Post-stroke shoulder pain (PSSP) is characterized by shoulder pain on the hemiplegic side, which can limit physical activity in patients with stroke. Acupuncture combined with rehabilitation training (AR) has been widely used in PSSP, but the evidence of its effectiveness is still unclear.The study aimed to evaluate the effect and safety of AR vs. rehabilitation training (RT) alone on PSSP.We searched PubMed, the Cochrane Library, the Chinese Biological Medicine Database (CBM), the Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI), and the WAN FANG database for relevant studies from their inception to February 2022. Only randomized controlled trials (RCTs) comparing the effect of AR with RT alone on PSSP were considered. The primary outcome was shoulder pain. Secondary outcomes included upper limb motor function, activities of daily living (ADL), shoulder range of motion (ROM), and adverse events (AEs). Subgroup analysis and sensitivity analysis were also conducted. Quality assessment was implemented based on Cochrane risk of bias (ROB) criteria, which consist of seven items. When more than four items in a study were judged as low ROB, the overall quality of this study was considered low risk.A total of 40 studies were included in the qualitative analysis, and 35 (87.5%) studies with 2,554 patients were included in the meta-analysis. Of the 40 studies, 14 (35.0%) were of moderate-to-high quality. The meta-analysis results showed that AR is better than RT alone in reducing shoulder pain , improving upper limb motor function , ADL , and shoulder ROM  without obvious AEs.AR may be better than RT alone for the improvement of shoulder pain, upper limb motor function, ADL, and shoulder ROM, without obvious AEs in patients with PSSP. However, considering the clinical and statistical heterogeneity, our findings need to be interpreted with caution. More rigorous RCTs in this area should be conducted in the future.www.crd.york.ac.uk], identifier [CRD42022326763].[ Post-stroke shoulder pain (PSSP) is a common complication of stroke, characterized by shoulder pain on the hemiplegic side –3. PSSP Rehabilitation training (RT) and symptomatic treatment  are the main intervention methods of PSSP , 17–20. In recent years, acupuncture has become an increasingly popular technique and is used worldwide for the management of pain, headache, musculoskeletal diseases, and other health problems . PreviouWe conducted this SR and MA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Only RCTs compared the efficacy of AR with RT alone on PSSP and published in Chinese or English were considered eligible for our MA. A total of six databases, such as PubMed and the Cochrane Library, were searched systematically from their inception to February 2022 for eligible studies. The protocol was registered in the International Prospective Register of Systematic Reviews (No. CRD42022326763). In this review, no ethical approval or patient consent was required because all data analyses were from previously published studies.We included all RCTs comparing the effectiveness of AR with RT alone for PSSP. The studies should be published in Chinese or English. We contacted the authors by email if there was any incomplete information, and studies were excluded if data remained incomplete. The studies would still be excluded if (1) the study compared the effect of different RT techniques, different acupuncture parameters, or different types of acupuncture; and (2) the study type is crossover trials, case reports, animal experiments, abstracts, thesis, or review articles.We included studies in which participants were diagnosed with ischemic or hemorrhagic stroke by recognized criteria or brain imaging technology . Studies were included if the participants in the study had hemiplegic shoulder pain following a stroke, and shoulder pain was assessed by using a visual analog scale (VAS), or other recognized instruments [e.g., McGi pain questionnaire (MPQ) , numericWe included studies assessing the effectiveness of AR vs. RT alone on PSSP. The types of acupuncture included auricular acupuncture, abdominal acupuncture (AA), balancing acupuncture (BAA), body acupuncture (BA), carpus–ankle acupuncture (CAA), electroacupuncture (EA), fire acupuncture (FA), relaxing needling at meridian-muscle nodes (RNN), scalp acupuncture (SA), traditional acupuncture (TA), and warm acupuncture (WA), but not moxibustion. The RT mainly included good limb position, Bobath, Brunnstrom, Rood, and shoulder joint ROM exercise. The participants in the AR group received AR, while the participants in the RT group, received RT alone. The RT regimens and base medicines in the two groups must be similar.via 11 questions, and the FPS uses different facial expressions to show six levels of pain. These scales indicate that the higher the score, the more severe the pain.The primary outcome was shoulder pain assessed by VAS, NRS, MPQ, or FPS at the end of treatment. The VAS score changes between 0 and 10 points, the NRS uses the numbers 0–10 to indicate pain intensity, the MPQ evaluates pain The secondary outcomes were the motor function of the upper limb, ADL, shoulder ROM, and adverse events (AEs). The assessment time of the outcomes was at the end of treatment. The upper limb motor function was assessed by the Fugl-Meyer scale for the upper limb (FMA-U), ADL evaluated by the Barthel Index (BI) or the modified Barthel Index (MBI), and shoulder ROM measured by the protractor. The FMA-U scale contains 33 items, with a full score of 66 points. The higher the FMA-U score, the better the upper limb function . The BI We searched six electronic databases from their inception to February 2022: PubMed, the Cochrane Library, the Chinese Biological Medicine Database (CBM), the Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI), and the WAN FANG database. We performed a systematic search using Medical Subject Headings, titles, keywords, and free words related to acupuncture, RT, and PSSP. The detailed electronic search strategies for all databases are provided in Initially, all articles were imported into EndNote (version X9) for automatic deduplication. After removing duplicates, two authors (XW and CT) independently reviewed the titles and abstracts of all articles to determine whether these articles met the inclusion and exclusion criteria. Full-text articles that potentially met the eligibility criteria were retrieved. Then, the same two authors independently read these full-text articles to identify eligible studies. When multiple studies described the same trial, we included only the earliest published study. During the study selection process, any disagreements could be resolved by discussion or by consulting with a third author (JZ) as necessary.Microsoft Excel was used by two authors (XY and PZ) independently to extract predefined data from the studies included. Where a study considered multiple intervention groups, data were extracted only for AR and RT groups. These authors conducted data extraction in duplicate and then checked the accuracy of these data. During the data extraction process, any disagreements could be resolved by discussion or by consulting with a third author (JZ), as necessary. The predefined data included (1) basic characteristics of the study, such as author name, publication year, sample size, gender, age, time since stroke, and type of stroke; (2) detailed information about interventions, such as types of acupuncture, selected acupoints, duration of needle retention, and frequency and duration of treatment; and (3) outcome measures, such as VAS, FMA-U, BI/MBI, shoulder ROM, and AEs.Cochrane Handbook for Systematic Reviews of Interventions (The risk of bias (ROB) assessment tool in the ventions  was usedWe used the post-treatment mean and standard deviation of the two groups to obtain the pooled effect size. When outcomes were evaluated by using the same scale, we used weighted mean differences (WMDs) with 95% confidence intervals (CIs) to describe continuous variables; otherwise, we used standardized mean differences (SMDs) with 95% CIs.We managed and analyzed the data of non-standard design studies in accordance with the guidelines recommended in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) .We contacted the corresponding authors or relevant authors of the studies included by email to obtain relevant data and information missing from the study. When the authors of these studies had provided data on at least one outcome among shoulder pain, upper limb motor function, and ADL before and after the intervention, we included those studies in our meta-analysis; otherwise, only a qualitative synthesis of those was performed.via analysis of the basic characteristics of participants , protocols of intervention , outcome measures, and trial design .We tested the clinical heterogeneity of studies included We tested the statistical heterogeneity of the studies included using the Cochrane I-squared statistic. The I-squared statistic quantified the percentage of heterogeneity in the outcome measures. When I-squared was more than 25, 50, and 75%, the heterogeneity between studies was considered low, moderate, or high, respectively.We tested the publication biases by using visual funnel plots and Egger’s test when the number of studies included was beyond 10.1 Shoulder pain was the primary outcome of this meta-analysis. Given the small number of studies included and moderate-to-high heterogeneity, we conducted a meta-analysis for the primary outcome using a random effects model. For secondary outcomes , we used a random effects model to pool data when the statistic heterogeneity was significant; otherwise, we used a fixed effects model to conduct the meta-analysis. Furthermore, we performed a narrative summary for AEs. For all meta-analyses, we considered two-tailed P-values less than 0.05 as statistically significant.We conducted statistical analyses using RevMan version 5.3  and RStudio Desktop 1.4.1717.Considering the clinical heterogeneity of studies included, we performed subgroup analyses based on different types of acupuncture as follows: EA plus RT vs. RT alone, BAA plus RT vs. RT alone, and TA plus RT vs. RT alone.We conducted a sensitivity analysis for the primary outcome by removing each study individually to test the robustness of the meta-analysis results.n = 614), we further excluded 1,307 articles by screening titles and abstracts, and then 169 articles were retained with full text. Of the 169 articles, 127 were removed for the following reasons: unrelated to PSSP (n = 11), not RCTs (n = 14), irrelevant intervention or comparison (n = 72), thesis (n = 24), separate articles for the same trial (n = 2), not published in Chinese or English (n = 2), and missing data (n = 2). Finally, 40 studies  were of moderate-to-high quality based on the ROB criteria. In terms of selection bias, 17 articles (42.5%) reported on the randomization process using a random number table approach were judged as low risk, two were considered high risk due to inappropriate randomization procedures, and 21 were considered an unclear risk due to lack of reporting. As for allocation concealment, only two (5%) articles were classified as low risk because correct allocation concealment processes using opaque envelopes were reported. Others were judged as an unclear risk due to the absence of the random number allocation process. For performance bias, patients could not be blinded because there were no sham or placebo controls, so we focused on whether the articles had blinding of acupuncture practitioners. Of all, only one RCT (2.5%) was considered low risk because its acupuncturists were blinded to the grouping. In terms of the blinding of outcome assessment, only three articles (7.5%) were judged as low risk and their outcomes were assessed by those who did not participate in acupuncture practice and unknown to the grouping. Two studies (5%) reported cases of dropouts but did not specify the reasons for dropout, and 38 studies (95%), which reported all outcome data, were considered as low ROB due to attrition bias. In total, seven studies (17.5%) were judged as high risk of reporting bias because one or more outcomes of interest to this SR were poorly or not reported in these studies, which prevented them from being included in the meta-analysis. Other biases were not found in all the studies. The risk of bias assessments of studies included is shown in I2 = 93%, P < 0.01). The results of pooling data showed that AR is superior to RT alone in reducing shoulder pain in patients with PSSP  (P < 0.05); one study with 60 patients used the FPS to assess the improvement of shoulder pain between AR and RT alone, and the difference between AR vs. RT alone was significant ; and one study including 25 patients used the MPQ to evaluate shoulder pain, and AR was better than RT alone in reducing shoulder pain .A total of 31 studies with 2,290 patients compared the effectiveness of AR vs. RT alone on shoulder pain assessed by using VAS. We used the random effects model to pool the data due to the high statistical heterogeneity ( < 0.01) . Only onI2 = 97.3%%, P < 0.01), we selected the random effects model to pool the data. The results of the meta-analysis showed that AR is better than RT alone in improving the upper limb motor function   .I2 = 35.4%, P = 0.11). The results of pooling data showed that the effectiveness of AR on ADL is better than that of RT alone   .I2 = 0.0%, P = 0.42; I2 = 62.4%, P = 0.10; respectively). AR for the improvement of ROM of shoulder internal rotation and backward extension was better than RT alone, respectively   .I2 = 95.0%, P < 0.01; I2 = 96.0%, P < 0.01; I2 = 98.0%, P < 0.01; respectively). The effect of AR on ROM of shoulder anteflexion, external rotation, and abduction, respectively, was better than that of RT alone   .Only one study reported no AEs related to AR or RT alone, and the other studies did not mention AEs.I2 = 91%, P < 0.01). The results of the meta-analysis showed that EA plus RT was better than that RT alone in reducing shoulder pain   .I2 = 80%, P < 0.01). There was a significant difference in reducing shoulder pain between TA plus RT and RT alone   .I2 = 70%, P = 0.04), we used a random effects model to pool the data. BAA plus RT was better than RT alone in reducing shoulder pain   .P < 0.01)  .t = −0.27, P = 0.79) and the MBI  also did not find obvious publication bias. However, some studies based on the FMA-U did not distribute inside 95% CIs, and Egger’s test  demonstrated obvious publication bias  were of moderate-to-high quality based on the ROB criteria. The meta-analysis results of 35 RCTs with 2554 patients demonstrated that AR is better than RT alone in reducing shoulder pain and improving upper limb motor function, ADL, and shoulder ROM, without obvious AEs. Nevertheless, these conclusions must be interpreted with caution on account of substantial heterogeneity between studies.In this meta-analysis, we found AR was superior to RT alone in the improvement of shoulder pain, motor function of the upper limb, ADL, and shoulder ROM of patients with PSSP. The robustness of the meta-analysis results was also confirmed by sensitivity analysis. In addition, a subgroup analysis of the efficacy of acupuncture on analgesia was conducted based on the different acupuncture types. Efficacy data of the same type of acupuncture from a single study were excluded for a more reliable result. The pooled results revealed that the EA, or TA, or BAA plus RT was better than that of RT alone on shoulder pain in patients with PSSP. Beyond that, when RT was combined with BAA, patients experienced a greater reduction in shoulder pain than combined with TA or EA, as well as with relatively low heterogeneity. The BAA seems to be a more promising solution for PSSP among the varied acupuncture. This may be a helpful finding for future research on acupuncture for PSSP. Overall, the heterogeneous sources of studies included mainly were diversified acupuncture regimens, such as the selected acupoints, manipulation of acupuncture, needle retention duration, and frequency and session of acupuncture. For instance, among RCTs using TA as intervention, one study  reportedFrom the perspective of traditional Chinese medicine, pain is caused by the blockage of the meridians and collaterals, and acupuncture uses metal needles to penetrate specific acupoints in the body to regulate the Qi in the meridians and achieve its analgesic effect by unblocking the meridians and collaterals –89. FromCompared with previous studies, three reviews are similar to ours, published in 2018 , 2015 4, and 201There were some advantages in this review. We performed a comprehensive literature search using a combination of machine and manual methods after consulting professional library searchers. Meanwhile, we also rigorously conducted this SR and MA in accordance with PRISMA and the guideline of Cochrane Collaboration. In addition, we performed subgroup analysis and sensitivity analysis on the included studies, further investigated the effects of different types of acupuncture therapy, and explored the possible sources of heterogeneity among the studies. This can help our conclusions be more reliable and helpful to the actual condition.There are some limitations to our study. First, we did not limit the intervention to a specific type of RT, which may lead to the amplification of the meta-analysis results. Second, we restricted the published languages of studies to Chinese or English, but only one eligible study was published in English, and all studies included were conducted in the Chinese population, which may lead to linguistic and regional biases that are difficult to eliminate. Third, due to the lack of clear descriptions of randomization, blinding, and allocation concealment in the protocols of most studies included, we cannot judge whether the authors performed these steps, which may affect the accuracy of our findings. Finally, there was a significantly statistical heterogeneity in this meta-analysis, which may increase the uncertainty of our results.In this review, we found AR is better than RT alone for the improvement of shoulder pain, upper limb motor function, ADL, and shoulder ROM, without obvious AEs in patients with PSSP. However, considering the clinical and statistical heterogeneity, our findings need to be interpreted with caution. In the future, more rigorous and standardized trials on AR for PSSP should be conducted.The original contributions presented in this study are included in the article/JZ, JL, and LL were responsible for the conception and design of this systematic review. JZ and XW drafted the manuscript. JL and LL revised the manuscript. JZ and LL designed the search strategies. JZ and PZ conducted the electronic search. XW, RC, and YD manually screened the reference lists of the included studies and all relevant reviews. XY and PZ extracted the data. CT and XY independently assessed the risk of bias. JZ, XW, and LL analyzed and interpreted the data. HC and JZ arbitrated any disagreements during the process of systematic review. All authors approved the submitted version of the manuscript.


Hemodynamic management is of paramount importance in patients with acute kidney injury (AKI). Central venous pressure (CVP) has been used to assess volume status. We intended to identify the optimal time window in which to obtain CVP to avoid the incidence of adverse outcomes in patients with AKI.The study was based on the Medical Information Mart for Intensive Care (MIMIC) IV database. The primary outcome was in-hospital mortality. Secondary outcomes included the number of ICU-free days and norepinephrine-free days at 28 days after ICU admission, and total fluid input and fluid balance during the first and second day. A time–dose–response relationship between wait time of CVP measurement and in-hospital mortality was implemented to find an inflection point for grouping, followed by propensity-score matching (PSM), which was used to compare the outcomes between the two groups.p < 0.001. E-value analysis suggested robustness to unmeasured confounding.Twenty Nine Thousand and Three Hundred Thirty Six patients with AKI were enrolled, and the risk of in-hospital mortality increased when the CVP acquisition time was >9 h in the Cox proportional hazards regression model. Compared with 8,071 patients (27.5%) who underwent CVP measurement within 9 h and were assigned to the early group, 21,265 patients (72.5%) who delayed or did not monitor CVP had a significantly higher in-hospital mortality in univariate and multivariate Cox regression analyses. After adjusting for potential confounders by PSM and adjusting for propensity score, pairwise algorithmic, overlap weight, and doubly robust analysis, the results were still stable. The HRs were 0.58–0.72, all Among adults with AKI in ICU, increased CVP wait time was associated with a greater risk of in-hospital mortality. In addition, early CVP monitoring perhaps contributed to shortening the length of ICU stays and days of norepinephrine use, as well as better fluid management. Acute kidney injury (AKI) is a broad clinical syndrome defined by an abrupt decrease in kidney function that includes, but is not limited to, acute renal failure. AKI has been considered to be a major public health problem affecting millions of people all over the world, leading to reduced survival, progression of underlying chronic kidney disease (CKD), and an occasional onset of new CKD . Fluid tCentral venous pressure (CVP) monitoring remains the most frequently used indicator for guiding fluid resuscitation in critically ill patients , 5. In pA population-based cohort study was conducted using critical care databases in Medical Information Mart for Intensive Care (MIMIC)-IV (version 1.0), which was built upon the MIMIC-III database , 13. MIMAdults (older than 18 years) who fulfilled the definition of AKI within 7 days after ICU admission in MIMIC-IV were eligible for our study. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria as previously reported , 15. EveThe primary independent variable was the wait time for CVP, which is defined as the total time elapsed from ICU admission until initial CVP measurement (in hours). Only the first CVP value of each patient was used in this study.2, glucose, hemoglobin, white blood cell (WBC) count, platelet, bicarbonate, creatinine, sodium, potassium). Comorbidities  were also recorded and the comorbidity disease index was calculated. AKI stage which was defined by KDIGO criteria was needed. Treatments  and disease severity score  were also required. The worst values of vital signs and laboratory tests on the first day were taken.Patient characteristics that were previously shown to explain most of the variation in mortality after AKI were measured. The following variables were included in our study: registered information of admission , vital signs, and laboratory tests , SPOThe primary outcome of the study was in-hospital mortality. Secondary outcomes included the number of ICU-free days and norepinephrine-free days at 28 days after ICU admission, total fluid input, and fluid balance during the first and second day.T-test, and Kruskal-Wallis test for the comparison of categorical, normally distributed, and non-normally distributed continuous variables, respectively. We applied the Kaplan–Meier and log-rank analyses to determine survival curves.Descriptive analysis was performed for all participants. Categorical variables were expressed as numbers and percentages. Continuous variables were expressed as mean and standard deviation (SD) for normal distributions or median and interquartile range for skewed distributions. We used the chi-square test, A time–dose–response association between CVP wait time and in-hospital mortality was implemented to find the inflection point. The patients were divided into early and delayed CVP groups based on the inflection point.Logistic regression, with propensity score matching (PSM), was used to estimate the probability that patients would measure CVP early and minimize the potential bias of allocation of CVP wait time and confounding. A 1:1 nearest neighbor matching algorithm was applied using a caliper width of 0.2. The variables mentioned above as covariates were selected to generate the propensity score. A standardized mean difference (SMD) was used to examine the degree of PSM. Less than 0.1 was considered an acceptable threshold.t-test was used to compare the second outcomes. The estimated propensity scores were used as weights. Pairwise algorithmic (PA)   and overmic (PA)  models wmic (PA)  combineshttp://www.R-project.org, The R Foundation) and Free Statistics software versions 1.4 . In-hospital mortality of patients in the early CVP group and delayed CVP group was 9.4%  and 16.5% , respectively. Kaplan–Meier curve showed that an early measurement of CVP had lower mortality by day 30 . In addition, we used a MIMIC-III cohort for further verification and found similar results  and early intervention. In addition, one of the most important roles of early CVP monitoring was fluid management.The value of CVP has been criticized as a poor predictor of hemodynamic responsiveness since it is influenced by many factors . HoweverThis study has several noteworthy limitations. First, some residual confounders may potentially exist, as with all retrospective analyses. We adjusted for possible confounders and minimized the influence of factors that may lead to outcome bias through the PSM, PA, OW, and doubly robust estimate. Second, as the study population only contains patients with AKI, it may not be generalizable to patients without AKI. Third, CVP grouping might induce some bias. We grouped according to time–dose–response effects rather than arbitrarily grouping the patients. Fourth, patients with CVP monitoring before ICU admission were divided into a delayed CVP group. Meanwhile, immortal time bias might exist in the delay CVP group. However, the two conditions above seemed to be misclassification resulting in some bias, led to an underestimation of the association between early central venous pressure monitoring and in-hospital mortality.Among adults with AKI in ICU, an increased CVP wait time was associated with a greater risk of in-hospital mortality. In addition, early CVP monitoring perhaps contributed to shortening the length of ICU stays and days of norepinephrine use, as well as better fluid management.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Massachusetts Institute of Technology and Beth Israel Deaconess Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.QY and WeixC conducted data analysis and wrote the manuscript. YW and JZ modified the manuscript and interpreted the analysis. JC and SY conducted the data collection. XC and WeiyC conducted data analysis and reviewed the manuscript. XX conducted data collection and data interpretation. DW and ZZ designed the study and conducted data analysis and reviewed the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: The objective of this study is to further highlight the differences between different ABO blood groups and Rhesus types with health biomarkers. Methods: In total 150 active healthy blood donors participated in our study comprising of 80 males from 19–61 years and 70 females aged from 21 to 64. Participants carrying blood group A were 55 individuals, blood group B 32, blood group O 51, and blood group AB 12, RHD+ 132, and RHD- 18. All the volunteer regular blood donors were selected recognizing them as a healthy population excluding drug and supplements intake. Their blood samples were analyzed just before blood donation for biochemical, hematological, and antioxidant markers. Statistical computations were performed using the SPSS tool, specifically, the one-way ANOVA test, Chi-square statistics, and logistic regression were used as statistical models. Results: O blood donors presented better iron absorption and the worst lipid profile. Indeed, a significant trend of high atheromatic index values revealed an increased risk for hyperlipidemia, in contrast with blood group A presenting a better lipid profile with lower atheromatic index values. There was also a gender related association for blood group A compared with O that was further highlighted using binary logistic regression. Conclusion: In this study, a significant difference was observed among the ABO blood groups in several of the examined biochemical and hematological biomarkers. O blood group appeared different behavior in comparison to all the tested blood groups and furthermore the RHD-group presented a better lipid profile in comparison to the RHD+ group. In order to obtain a more comprehensive view of the correlation between the ABO blood group and biochemical markers, further studies are required. H. pylori, and cholera has been suspected mainly because of the absence or not of the A and B antigens. These antigens can be used as receptors, so the blood group O individuals seem to be protected [The ABO system was discovered in the year of 1901 and afterward, an association between the ABO blood system and diseases such as malaria, hemolytic disorders, cancer, and life expectancy  was suggrotected ,23,24 frrotected . The mosrotected . Moreoverotected . The molrotected ,29.It is of great interest to point out the correlation of the RhD system with diseases as well. RhD protein is a component of NH(3) or CO(2) pump whose physiological role is unknown and is known to be able to cause hemolytic anemia, jaundice, and also liver and heart problems in newborns who are incompatible in their rhesus type with mothers rhesus type. Moreover, the absence of Rhesus protein is associated with allergic problems, digestive, heart, hematological, immunity, mental health, and neurological problems and they differ in their tolerance to certain biological factors, including Toxoplasma infection, aging, and fatigue.The target of our study is to investigate if the ABO blood group, Rhesus types, and a combination of those, present a possible risk factor for the health benefits of the hematological (hematocrit and hemoglobin) and biochemical levels  of regular blood donors. Consequently, we aimed to evaluate the role of ABO and RhD blood types as risk factors in pathological conditions .A pilot study was carried out at the Blood Bank of Naousa Hospital Greece from January 2019 to December 2019, . The regThe sample size was calculated using a single-population proportion for the outcome variable and a double-population proportion for factors. The final sample size was 150. All participants provided written informed consent before the study and were asked to fill out a short questionnaire about sociodemographic characteristics such as age, sex, body mass index (BMI), smoking habits, and residence of blood donors. All the volunteer regular blood donors (rBDs) were selected recognizing them as a healthy population, excluding drug supplement intake and females with menstruation and recent childbirth.3ETDA, respectively). For antioxidant status analysis, the blood was centrifuged, and the serum was stored at −80 °C.Just before blood donation, 10 mL of blood samples were collected in two tubes for biochemical and hematological analysis , and alanine aminotransferase (ALT) levels were measured using a biochemical analyzer ROCHE in the laboratory of the General Hospital of Naousa. Serum levels of Total Antioxidant Status (TAS) was measured photometrically using the TAS assay kit of Cayman in the laboratory of the International Hellenic University.Hematocrit and Hemoglobin (Hb) was also measured in Abbott Ruby cell_dyn, Roche Integra 400 plus in the laboratory of the General Hospital of Naousa.A, B, O, AB, and RhD groups were obtained for all participants from the Blood Bank in the General Hospital in Naousa using a column agglutination anti-A, anti-B anti-D Ortho Biovue clinical diagnostics serological system .The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Ethical approval to perform the present study was obtained from the Ethical committee of the General Hospital of Naousa. The confidentiality of participants was wholly preserved.t-test) was used for investigating the possible differences between two blood groups regarding biochemical markers’ status. One-way ANOVA test further evaluated possible differences in lipidemic and anemia predisposition among blood groups. In all statistical analyses, the level of significance  was set at α = 0.1. The independent variables with p < 0.1 in bivariate correlation analysis were enrolled in binary logistic regression for further analysis. A logistic regression model was used to examine the effect of particular independent variables on different ABO blood groups.To compare biochemical markers with ABO blood group and Rhesus type statistical analysis was performed using SPSS tool version 22.0. Descriptive statistics presented as mean ± standard deviation was performed. Additionally, inferential statistical analysis (In n = 150), firstly processing the descriptive statistical analysis, we are taking into consideration only the mean and standard deviation values. Biochemical and hematological parameters related to ABO blood groups are shown in p-value < 0.05). BDs with O blood group presented the highest atheromatic index with 4.46 in comparison with 4.01 (group A) and 3.88 (group B) . Interestingly, uric acid and glucose levels of blood group O presented higher amounts in comparison to the other groups . In relation to antioxidant status, slight differences have been observed for TAS levels, only blood group AB presented lower levels of TAS in comparison to the other groups. The ALT and AST liver enzymes had no differences between the blood groups as all the participants were healthy BDs and all the biomarkers were between the normal ranges. Furthermore, analyzing the hematological-related parameters, blood group B revealed slightly higher levels of hematocrit and hemoglobin but with no statistical significance, and group AB had significantly higher levels of iron. Looking at the mean concentration of serum ferritin, a difference has been observed in blood group O in comparison to the other groups. , respectively. In addition to our analysis, further statistical evaluation was employed. Taking into consideration the limitation regarding the sample size in addition to the non harmonized group size among different ABO blood groups, we calculate the mean values between them in order to depict the relationship between blood groups and atheromatic index variables. Two distinct subgroups were observed. Comparing the mean values of the atheromatic index variable for groups A and B vs. AB and O, we observed that were different. Replacing the variables’ values with 1  and 0 , we observed that the major differentiations are revealed regarding total cholesterol, triglycerides, and LDL values.  among ABO blood group groups. Considering that only atheromatic index variables are linearly correlated with ABO blood group groups, the atheromatic index was used in the logistic regression model to determine the effect of the ABO blood group on the atheromatic index appearance. In the binary logistic regression analysis, the model with gender, age, BMI, and blood group was apparently correlated with atheromatic index values. The Hosmer and Lemeshow test with p values of 0.72, effectively indicated the better model goodness of fit and further highlighted the role of the blood group A in the model, compared with blood group O  Iron: Rh+ 110.24 μg/dL vs. Rh− 102.12 μg/dL, Ht%: Rh+ 45.2 vs. Rh− 43.4, Hb/g/dL: Rh+ 15.85 vs. Rh− 14.24, Glucose levels: Rh+ 104.5 mg/dL vs. Rh− 97.5 mg/dL). In relation to antioxidant status, the positive-Rhesus type presented significantly higher levels of antioxidants . Only total cholesterol levels were higher in males with blood group A. Higher Total antioxidant levels (258.12 mM) in males with blood group O and lower in males with blood group AB (189.25 mM)  compared to groups A (242.35 mM) and B (242.85 mM) a significant differentiation among the blood groups neither the ABO nor the Rhesus type. It is well known that serum iron, serum ferritin, uric acid, Ht, and Hb are sex related parameters. Uric acid was found to increase in group B in females (5.38 mg/dL) compared to the other blood groups and in group O in males (6.45 mg/dL). In men, serum ferritin levels were increased in blood group O  and in females in blood group B. As expected in all-female groups, ferritin levels were lower than in males . On the other hand, the statistically significantly higher atheromatic index , which resulted in small numbers in some subgroups, particularly the relatively small number of donors with blood group AB (n = 12). Lack of associations may therefore reflect limited statistical power to detect smaller  differences between groups. This also limits the generalizability of study findings. However, because this study incorporated about 70% of the healthy blood donors’ pool, our population is considered representative of the Naousas Blood bank. Secondly, other factors such as age, smoking habits, and BMI also impacted our study.Certain limitations of this study should also be suppressed. First, the sample size of this study was small . The classification of different blood groups is defined by different carbohydrate structures and thus different biochemical profiles seem to associate with different blood groups. Also, race, gender, and ethnicity affect the blood group and lipid profile of individuals. These differences in metabotypes of blood groups can influence health and may contribute to better nutritional and drug therapies ,55. FollConsidering that the atheromatic index variable is linearly correlated with ABO blood groups, the atheromatic index effectively indicated the role of the blood group A in the model, compared with blood group O. Moreover, the O blood group appeared better iron absorption and increased risk for hyperlipidemia and oxidative stress. RHD− group presented also a better lipid profile in comparison to the RHD+ group. With further studies, it can be confirmed that blood groups and types can be considered as risk factors for different diseases alone or in combination, such as CVD, diabetes mellitus, cancer, Covid-19, and the risk profile can be estimated in relation to the other biochemical, hematological parameters and the antioxidant status too.


Neuropsychiatric systemic lupus erythematosus is a serious complication of systemic lupus erythematosus. A 33-year-old female patient had repeated hair loss for more than 3 years. A dermatologic examination showed several pieces of irregularly shaped hair loss patterns in the center of the patient's scalp. The systemic treatment included oral hydroxychloroquine, aspirin enteric-coated tablets and prednisone, and intrathecal injection of dexamethasone and methotrexate. The local treatment included intralesional injection of triamcinolone acetonide and lidocaine in the lesion area, 0.1% tacrolimus ointment for external use. After 2-month treatment, hair regrew in a non-scarring patchy alopecia region with no further hair loss. Neuropsychiatric systemic lupus erythematosus (NPSLE) is a complication of systemic lupus erythematosus (SLE) with an incidence rate of 21–95%. It has become the main cause of death in the activity period of SLE , 4.According to the American College of Rheumatology, twelve central nervous systems (CNS) symptoms and seven peripheral nervous systems (PNS) symptoms are related to NPSLE . Lupus pThe diagnosis of NPSLE mainly includes the detection of autoantibodies, cerebrospinal fluid analysis, electrophysiological studies, neuropsychological assessment, and neuroimaging detection. However, none of the above methods has been accepted as a gold diagnosis standard. A previous study showed that the positive rate of serum antiphospholipid (APL) antibodies was significantly higher in patients with NPSLE than that in other patients with SLE . Thus, tA 33-year-old female patient with repeated alopecia for over 3 years visited our hospital in August 2015. Initially, a piece of alopecia area with an irregular shape of a broad bean size was inadvertently found on the top of the head. There were no obvious itches, rashes, or pain in the alopecia areas and their surroundings. The patient was diagnosed with “alopecia areata” in a local hospital, treated with medication (details were unknown), and the condition was improved. However, the alopecia recurred later, and the patient occasionally went to a local hospital for treatment. The diagnosis was ibid, but the curative effect was poor. The area of alopecia had a gradually expanding trend. More than 1 month ago, the area of alopecia rapidly expanded based on the original alopecia with no obvious incentives. The patient felt no other discomfort and visited our hospital. Her appetite, stool, and urine were fair, and her sleep was poor. The medical history of this patient showed that she suffered from schizophrenia 10 years ago and was treated by long-term oral administration of risperidone. The mental condition of the patient was stable. The affected area did not have a history of trauma. None of her family members had a similar disease. The patient had a childbearing history 5 years ago, and the spouse and child were healthy. There were no obvious abnormalities in the menstrual cycle and its amount. The consent from the patient for the publication of the case was obtained.2O, and protein concentration was 0.6 g/L. No abnormalities were found in the number of cells, glucose, and chloride. MRI results showed multiple diffused abnormal signals in the bilateral cerebral hemisphere and basal ganglia. No abnormalities were found in Chest X-ray, electrocardiogram, and abdominal color Doppler.Physical examination: no abnormalities were found. Conditions of dermatology: multiple areas of alopecia with irregular shapes were involved in the double temporal sides, parts were fused , and strSystemic lupus erythematosus complicated with neuropsychiatric systemic lupus erythematosus.2O. Protein concentration was 0.56 g/l. No abnormalities were found in cell number, glucose, and chloride.Oral administration of hydroxychloroquine, 200 mg, bid; aspirin enteric coated tablets 200 mg, QD; prednisone 60 mg, QD, administrated for 3 consecutive weeks. The dose was reduced when the disease was under control, every 10 mg was reduced per 1–2 weeks, and the dose was reduced to 30 mg in 2 months, QD. Dexamethasone and methotrexone were each 10 mg intrathecal injected once weekly for two weeks. Triamcinolone acetonide 50 mg combined with lidocaine hydrochloride 5 ml were intralesional injected once every two weeks for four times; and 0.1% tacrolimus was applied outside, BID. At the same time, the patient was ordered to avoid sun exposure, and prevent fatigue and infection. 2 months post treatment, no further alopecia was found, and new hair grew in the non-cicatricial patchy alopecia area. The WBC, PLT, C3, and ESR values were 8.6 × 10 E9/L, 101 × 10 E9/L, 0.9301 g/l, and 13 mm/H, respectively. Cerebrospinal fluid pressure was 146 mmHAlopecia is a common clinical manifestation of SLE with an incidence rate of 17.3–54% . AlopeciIn SLE alopecia areata, the scalp may be pale red or red and the follicular orifice is well-preserved. The typical dermoscopic signs in alopecia areata, such as exclamation-like hair, broken hair, and black spot signs, as well as the infiltration of thronged-like lymphocytic around anagen follicles, are not observed in SLE alopecia areata .The life quality and mental health scores were lower in patients with SEL with NPSLE compared to the ones without alopecia. Even after the systemic disease has been relieved, alopecia might still compromise the patient's self-esteem and leads to long-term depression .In this case, we found that the diagnosis of NPSLE was difficult. When mental disorder was the main clinical symptom, the imaging results were often normal or mildly damaged. Childbearing might be an important factor that induced the aggravation of this disease, as SLE exacerbations generally occurred during the period of late pregnancy or post-parturition. If cicatricial alopecia occurs in women of childbearing age, the pathogenesis needs to be further investigated. The early diagnosis and early treatment of this disease not only reduce the visceral damage but also prevent permanent baldness and subsequent psychological problems.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.XH was involved in drafting the manuscript. J-SL revised it critically for important intellectual content and conception and design. All authors given final approval of the version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Surgical resection could improve the survival of patients with early-stage small cell lung cancer (SCLC). However, there is a lack of dedicated studies concentrating on surgical treatment in older patients with T1-2N0M0 SCLC. Thus, we performed this population-based study to investigate whether older patients with T1-2N0M0 SCLC could benefit from surgery.We collected the data of patients with SCLC between 2000 and 2015 from the Surveillance, Epidemiology, and End Results Program database. Older patients (≥ 65 years) with T1-2N0M0 SCLC were included, and we converted the staging information into those of the eighth edition. The propensity score matching (PSM) was used to balance the distribution of clinical characteristics between surgery and no-surgery groups.P < 0.001). After 1:2 PSM, the distribution proportions of clinical characteristics in 683 patients were balanced . The OS and CSS of patients in the surgery group were still better than that of patients in the no-surgery group , and subgroup analysis showed that the surgery was a protective factor for OS and CSS in all clinical characteristics subgroups . The multivariate Cox analysis further confirmed this result . The result of subgroup analysis based on age, T stage, and adjuvant therapy showed that surgery was related to better OS and CSS compared with non-surgery group  and that lobectomy exhibited the longer survival than sublobectomy. Age, sex, and race were the independent prognostic factors for OS in patients undergoing surgery, whereas only the factor of age affects the CSS in patients with surgery.Before PSM, the distribution proportions of clinical characteristics in 1,229 patients were unbalanced. The Kaplan–Meier curves of overall survival (OS) and cancer-specific survival (CSS) showed that the patients in the surgery group were better than those in the non-surgery group (all Older patients with T1-2N0M0 SCLC can benefit significantly from surgical treatment, and lobectomy provides better prognosis than sublobectomy. Lung cancer is the leading cause of malignancy incidence and mortality . Small cHowever, compared with young people, the older patients may be frail with complex underlying diseases, poor performance status, and increased treatment-related complications . TherefoIn this study, we performed strict matching of clinical data between the surgical and non-surgical groups by propensity score matching (PSM), so as to eliminate the confounding effect of clinical characteristics of the two groups. Finally, we evaluated the effect of surgery on the long-term survival in older patients (≥ 65 years) with T1-2N0M0 SCLC based on the Surveillance, Epidemiology, and End Results (SEER) Program database.The SEER database is an authoritative source for cancer statistics that covers approximately 28% of the US population and contains data on cancer occurrences in 18 areas of the United States. The selected patients diagnosed with SCLC were identified using the SEER * Stat version 8.3.9 . The study cohort consisted of the patients with the International Classification of Disease for Oncology Third Edition (ICD-O-3) morphology codes  and site codes . The exclusion criteria were as follows: (I) not receiving regular follow-up or no follow-up; (II) patients having at least one prior malignancy; (III) not pathologically confirmed by immunohistochemistry; and (IV) patients with missing information concerning primary tumor size (T), regional lymph node (N), or distant metastasis (M) stage and clinical information. After that, we also set up the including criteria for the patients meeting the above exclusion criteria: aged ≥ 65 years; patients with the eighth edition of American Joint Committee on Cancer (AJCC) staging system, stage T1-2N0M0 Figure 1To facilitate data analysis, we converted continuous variables into categorical variables. The extracted clinical information included sex, age , race, laterality (left and right), T stage , surgery (surgery and no surgery), radiotherapy or not, chemotherapy or not, survival months, causes of death, and vital status. In terms of surgery, we defined the resection of less than one lobe as sublobectomy as some surgical procedures were not clear in the SEER database or the number was so small that we cannot analyze them separately. In addition, we converted the TNM categories for each patient according to the Collaborative Staging Manual and Coding Instructions for the eighth edition of the AJCC staging system using tumor size and tumor CS extension. For chemotherapy or radiotherapy, we were unable to define neoadjuvant or adjuvant therapy due to the lack of sequence of the treatment. The primary outcome was defined as overall survival (OS) and cancer-specific survival (CSS). The time of the last follow-up was November 2020. OS was defined as the interval between cancer diagnosis and death resulting from any cause or the last follow-up for patients still alive. CSS was defined as the length of time from cancer diagnosis to death from SCLC.2 test and the Fisher’s exact test before and after PSM as deemed appropriate. Kaplan–Meier survival curves were plotted to assess distinctions in prognosis by applying the log-rank test. We used Cox proportional hazards regression analyses with both univariate and multivariate Cox regression analyses. Moreover, the multivariate Cox proportional hazards regression models were also performed to assess the risk factors in subgroup analyses. In addition, the forest plot of hazard ratios was constructed from univariate and multivariate Cox regression analyses. All data analyses were performed using RStudio version 4.1.2 . A two-sided P-value < 0.05 was deemed significant.The baseline characteristics of patients in the surgery group and the no-surgery group are described using frequencies and percentage. PSM was performed between the two groups to reduce potential bias and possible confounding interference. The baseline demographic data for the two groups were compared using the Student’s t-test or χA total of 1,229 patients aged ≥65 years who had been diagnosed with T1-2N0M0 SCLC were included in our study. Of the population included, 71.6% of patients (880 patients) did not receive the surgical resection. The baseline characteristics of patients and tumors are shown in Univariate Cox analysis showed that the OS of patients was associated with age, T stage, surgery, radiotherapy, and chemotherapy , sex , and race (black) were the statistically positive influence factors for OS of patients . Subgroup analysis also showed that surgical intervention was a protective factor for OS and CSS for almost clinical characteristics in older patients with SCLC. These results showed that a more aggressive treatment strategy may be beneficial in older patients with T1-2N0M0 SCLC, leading to a better survival of OS and CSS for these patients. Moreover, our study also noted that the factor of age 65–70 years was a protective factor of prognosis in older patients with SCLC undergoing surgery regardless of OS or CSS. Sex and race were independent predictors of OS in surgical patients and were not statistically significant in CSS, which is similar to the results of previous studies (Before PSM, our results demonstrated that surgical treatment was the most significant protective factor of all clinical factors for OS and CSS, although a severe imbalance in the distribution of clinicopathological features between the surgery and non-surgery groups existed in our study. Whereas, the biases in data distribution in terms of baseline characteristics would interfere with the comparison between groups and the accuracy of the Cox regression model , 35. To  studies , 30, 32.The standard treatment for patients with limited-stage SCLC is chemotherapy and radiotherapy. However, considering the several physiological changes of organ function in older patients that could alter drug pharmacokinetics and have an impact on cytotoxic chemotherapy tolerability and toxicity, the treatment regimens may be different among different age . LudbrooAccording to the NCCN guidelines, surgery is recommended for patients with T1-2N0M0 SCLC, and it points out that lobectomy is superior to sublobectomy . HoweverThe current study had some limitations. First, as a retrospective study, the population selection may be biased inevitably and could not control for confounding factors as strictly as prospective studies. Although we have performed the PSM to reduce the potential bias, there might be a potential unknown bias that the PSM failed to rectify. After that, it is not clear how patients were selected for different treatment in the SEER database. Second, the SEER database lacked routinely available data including performance status, lung function, smoking status, and comorbidities. In particular, comorbidities could greatly influence treatment strategies and prognosis assessment and might be the reason why patients who undergo surgery have better survival than those who did not. Third, the information on the status of surgical margin, disease-free survival, chemotherapy regimen and cycles, radiotherapy dose and location, and further treatment after recurrence was not available. Moreover, we are uncertain whether these factors had an impact on our study, for which we should draw the conclusions carefully. In addition, the data in our study were extracted from the American population, and the results need to be verified using the data from Chinese population. Overall, further multicenter prospective studies with relatively complete information of clinicopathological variables, performance status, and treatments in detail should be performed to validate our conclusions and provide more reliable clinical guidance.In conclusion, our study found that the long-term survival of older patients with T1-2N0M0 SCLC who received surgical treatment was significantly better than that of patients who did not undergo surgery after balancing all clinical characteristics and that lobectomy could provide a better prognosis than sublobectomy. For patients unsuitable for lobectomy, this special subset of patients also could benefit from sublobectomy. Age, sex, and race were independent prognostic factors of survival outcomes in older patients undergoing surgery. Therefore, the surgery should be performed for older patients with T1-2N0M0 SCLC after careful consideration and assessment combined with relevant clinical factors, but further exploration in larger prospective clinical trials is also needed to validate our conclusions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.All authors participated in manuscript writing and approved the final version of the manuscript. JN, TG, YM, SZ conceived and designed the analysis. Collection and assembly of data were performed by JN, TG, SZ, YH, SR. Analysis and interpretation of the data were supported by JN, TG, SZ. YM, RL conducted a critical review of the manuscript, contributing important intellectual content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


P = 0.003, I2 = 64%). According to the meta-analysis, CS can be employed for the clinical evaluation of BLT for patients with depressive disorder and exposure to H-CS lighting significantly reduced depressive symptoms among adults. A range of CS > 0.57 was obtained, during which different lighting parameter combinations  could achieve better treatment for depression.Although bright light therapy (BLT) has been widely used in the clinical treatment of depression, the antidepressant effect of BLT is not well understood. Considering the connection between depression and disrupted circadian rhythm, we assumed the model of human circadian phototransduction could be more accurate in evaluating the efficacy of BLT for depression compared to light level and spectrum. A systematic review and meta-analysis were conducted and the CS (circadian stimulus) model was used to quantify the efficacy of lighting in BLT. Articles published up to June 2022 were searched in COCHRANE, EMBASE, MEDLINE, and Web of Science. Randomized clinical trials included articles using high circadian stimulus  as lighting therapy for people with depressive disorder vs. a control group (CS < 0.1). The treatment effect was estimated by calculating the mean difference (MD) with 95% confidence intervals (CIs). Seven trials involving 258 participants met the inclusion criteria. In this sample size, H-CS lighting was associated with a significant reduction in depressive symptoms (MD = −5.56, 95% CI = −9.22 to −1.90, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021253648. BLT has been proven to be an effective and comparatively safe form of depression therapy. It is widely used in clinical practice, and is included in therapeutic guidelines for both seasonal affective disorder (SAD) and non-seasonal depression (NSD)  , developed by Rea et al., which is based on the principles of retinal neurophysiology and psychophysics experiments  of the depression scale was calculated to assess the efficacy of BLT. Using the reported light levels, spectral data, and the lighting distribution over time and space, the findings of the existing trials were screened based on the CS values. A systematic literature review and meta-analysis were conducted to verify the correlation between CS value and therapeutic effect, thus providing scientific metrics for lighting dose quantification of lighting therapy in clinical applications.This systematic review was registered with PROSPERO under code number CRD42021253648 and was conducted in accordance with the PRISMA guidelines   clinical trials with randomized allocation; (B) patients diagnosed with SAD or NSD by standard clinical methods; (C) patients not in a specific physiological state (such as the period before and after pregnancy) and having no other physiological diseases; (D) patient consented to light therapy as the only independent intervention, with no antidepressant medication or other treatment modalities; (E) the CS of the control/placebo groups  was relatively low (< 0.1) while the CS of the intervention group was relatively high (>0.1); (F) the outcome variable and effect size were reported in terms of standardized depression scales. The inclusion and exclusion protocols are summarized as a PRISMA flow chart in The following data were extracted from the identified trials: participant characteristics, sample size, assessment modalities, types of depression, sex, diagnostic criteria for depression, illumination parameters, duration of lighting intervention, the definition of the control group, and basic conclusion. The parameters of the interventional lighting used to calculate CS included illuminance, spectra, duration of exposure, and light distribution (illumination configuration).Two reviewers independently assessed trial quality using the “Risk of Bias Table” from the Cochrane Handbook. This table was amended to include selection bias, performance bias, detection bias, attrition bias, and reporting bias, and was used to evaluate the randomization and blinding methods, outcome measures, and loss to follow-up of the included trials. The final score for each study was quantified as “Low risk,” “Unclear risk,” or “High risk.”P and I2 values, and different effect models were selected according to the results of the heterogeneity analysis. In addition, sensitivity analysis was performed to test the stability of the model, which involved examining the heterogeneity and effect size before and after a specific study was deleted.Although the identified trials included cases of seasonal and non-seasonal depression, they used the same continuous outcome variable, namely SIGH-SAD scores. The mean difference (MD) and weighted mean difference with 95% CI were chosen as the effect size. The meta-analysis factored in the mean, standard deviation (SD), sample size, and weight of each original study. In this study, the weight was the inverse of the variance calculated by Review Manager Software (version 5.3.0). The heterogeneity was assessed by evaluating the Of 1,091 studies identified in the database, 7 were included in the meta-analysis. The eligible studies were all randomized controlled trials and the quality of evidence was evaluated with the Revised Cochrane Risk of Bias Tool  (2 = 64%) . This fiP = 0.005, I2 = 29%). Data were also subgrouped based on the length of treatment. The result showed that the short-term exposure to H-CS lighting therapy  was not significantly different compared to exposure to long-term exposure .Sensitivity analysis was conducted to assess the stability of the results and the influence of each study on the total estimate, by omitting one study at a time . When anCS can be used as a new metric quantification method of lighting, which might more accurately represent the dose of light therapy in depression than vision parameters. In this review, H-CS lighting was associated with a significant reduction in depressive symptoms across 7 studies regardless of participant characteristics  or individual lighting features .The funnel plot does not reliably represent the risk of publication bias due to the small number of trials included in this study. Moreover, the presence of low sample size trials can indirectly contribute to publication bias  may be inadequate for evaluating the dose in BLT studies. For example, the therapeutic effect of blue-appearing light with an illumination of 98 lx was similar to that of white-appearing light with an illumination of 700 lx  and the blue light group (CS = 0.68 ± 0.06) had a significant treatment effect and there was no significantly different between the two groups  showing no significant advantage over the short-term group (1–3 weeks). Thus, the non-visual impact of light may have a cumulative efficacy over a limited period and reaches saturation after a specific duration.N = 258) were included in the meta-analysis, which restricts the quality of the evidence. Notably, according to the inclusion criterion (E) for the intervention group, when the CS value was larger than 0.1, the research can be incorporated into the meta-analysis. However, the article screening results yielded only CS values above 0.57 in the intervention group, and intermediate CS values were missing. Therefore, the treatment effect of CS in depression could only be determined for two extreme cases. In conclusion, a significant treatment effect of H-CS photomedicine was achieved with CS higher than 0.57; the present analysis did not establish a therapeutic effect for CS in the range of 0.1–0.57.Nevertheless, this study has several limitations. Only seven studies . Future trials should also include additional intermediate CS values to establish a model based on treatment outcomes and non-visual light parameters. Moreover, in comparison with visual parameters, non-visual optical parameters have been poorly researched to date. Future studies may identify new parameters that are more appropriate for the accurate evaluation of the therapeutic effect of lighting.By controlling the spectrum and level of the light for depression disorder therapy, H-CS light mode may be achieved with a preferred color or a gentle light level, improving comfort for the patients, and increasing the effects of light therapy.Data from this review support the use of CS as a new quantitative measure for the evaluation of bright light therapy in depression. Compared with visual parameters, CS accounts for spectra, illumination, duration, and spatial distribution and how the circadian system responds to them. Based on this sample size, a relatively better therapeutic effect was achieved when the CS value was above 0.57 (H-CS lighting therapy).Furthermore, additional clinical research should be conducted by using the same CS values to validate this model. Meanwhile, the therapeutic effect of light therapy with CS in the 0.1–0.57 range remains unknown, and future studies should investigate the effect of these intermediate CS values.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.YL supervised the research and built the article framework. All authors contributed to the literature search. Data collection and analysis were performed by LZ and DH. Study quality and risk-of-bias assessments were performed by LZ, YW, and SZ. The first draft of the manuscript was written by LZ and all authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.This study was funded by the Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The frequencies of L-ACh-induced coronary spasm  and TOC  were higher in the MVS group than in the SVS group. The average number of coronary vasodilators at discharge was higher in the MVS group (1.2 ± 0.4) than in the SVS group . The frequency of MACE was not different between the two groups. (4) Conclusions: Patients with MVS may have higher VSA activity on SPT and have more aggressive medications, leading to a comparable prognosis in VSA patients with SVS. MVS is an important indicator of at least VSA activity, and cardiologists should confirm this in SPT whenever possible. Further studies should confirm whether lower FBS levels and higher cystatin-C levels are any markers of MVS.(1) Background: We have sometimes experienced patients with vasospastic angina (VSA) who presented multi-vessel spasm (MVS) on coronary angiography and spasm provocation test (SPT). However, the clinical characteristics of VSA patients with MVS and the prognosis of such patients in the clinical setting have not been clarified. Therefore, we compared the clinical characteristics and prognosis in VSA patients with MVS with those in VSA patients with single-vessel spasm (SVS). (2) Methods: A total of 152 patients  with VSA, in which the presence of coronary spasm was assessed in both left coronary artery (LCA) and right coronary artery (RCA) on SPT, were enrolled. We defined VSA as the presence of >90% narrowing of the epicardial coronary artery on angiograms, accompanied by usual chest symptoms and/or ischaemic ST-T changes on the electrocardiogram. On SPT, MVS was defined as the presence of spasms on ≥2 major coronary arteries. Based on the presence of MVS, patients were divided into the MVS group and the SVS group. The frequencies of conventional coronary risk factors, blood chemical parameters, average times of anginal attack, SPT findings such as spasm provocation induced by a low dose of acetylcholine (L-ACh) and total occlusion due to coronary spasm (TOC), number of coronary vasodilators at discharge and major cardiovascular events  were compared between the two groups. (3) Results: The MVS and SVS groups were comprised of 98 (64%) and 54 (36%) patients, respectively. The level of fasting blood glucose (FBS) was lower ( Vasospastic angina (VSA) is characterised by the transient vasoconstriction of the epicardial coronary arteries, leading to myocardial ischaemia ,2. With Regarding MVS, we have experienced some patients demonstrating a relationship between MVS and poor prognosis or fatal cardiac events ,10. AlthThus, to confirm the clinical characteristics and prognosis in patients with MVS, we retrospectively investigated those in patients with MVS and compared those in patients with single-vessel spasm (SVS) at our institution.n = 10) or left ventricular wall motion abnormality (n = 15). During the study period, spasm provocation at our institution was performed first in the right coronary artery (RCA). To assess the presence of MVS among the three coronary vessels, we also excluded patients for whom spasm provocation could not be performed in the RCA because of its small size or the inability to place a catheter into the ostium of the RCA (n = 25). Of the 211 patients whose SPT was planted in both RCA and left coronary artery (LCA), an unavoidable use of nitroglycerin (NTG) with 0.3 mg was administered intracoronary for prolonged coronary spasm or unstable haemodynamics due to coronary spasm . Among 92 patients with an unavoidable use of NTG, there were 16 patients who underwent SPT only in the RCA because of a positive SPT. Among the 76 patients with another SPT for LCA, 33 had positive SPT in the LCA. Finally, 152 patients, including 119 patients who had completed SPT without NTG for the final angiograms and the aforementioned 33 patients who had positive SPT in the LCA despite unavoidable use of NTG in the RCA, were enrolled in the present study , 382 patients (27%) underwent a spasm provocation test (SPT) to investigate chest pain at rest or on exertion, or both. Of these, 261 patients (68%) were diagnosed with VSA due to positive SPT. We excluded patients with a previous history of percutaneous coronary intervention (nt study . The stuWe conducted an SPT utilising the procedures previously published . BrieflyThe coronary artery diameters were measured as previously described . Atheros2) was calculated using the standard formula, and the presence of CKD was defined using standard criteria [Regarding the patients’ characteristics, information regarding the patient’s current smoking status and any family history of coronary artery disease (FH-CAD) was collected. Hypertension was defined as a systolic blood pressure of ≥140 mmHg, a diastolic blood pressure of ≥90 mmHg, or the use of antihypertensive medication. Blood chemical parameters were checked in the morning fasting state before CAG. We measured the levels of triglycerides, low-density lipoprotein cholesterol, fasting blood sugar (FBS), haemoglobin A1c (HgA1c), creatinine, C-reactive protein (CRP), brain natriuretic peptide (BNP) and cystatin-C. We also measured the D-dimer level with a lower cut-off level of 0.5 μg/mL, and a value <0.5 μg/mL was counted as 0.5 μg/mL. The estimated glomerular filtration rate  or frequency of VA were checked. In some cases, only one anginal attack occurred, but in these cases, the number of anginal attacks was calculated as the number of anginal attacks per month estimated from the time of chest pain onset to hospitalisation.Patients were followed up at our institution as much as feasible after discharge, and all study patients were seen for at least one follow-up. The final data collection period was set to run through March 2022. The follow-up assessments included information about patients’ medications from their medication diaries who had a recent follow-up. In the previous 3 months, we counted the number of coronary vasodilators used and the number of angina attacks (per month). The number of coronary vasodilators was evaluated at admission, discharge, and final follow-up. In each patient, cardiac events were documented, including readmission for angina or other cardiovascular disorders, and death from cardiac causes or readmission for cardiovascular reasons were considered major adverse cardiac events (MACEs).Since this paper contains many abbreviations, a table of abbreviations is included in t-tests, Wilcoxon signed-rank tests, or these two analyses were used to compare groups’ baseline characteristics. The Kaplan–Meier survival curve was used, along with the log-rank test, to determine MACEs. These analyses were also applied to the analysis according to the number of spastic vessels or to the analysis of patients who completed the SPT without NTG injection to the final angiograms (n = 119). A significant p value was set at 0.05.Non-normally distributed data and noncontinuous variables are reported as mean with standard deviation (SD) or medians with interquartile ranges, respectively. Student’s unpaired p = 0.13). The frequencies of statin and antiplatelet therapies were not different between the two groups. Regarding the blood chemical parameters, the level of fasting blood glucose (FBS) was significantly lower in the MVS group than in the SVS group (p < 0.01), whereas the level of HgA1c was comparable between the two groups (p = 0.45). The levels of D-dimer, CRP, and BNP were not different between the two groups. The cystatin-C level tended to be higher in the MVS group (n = 60) than in the SVS group . Regarding echographic parameters, LVEF, FMD, and NID were not different between the two groups (The study included 98 patients with MVS (64%) and 54 patients with SVS (36%). No significant differences were found in the conventional coronary risk factors in the two groups . The freo groups .p = 0.08). The number of coronary vasodilators at admission tended to be lower in the MVS group than in the SVS group (p = 0.09)  .p = 0.04), TOC caused by coronary spasm (p < 0.01) and ST elevation on ECG (p = 0.03) were significantly higher in the MVS group than in the SVS group. In the MVS group, 81 patients had two-vessel spasms and 13 patients had three-vessel spasms. The MVS group included 33 patients who had positive SPT findings in the LCA after an unavoidable use of NTG for RCA spasms. The frequency of severe complications was comparable between the two groups. The number of coronary vasodilators at discharge was significantly higher in the MVS group than in the SVS group .The frequencies of the presence of atherosclerotic lesions and myocardial bridge were not different between the two groups . Moreoven = 78 and 42 in the MVS and SVS groups, respectively). According to the number of spasm vessels, the frequency of MACE was not different among the three groups .The median follow-up period was 82  months, and the occurrence of MACE was not different between the two groups a. The avIn this study, we investigated the clinical parameters in patients with MVS, comparing those in patients with SVS. Our main findings were as follows: (1) The FBS level was lower in the MVS group than in the SVS group, and the cystatin-C level tended to be higher in the MVS group than in the SVS group, whereas other factors, such as smoking, FH-CAD, and endothelial function, were not different between the two groups. (2) VSA activity during the SPT, assessed by the presence of LAD spasm, L-ACh-induced coronary spasm, TOC, and ST elevation were higher in the MVS group than in the SVS group, leading to a higher number of coronary vasodilators at discharge. (3) During the follow-up with a median of 84 months, the occurrence of MACEs between patients with MVS and SVS was not different.Several studies have revealed the prognostic effect of MVS on patients with VSA ,8. As anIn this study, regarding blood chemical parameters, the FBS level was lower, whereas the level of cystatin-C tended to be higher. In the former, the frequency of DM, drugs taken that may affect the glucose level, such as statins, β-blockers, and diuretic drugs ,27, wereIn this study, the prognosis was not different between patients with MVS and SVS. Higher VSA activities of MVS with higher frequencies of LAD spasm, L-ACh-induced coronary spasm, TOC, and ST elevation were assessed during the SPT, and the growing recognition that MVS is a factor influencing the prognosis of VSA  may leadThis study has an important clinical implication. SPT is an important examination; although it does not diagnose VSA, it can determine the VSA activity or provide prognostic information on several factors, such as the presence of significant coronary stenosis, LAD spasm, focal spasm, and MVS ,6,7,8. IThis study has several limitations. First, this study had a small sample size and was retrospectively performed at only one institution. The characteristics of the patients with MVS may not account for all the patients with VSA, and these will be confirmed in further studies. Second, patients who had no coronary provocation in the LCA after an unavoidable use of NTG for the RCA spasm were excluded, and these patients may account for the patients with MVS. Thus, based on such results, the frequency of MVS and patients’ characteristics may be different. Third, as mentioned above, patients whose SPT was started from the RCA were included in this study because of their long-term follow-up. Forth, Seattle Angina Questionnaire (SAQ) and other methods are available to evaluate the quality of chest pain, but we were not able to evaluate them in this study. Finally, we failed to follow the patients closely enough, and we may not have collected sufficient prognostic information.We investigated the clinical parameters in patients with MVS in comparison with those in patients with SVS. The VSA activity during the SPT was higher in the MVS group than in the SVS group, leading to the aggressive medication and a similar prognosis in such patients. Thus, cardiologists should consider the VSA activity and possible prognostic factors of MVS and should try to detect the presence of MVS in SPT.


Floral nectar contains mainly sugars as well as smaller amounts of amino acids and further compounds. The nectar composition varies between different plant species and it is related to the pollination type of the plant. In addition to this, other factors can influence the composition. Nectar is produced in and secreted from nectaries. A few models exist to explain the origin of nectar for dicotyl plant species, a complete elucidation of the processes, however, has not yet been achieved. This is particularly true for monocots or plant species with CAM photosynthesis. To get closer to such an elucidation, nectar, nectaries, and leaves of 36 bromeliad species were analyzed for sugars, starch, amino acids, and inorganic ions. The species studied include different photosynthesis types (CAM/C3), different pollination types (trochilophilous/chiropterophilous), or different live forms. The main sugars in nectar and nectaries were glucose, fructose, and sucrose, the total sugar concentration was about twofold higher in nectar than in nectaries, which suggests that sugars are actively transported from the nectaries into the nectar. The composition of amino acids in nectar is already determined in the nectaries, but the concentration is much lower in nectar than in nectaries, which suggests selective retention of amino acids during nectar secretion. The same applies to inorganic ions. Statistical analyses showed that the photosynthesis type and the pollination type can explain more data variation in nectar than in nectaries and leaves. Furthermore, the pollinator type has a stronger influence on the nectar or nectary composition than the photosynthesis type. Trochilophilous C3 plants showed significant correlations between the nitrate concentration in leaves and the amino acid concentration in nectaries and nectar. It can be assumed that the more nitrate is taken up, the more amino acids are synthesized in leaves and transported to the nectaries and nectar. However, chiropterophilous C3 plants show no such correlation, which means that the secretion of amino acids into the nectar is regulated by further factors. The results help understand the physiological properties that influence nectaries and nectar as well as the manner of metabolite and ion secretion from nectaries to nectar. Floral nectar is a biochemical complex solution and nectar composition varies between plant species. Nectar is produced in nectaries and secreted from this tissue. Sugars, mainly the hexoses glucose and fructose, as well as the disaccharide sucrose, are dominant. Besides, nectar contains numerous other compounds, including amino acids, inorganic ions, organic acids, and further secondary compounds, albeit in much lower concentrations than sugars . The maiNicotiana  as well as in the plant’s pollinator type (trochilophilous or chiropterophilous). Furthermore, the metabolites and ions were analyzed in the leaves of the bromeliads in pursuit of the question whether the nectar and/or nectary composition correlates with the metabolite and ion contents in the whole plant.We hypothesize that the nectar composition is already prescribed by the metabolite and ion composition in the nectaries. Furthermore, both the photosynthesis type and pollination type of the plant species influence the composition in nectar as well as in nectaries. Finally, increased metabolite contents in the whole plant may also result in increased contents in nectaries as well as in nectar.The plant material and nectar samples were obtained from bromeliads grown in tropical glasshouses in the Botanical Garden and Botanical Museum Berlin (Germany), the Botanical Garden of the University of Göttingen (Germany), the Botanical Garden of the University of Heidelberg (Germany) and at the University of Wuppertal (Germany).Aechmea, Alcantarea, Billbergia, Guzmania, Lutheria, Pitcairnia, Portea, Pseudalcantarea, Quesnelia, Tillandsia, Vriesea, Werauhia) were used. The species differ in the type of photosynthesis (14 species with CAM and 22 species with C3 photosynthesis) and the pollination type  and 12 genera  and night-pollinated (chiropterophilous) bromeliads shortly after anthesis. Nectar samples (5–10 μl) were collected from single flowers with the help of a micropipette . As periSoluble metabolites or inorganic ions were extracted using finely milled powder of 25 mg nectary tissue or 200 mg leaf tissue by chloroform-methanol-water extraction .via HPLC (Thermo Fisher Scientific Dionex ICS-5000 HPIC System) according to –1 fresh weight (FW). Using the water content of leaf cells (86%) and nectary cells  according to § 125-4 using Superspher§ 100 RP-18 endcapped). The concentrations in nectar, nectary tissue, and leaf tissue were determined using calibration curves for the different amino acids (Chromeleon 7.2). The amino acid concentrations in nectar are given in millimolar (mM) and in the nectary and leaf tissues in μmol⋅g–1 fresh weight (FW). Using the water content of leaf cells (86%) and nectary cells . Using the water content of leaf cells (86%) and nectary cells  and cations , their concentrations in nectar, nectaries, and leaves were determined separately lls 75%; , metabolIn nectaries and leaf tissues the content of starch was analyzed according to 1 The metabolite and ion compositions of nectar, nectary tissue, and leaf tissues in 36 bromeliad species with different photosynthesis types  as well as pollination types  were compared using an ANOVA followed by a post-hoc test . Further, to determine whether there is a significant difference between two groups of samples, t-tests were applied.All statistical analyses were performed using R (version 4.1.2).Alcantarea, Guzmania, Pitcairnia, Tillandsia, and Vriesea were examined. The selection of data resulted in a balanced design, the heterogeneity of which is very robust in Permutational Multivariate Analysis of Variance (PERMANOVA)  according to RMANOVA) , which wRMANOVA) . The ana routine .p ≤ 0.001 using the “corrplot” package  in leaves, nectaries, and nectar. Simultaneously, the Pearson correlation coefficient r was determined. To calculate the correlation matrix, the “cor” function in R was used. The correlation matrices were visualized as heatmaps with a considered significance for  package . To distThe concentrations of sugars, amino acids, and inorganic ions in nectar, nectaries, and leaves of 36 bromeliad species  were detp < 0.01), whereas the sugar concentrations in leaves as well as in nectaries of both photosynthesis types were similar , and the pollinator type 35% of the data variation also on a significant level (p < 0.001). The category genus explains 51% (p < 0.001) for the variable photosynthesis type and 16% (p < 0.05) for the variable pollinator type. However, the significant p-value (p < 0.001) for the category genus in PERMDISP indicates that significant p-values in PERMANOVA cannot be considered  and 22% . Considering the leaf samples, the lowest explanation of data variation can be found by photosynthesis and pollinators, each at 9%. However, PERMDISP (p < 0.05) indicates mostly that the influence of genus is caused by location and dispersion effects. The percentage explained by the categories photosynthesis and pollinator decreases accordingly from nectar to the nectaries and further to the leaves, with the higher influence of the pollinator type compared to the photosynthesis type in nectar and nectaries , as well as the sucrose concentration in nectar . Several amino acids correlate positively with each other in leaves, nectaries and nectar , whereby the highest correlations were found in nectar . Furthermore, the concentration of several amino acids in nectaries correlate with those in nectar , and the nitrate concentration in leaves positively correlates with the concentration of several amino acids in nectaries  and in nectar .Considering all 36 species , a positr = 0.49–0.88; p < 0.001), nectaries , and nectar , however, no significant correlations were found between the amino acid concentration in nectaries and nectar , whereas correlations can be found in nectaries  and in nectar . Further, several amino acids in nectaries correlate with amino acids in nectar , and the nitrate concentration in leaves positively correlates with the concentration of several amino acids in nectaries  and in nectar . In comparison, the matrix of chiropterophilic C3 species .In CAM species, several amino acids correlate positively with each other in leaves  and the sugar concentration in nectar were found  and the pollination type (trochilophilous/chiropterophilous) can explain more data variation in nectar than in nectaries and leaves, but the pollinator type has a stronger influence on the nectar or nectary composition than the photosynthesis type. However, more research is needed to fully understand the origin of nectar compounds, especially with respect to monocots, CAM plants, and plant species with other physiological properties or life forms.The original contributions presented in this study are included in the article/GL planned and designed the research. TG designed and performed the experiments. TG and GL carried out the data analysis and wrote the manuscript. Both authors contributed to the article and approved the submitted version.