case of early senile dementia, the loss of spatial memory can appear. Therefore, the Barnes maze test is suitable for seeking the early senile dementia, at present. Second, more biomarkers should be measured , as well as antioxidative-related biomarkers in the brain and plasma . Third, SAMP8 mice were still in the early stage at the end of the experiment, which may have resulted in inconspicuous improvements in hippocampal damage by CSSE. Extension of the experimental period is necessary in future studies. Additionally, further studies also need to separate and identify the active components in Coriandrum sativum seed extract (200 mg/kg BW) exhibited ameliorative effects on memory impairment in SAMP8 mice. We speculated that the mechanisms involved in repairing memory deficits by Coriandrum sativum seed extract were associated with increased NF-L mRNA and decreased nNOS mRNA in the frontal lobe of the brain.This study demonstrated that administration of