Background: Blood pressure (BP) variation may result in poor cardiovascular and renal outcomes. We investigated the pattern of seasonal BP change and its association with outcomes in patients with chronic kidney disease (CKD) living in southern Taiwan.Methods: We conducted a retrospective analysis of a prospective observational cohort consisting of outpatients with CKD for the period between December 2014 and December 2019. These patients were grouped according to the pattern of seasonal BP variation, namely, consistently higher average systolic BP (≥8 mmHg) in wintertime than summertime (Group A), consistently lower average systolic BP (≥8 mmHg) in wintertime than summertime (Group B), large variation of average systolic BP (≥8 mmHg) without a specific pattern related to weather (Group C), and little fluctuation of average systolic BP (<8 mmHg) throughout the years (Group D). The study endpoints were ≥40% reduction in estimated glomerular filtration rate (eGFR), end stage renal disease , or death.Results: We analyzed 507 eligible patients, of whom 17.2% exhibited consistent BP elevation in the wintertime. There were 56.8% of patients conducting regular home BP monitoring. Cox regression analysis showed home BP monitoring was independently associated with better outcome in 507 CKD patients . Compared with the other three groups, patients with BP elevation in the wintertime (Group A) were older, had a higher prevalence of diabetic nephropathy and nephrotoxic agent use, a lower prevalence of statin use, higher eGFR decline rate, and a worse outcome. Patients with BP reduction in the wintertime (Group B) were associated with the best outcome. Cox regression analysis indicated that consistent BP elevation in the wintertime in 288 CKD patients with home BP monitoring was significantly associated with a worse composite outcome  after adjustment for various confounding factors.Conclusion: Home BP monitoring is crucial, and associated with better outcome in CKD patients. Consistent home BP elevation from summertime to wintertime in patients with CKD was associated with a poorer composite outcome. Blood pressure (BP) is a dynamic physical parameter that fluctuates according to environmental changes as well as the physical and emotional status of an individual. Greater BP variation may result in poorer cardiovascular and renal outcomes , 2. SelfThe mechanism of BP elevation in winter may be related to sympathetic activation and release of hormones such as arginine vasopressin, norepinephrine, epinephrine, and angiotensin II in response to cold weather . Cold exTainan, located in southern Taiwan, has a tropical monsoon climate, where extreme weather, such as heat waves or blizzards, is unlikely to occur. Despite moderate temperature variations, a lower ambient temperature in the wintertime still results in considerable BP elevation, as was demonstrated in a Taiwanese observational study of patients with chronic cardiovascular diseases . In the This study, involving a retrospective analysis of a prospective observational cohort, was conducted at National Cheng Kung University Hospital. It was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital, Tainan, Taiwan (B-ER-109-402). The study population was patients with CKD aged ≥20, generally with CKD stage ≥3b. These patients had been enrolled in the Taiwan pre-end-stage renal disease management program and received regular follow-up at the nephrology outpatient clinic. The program was staffed by a multidisciplinary team, including nephrologists, renal nurses, and dieticians, who cared for patients with various CKD stages . We exclWe collected data on age, sex, comorbidity, cause of renal failure, medication use, and exposure to nephrotoxins or radiocontrast agents. BP measurement was performed during every outpatient visit using a standard sphygmomanometer device and measurement technique. Patients received relevant guidance and were instructed to measure and record their home BP once a week at least. Home BP was based on an average of ≥2 measurements obtained on different time points. For each monitoring period (wintertime and summertime), the arithmetic mean of all home BP readings was calculated . Then thCKD was defined according to the guideline . CKD staWintertime was defined as the period from December 1 to February 28 (29), and summertime as the period from June 1 to September 30 on the basis of the average ambient temperature in southern Taiwan as published by the Central Weather Bureau of Taiwan. Home BP was adopted for patient classification and analysis, but office BP was applied in patients with CKD who did not perform home BP monitoring. The patients were divided into four groups according to the pattern of seasonal BP variation within the first 2 years of enrollment. BP elevation in the wintertime was defined as a consistently elevated wintertime (≥8 mmHg) average systolic BP compared with that in the summertime (group A). BP reduction in the wintertime was defined as a consistently lower (≥8 mmHg) average systolic BP in the wintertime (group B). Large BP variation was defined as a change in average systolic BP of 8 mmHg or more from summertime to wintertime without a specific pattern related to weather (group C). Stable BP was defined as a change in average systolic BP of <8 mmHg from summertime to wintertime throughout the years (group D). Except the group C, a consistent pattern of seasonal BP change was required for the groups A, B, and D. After the first 2 years of enrollment, the patients were followed up until the end of the study period or when they met any of the following endpoints, which were regarded as poor outcomes. A composite outcome was defined as: ≥40% reduction in eGFR, end stage renal disease  or death, whichever came first.t-test or one-way analysis of variance was conducted for normally distributed data, and the non-parametric Mann–Whitney U-test or Kruskall–Wallis test was used for continuous variables. We used Cox regression analysis (on the stratum of BP elevation in the wintertime) for factors associated with poor outcome  in all the included patients and Cox proportional hazard model by adjusting for various subsets of covariates to analyze the association between BP elevation in the wintertime and outcomes in CKD patients with home BP monitoring. A p-value of <0.05 indicated statistical significance. All statistical analyses were performed using JMP .Data are presented as mean ± standard deviation, median (interquartile range), or number (percentage) when appropriate. Pearson's chi-square test or Fisher's exact test (two-tailed) was used for categorical variables. Student's We enrolled 1,383 patients with CKD who underwent regular follow-up at our nephrology clinic between December 1, 2014, and December 31, 2019. We excluded 876 patients because of missing data, initiation of dialysis, kidney transplantation, death, or loss to follow up within the first 2 years of enrollment. The remaining 507 patients were enrolled, and their baseline characteristics are listed in The comparison between included and excluded patients is shown in Patients with BP elevation in the wintertime were older, and they had a higher prevalence of diabetic nephropathy and poorer outcome than the other groups. Patients with consistently lower BP in wintertime had a higher prevalence of coronary artery disease (CAD) and heart failure than the other groups. Compared with those in the other groups, patients with stable BP were younger and had a lower prevalence of diabetes mellitus, diabetic nephropathy, CAD, and heart failure, higher prevalence of statin use, higher values for estimated glomerular filtration rate (eGFR) and hemoglobin, and a more favorable outcome .P < 0.0001), higher hemoglobin levels  and more favorable baseline renal function  and composite outcome . P = 0.0002) and had higher prevalence of diabetic nephropathy , lower prevalence of statin use , lower baseline eGFR , and worse outcome  than those in the others.Of the study population, 56.8% of patients conducted regular home BP monitoring. Their baseline characteristics were compared with those patients with only office BP measurement . PatientP = 0.0162)   . Cox regctively) .Our review of the literature suggests that this study is the first to demonstrate the association between seasonal BP change and outcome in patients with CKD. Using real-world data related to the management of patient with CKD, we endeavored to highlight the importance of home BP monitoring. According to the pattern of seasonal BP change based on home BP measurement, a consistently elevated BP in the wintertime in those with CKD was associated with a worse composite patient outcome .Hanazawa et al. reported that patients with large BP variation, defined as an elevation of systolic BP ≥ 9.1 mmHg during winter, comprised 22.9% of their study population . By contRelated studies have generally reported that home BP monitoring has a higher predictive value than office BP measurements. A study on the prognostic significance of home BP control on renal and cardiovascular outcomes in older patients with CKD revealed the importance of home BP in predicting renal function deterioration . Celis eOur study revealed that patients with CKD with an elevated home-measured BP in the wintertime were significantly older and were more likely to have diabetic nephropathy and advanced CKD stages. Age-related endothelial dysfunction is inevitable with advancing age , 18. It The exact mechanisms for the association of other BP groups with renal outcomes in CKD patients are not clear. The visit-visit BP variability has been proved to be a good predictor of cardiovascular risk and all-cause mortality, especially in hypertensive patients on treatment . The undThis study has several limitations. We analyzed the data of only 507 patients with CKD from a single tertiary center. This study's relatively small sample size, accompanied by few events, impeded the analysis of each component of the composite outcome because of limited statistical power. The BP and clinical data were collected from electronic medical records; thus, the consistency and accuracy of BP measurement could not be confirmed. Large interindividual and intraindividual BP variability helped reduce the specificity of the BP variation pattern; however, the impact of high BP on the seasonal BP change and outcomes was not evaluated in this study. Therefore, we emphasized the association between patient outcomes and BP change from summertime to wintertime instead of employing absolute BP value or BP control. Because this was a retrospective, cross sectional study, the results suggest an association between the clinical variables rather than a cause–effect relationship. Nevertheless, incorporating our findings-that effective BP control in the wintertime helps improve outcomes-into daily clinical practice is reasonable. A prospective, multicenter study with a larger sample size and longer follow-up duration is required to confirm that BP elevation in the wintertime is a major predictor of poor outcomes in patients with CKD.In conclusion, we demonstrated the impact of seasonal BP change on the outcomes of patients with CKD: those presenting consistent BP elevation from summertime to wintertime exhibited significantly worse outcomes. This phenomenon was observed in southern Taiwan, where has a modest temperature variation, in CKD patients with home BP monitoring.The original contributions presented in the study are included in the article/This study involving human participants was reviewed and approved by the Institutional Review Board of National Cheng Kung University Hospital. PS: Written informed consent was not required to this retrospective study.CYS and M-CW contributed to the conception and design of the study. CYS organized the database and wrote the first draft of the manuscript. M-CW performed the statistical analysis. M-CW and T-HK revising it critically for important intellectual content. 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.


Kidney disease is a health condition affecting a high number of patients with an estimated worldwide prevalence of 10% .The close relationship between the kidneys and the cardiovascular system has long been recognized. While the main cause of death in chronic kidney disease (CKD) patients is related to major cardiovascular events, acute or chronic heart failure may also result in kidney damage  play in the cardiorenal syndrome pathology through modulating inflammation and oxidative stress. Though more studies are required, the current evidence points out for a role of CaMKs in CKD-associated cardiac injury. Finally, Lowenstein and Nigam, present an integrative view of the multi-organ effects of uremic toxin accumulation when kidney function is compromised with special focus on the role of uremic toxins and drug transporters in inter-organ communication (intestine-liver-kidney-brain) and inter organismal communication, for example the host with the microbiome.Three review papers addressed the mechanisms linking CKD and cardiovascular complications. Xiao et al. studied the effect of the treatment with oxymatrine (OMT) in renal fibrosis induced by type 2 diabetes in mice. Following 8 weeks of treatment with OMT, diabetic mice presented decreased renal expression of fibrotic markers and increased expression of E-cadherin as an epithelial marker. This protective effect was mediated via upregulation of the inhibitor of differentiation-2 which would bind and inhibit Twist-mediated epithelial to mesenchymal transition. This mechanism was corroborated in tubular epithelial cells cultured in high glucose. Another strategy to target renal fibrosis was tested in the article by Rui-Zhi et al. who showed that the Astragalus mongholicus Bunge and Panax notoginseng formula and Bifidobacterium administration has functional and structural renal protective effects in a mouse model of CKD induced by 5/6th nephrectomy through the inhibition of inflammatory M1 macrophages via Mincle/NfkB pathway inhibition in the kidney. Similarly, mincle/NFkB pathway was also inhibited in the intestine, leading to the restoration of the intestinal barrier in CKD mice and a recovery of the intestinal flora similar to the one present in normal mice. Thus, by inhibiting inflammation in both, the kidney and the gut this treatment reduced renal and intestine injury induced by CKD, highlighting the role of inflammation in intestine changes observed during CKD.A major complication of diabetes is diabetic kidney disease, for which the therapeutic options are limited  at dialysis initiation was found to be a predictor for chronic leukopenia and thrombocytopenia, while chronic liver disease and high serum ferritin levels (>800 mg/dL) were risk factors for chronic thrombocytopenia. In patients in maintenance HD, Zhang Y. et al. showed that moderate to severe tricuspid regurgitation occurs in 62.6% of the patients and that sodium, decreased fractional shortening and increased right atrium diameter were independently associated to moderate to severe tricuspid regurgitation. Zhang Q. et al. showed that increased arterial stiffness determined by pulse wave velocity together with high plasma galectin-3 levels predicted mortality and cerebral and cardiovascular events in stable HD patients. These studies are important as proof of concept that these parameters might be used to predict adverse cardiovascular events in CKD patients and further confirmation is required in larger cohorts.Hematological alterations other than anemia are a less explored complication observed in hemodialysis (HD) patients for which the risk factors need to be known by healthcare providers to deliver an accurate management. In a single-center study, Lu H. et al. present an observational retrospective single-center study to assess the prevalence of hyponatremia in hospitalized patients and its related adverse outcomes. The authors found a prevalence of hyponatremia of 32.5% and was associated with higher hospital costs and length of stay and in-hospital and 30-day mortality.Burek et al. the authors created an in vitro model to gain insights into the kidney-brain crosstalk during disease. They showed that hypoxic and glucose starved tubular cells co-cultured with brain microvascular endothelial cells (BMEC) on a transwell system and with the addition of uremic toxins induced changes in the expression of blood brain barrier (BBB) transporters, receptors and tight junction proteins in BMEC. This changes in BBB efflux and influx transporter expression were validated in brain capillaries isolated from mice after 24 h of ischemic AKI induction.Kidney disease is often associated to neurological disorders. While the mechanisms remain elusive, ischemic AKI has been associated with a long-term risk of stroke and dementia  (Vijayan and Humphreys, The contributions to this Research Topic illustrate the complexity of the communication between the kidneys and other organs in health and disease conditions, providing new therapeutic and diagnosis tools, and contributing to mechanistic insights into the connection of kidney disease and distant organ disorders. The review articles also highlight that further efforts are needed in order to gain complete understanding of the molecular processes involved in these pathological connections, which will help to propose novel therapeutic avenues for kidney disease and its associated distant organ injuries.All authors contributed to the editorial, approved the submitted version, and performed editorial assignments for this Research Topic.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.


Chronic oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most troublesome and dose-limiting side effect of oxaliplatin. There is no effective treatment for chronic OIPN. We conducted a randomised controlled trial to investigate the efficacy of monosialotetrahexosylganglioside (GM1) in treating chronic OIPN.In this single-centre, double-blind, phase Ⅲ trial, gastrointestinal cancer patients with persistent chronic OIPN were randomised in 1:1 ratio to receive either GM1 or placebo at Tianjin Medical University Cancer Institute and Hospital, China. GM1 was dosed at 60 mg daily for every 3 weeks or 40 mg daily for every 2 weeks. Seven- and fourteen- day infusions were administered to concurrent oxaliplatin users and oxaliplatin discontinuation patients, respectively. The primary endpoint was the relief of neurotoxicity (≥30% improvement), measured by a newly developed patient reported outcome measure (MCIPN) based on prior questionnaires including the European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy Induced Peripheral Neuropathy Questionnaire twenty-item scale. Visual analogue score (VAS) was used as another instrument for patients to evaluate the total Chronic OIPN treatment effect. VAS responders (≥30% improvement), double responders (≥30% improvement in both MCIPN and VAS), and high responders  were also calculated. The secondary endpoints were safety and quality of life. The additional endpoints are progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), and tumour response. .P < ·01). Analyses were also performed in concurrent oxaliplatin users. The results were consistent with those of the whole group. No deleterious effects of GM1 on survival or tumour response were found. There were no ≥G3 GM1-related adverse events.Between May 2015 to December 2017, 145 patients were randomly assigned to receive either GM1 (n=73) and placebo (n=72). Majority of the patients in both arms (90% in GM1 and 83% in placebo) continued receiving oxaliplatin on the trial. More patients responded in the GM1 group than in the placebo group . There was no effective treatment for chronic oxaliplatin-induced peripheral neurotoxicity (OIPN). Duloxetine was the only drug that showed benefit in treating post-chemotherapy neuropathic pain induced by oxaliplatin and paclitaxel. However, its effectiveness in non-painful chemotherapy-induced peripheral neurotoxicity or chemotherapy concurrent user has not been proven. Furthermore, 11% of patients discontinued duloxetine because of adverse events. Monosialotetrahexosylganglioside (GM1) is an active and safe agent to treat diabetic peripheral neuropathy and Parkinson's disease.The TJMUCH-GI-001 study showed the patients who received GM1 had a clinically meaningful improvement of chronic OIPN versus placebo. The chronic OIPN improvement was also seen in the oxaliplatin concurrent users which accounted for majority of the study patients. The response to GM1 treatment was fast onset and the improvement was detected as soon as after the first treatment cycle. More importantly, GM1 was well tolerated. There were no increased adverse events after adding GM1 to chemotherapy. To our knowledge, the TJMUCH-GI-001 study is the first randomised study demonstrating significant improvement of chronic OIPN with an agent in oxaliplatin concurrent users.There is a substantial unmet need for new therapies in chronic OIPN. The results of the TJMUCH-GI-001study show that GM1 can provide a notable improvement of chronic OIPN in oxaliplatin concurrent users, suggesting that GM1 could be a useful treatment option in patients with chronic OIPN.Alt-text: Unlabelled box1Oxaliplatin is a third-generation platinum complex which combined with other chemotherapy agents such as irinotecan, docetaxel, fluorouracil (5-FU), and 5-FU analogues, has become a central component of treatment regimen for gastrointestinal (GI) cancers in almost all disease phases in the neoadjuvant, adjuvant, perioperative, and palliative settings Oxaliplatin-induced peripheral neurotoxicity (OIPN) is the most severe and dose-limiting toxicity of oxaliplatin-containing chemotherapy. OIPN is associated with high morbidity (> 85%) in both acute and chronic forms . The Nat2 of accumulative oxaliplatin Chronic OIPN usually affects patients who receive ≥ 540 mg/mThe typical extremital “stocking and glove” paresthesia and dysesthesia of chronic OIPN result in impairment of quality of life (QoL) and cause physical dysfunction, both during chemotherapy and after its cessation. Chronic OIPN also affects emotional functioning causing anxious/depressive symptoms and sleep disturbance ,23. Stud+ channelopathy, which shows hyperexcitability of neurons and slows potential activation + current but also oxaliplatin accumulation at the dorsal root ganglia (DRG) and spinal cord; therefore, causing DRG neurons atrophy and apoptosis The precise pathophysiologic mechanism of OPIN remains unclear. Acute OIPN is a NaMany attempts to reduce or prevent chronic OIPN have been made, including alternating chemotherapy regimens to reduce oxaliplatin cumulative dosage and using chemoprotectants. Unfortunately, no prophylactic agents have been proven effective in preventing chronic OIPN in phase III studies. Duloxetine was the only drug beneficial for the treatment of neuropathic pain caused by oxaliplatin and paclitaxel after chemotherapy; Since the most common events such as hematological toxicity and nausea/vomiting are now effectively managed, chronic OIPN has become the most survival-limiting adverse event (AE). The failure of chronic OIPN management has made it urgent to find a safe and effective agent for its treatment/prevention.Monosialotetrahexosylganglioside (GM1) is an active agent for diabetic peripheral neuropathy (DPN) Based on the aforementioned neuroprotective effects of GM1, we hypothesised that GM1 would ameliorate chronic OIPN. Therefore, we conducted a randomised phase Ⅲ trial, called the 001 trial of gastrointestinal oncology department of Tianjin Medical University Cancer Institute and Hospital (TJMUCH-GI-001), to investigate the efficacy of GM1 in treating chronic OIPN.22.1The GI cancer patients included in this study were of any age with persistent chronic OIPN, which was defined as experiencing daily paresthesia and/or dysesthesia during oxaliplatin-containing chemotherapy duration  for oxaliplatin concurrent user. For patients who stopped taking oxaliplatin, persistent chronic OIPN was defined as experiencing daily paresthesia and/or dysesthesia from the last dose of oxaliplatin (the duration should be more than 1 week and less than 4 weeks). Other eligibility criteria included adequate organ functions, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2. Diabetics patients who had preexisted neuropathic symptoms (paresthesia and/or dysesthesia) before first oxaliplatin dose were excluded. Details of the other inclusion and exclusion criteria are presented in the Supplementary file. Informed consent was obtained from all the participants. This study was approved by the Institutional Review Board of Tianjin Medical University Cancer Institute and Hospital and registered at ClinicalTrials.gov (NCT02486198).2.2In this single-centre , double-blind (blind to both investigators and patients), phase Ⅲ trial, patients who have received at least one cycle of oxaliplatin infusion, were randomised in a 1:1 ratio to receive porcine brain-derived GM1 or identical-appearing placebo by intravenous infusion. GM1 and placebo were obtained from Qilu Pharmaceutical Co., Ltd, Shandong, China. The urn model of randomisation was applied, and the allocation procedure was masked. The investigators generated the random allocation sequence by blindly choosing one coloured ball from two different coloured balls once in a dark box . One investigator (Zhou) assigned participants to interventions according to the allocation sequence. Considering that the ultracentrifugable platinum elimination of oxaliplatin was of 7·15 days and the clinical practicality Treatment was discontinued if any of the following conditions were met: (1) chronic OIPN progression defined as modified chemotherapy induced peripheral neuropathy questionnaire (MCIPN) total scores or visual analogue scale (VAS) showed ≥ 30% deterioration compared with baseline; (2) patients refused further treatment; (3) non-myelosuppressive serious AEs attributed to GM1. All subjects were followed up after drop-out from the trial. The follow-up frequency was once every 12 weeks by telephone.2.3The European Organization for Research and Treatment of Cancer Quality of Life Chemotherapy Induced Peripheral Neuropathy Questionnaire twenty-item scale (EORTC QLQ‐CIPN20) was one of the most widely accepted tools for chemotherapy-induced peripheral neuropathy (CIPN) assessment. Because some items were not suitable for patients receiving oxaliplatin and no Chinese version of EORTC QLQ-CIPN20 at the onset of our clinical trial, a patient reported outcome measure based on prior questionnaires including the EORTC CIPN20 were made as MCIPN, with most items the same as EORTC QLQ-CIPN20, to meet the characteristics of oxaliplatin after face-to-face interviews with patients. It addressed sensory symptoms in the upper (six questions) and lower extremities (seven questions), temperature sensation (one question), and hearing sensation (one question). It also addressed motor and autonomic functions with five and three questions, respectively. A linear scale was applied to each question ,49. QuesAt baseline (within the 72 hours before study drugs infusion after enrolled), chronic OIPN was assessed using two questionnaire tools . Then, for oxaliplatin concurrent user, all three questionnaire tools  were measured within 72 hours before each GM1 infusion cycle. For patients who stopped taking oxaliplatin, all the three questionnaire tools were measured every 14 days after patients enrolled. All patients who dropped out without chronic OIPN progression were also assessed chronic OIPN  after the last treatment cycle. Acute OIPN was assessed using 11-item questionnaires (yes/no response format) for 5 days after oxaliplatin administration of each cycle of chemotherapy ,50. The AEs were evaluated according to NCI-CTCAE v4·03 during and after the treatment completion.2.436,51The secondary endpoints were safety and quality of life. Because whether GM1 has influence on tumour is unclear, additional endpoints, including progression-free survival (PFS), disease-free survival (DFS), overall survival (OS) and tumour response , were also measured as additional endpoints. Tumour response was assessed by each investigator.The primary endpoint was the relief of neurotoxicity (i.e. MCIPN responder). It was defined as ≥30% improvement in MCIPN total score compared to the baseline at any point and such improvement was durable until end of the study. Visual analogue score (VAS) was used as another instrument for patients to evaluate the total chronic OIPN treatment effect. Thirty percent improvement was considered clinically significant based on prior CIPN and pain-related studies 2.5As the natural history of chronic OIPN in Chinese has not been well described, we first followed 79 patients in our department who experienced persistent chronic OIPN from 2014 to 2015 by telephone. Only 2·5% of these patients had any kind of sensory neurotoxicity relief within the first 3 months after oxaliplatin. We assumed at least 30% responders, which was considered clinically meaningful, in the GM1 group and 3·0% in the placebo group. The sample size calculation showed that 144 patients (72 each arm) were required, with alpha and beta errors of 0·05 and 0·2, respectively.P < ·05 was considered statistically significant.Progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS) were compared between the treatment arms using a log-rank test with Kaplan-Meier curves. Chi-square tests were used to test the differences in proportions, and Student's t-test was used to compare continuous variables. Risk ratio and hazard ratios with their 95% confidence intervals were calculated. A two-tailed The Consolidated Standards of Reporting Trails (CONSORT) checklist was listed in the supplementary file and this randomised trial was adherent to CONSORT.2.6This study was funded by clinical trial development fund of Tianjin Medical University Cancer Institute and Hospital (No.C1706). The funding had no role in the study design or the data collection, analysis, and data interpretation, or in the writing of the manuscript, and in the decision to publish the results.33.1From May 2015 to December 2017, 149 consecutive eligible cases were screened. One patient withdrew consent before randomisation. One patient refused to fill out questionnaires after one cycle infusion, although she declared chronic OIPN improvement without discomfort. Two other patients refused to infuse the study drugs after 1 day and 2 days of infusion without AEs, respectively. Finally, 73 patients in the GM1 group and 72 in the placebo group, who received at least one cycle of the study drug, were analysed for efficacy and safety . Among tAll baseline characteristics were balanced except that the MCIPN score was higher in the GM1 group. The details of patient baseline characteristics are summarised in 3.2P <·05). Furthermore, the negative association between baseline MCIPN scores and SF-36 scores was strong  , whereby patients with higher MCIPN scores had lower SF-36 scores, which meant lower QoL.Because MCIPN had not been validated, we first tested the correlation of baseline MCIPN scores with NCI-CTCAE neuropathy grades and SF-36 scores. Marked differences were detected in MCIPN scores between NCI-CTCAE grade 3 and grade 2 . There were more patients measured as MCIPN, VAS, double, and high responders in the GM1 group than in the placebo group . Using NCI-CTCAE as the assessment standard, more patients in the GM1 group showed a neurotoxicity improvement of ≥ 1 grade but without statistical significance. However, there was no significant difference between the two groups in patients who had at least one symptom of acute OIPN . The results are summarised in P = ·005). After having achieved planned oxaliplatin cycles, 20 and 9 patients transitioned over to maintenance in GM1 group and placebo group, respectively. Among the 20 patients who transitioned over to maintenance in GM1 group, 15 were responders and the other 5 were non-responders. In contrast, two and seven patients were responders and non-responders in placebo group, respectively.The mean GM1/placebo treatment cycles were 2·2  in the GM1 group and 1·8 (range 1–5) in the placebo group (P = ·009).To further elucidate the effectiveness of GM1 in chronic OIPN, analysis was performed for concurrent oxaliplatin users and post oxaliplatin users. The results were consistent with those of the whole group (Supplementary Table S1 and Table S2). In additional, more patients in GM1 group benefited after each cycle of study drug . Consistently, more patients benefited from GM1 with accumulative treatment cycles . During therapy, 18/66 in the GM1 group and 30/60 in the placebo group experienced chronic OIPN progression among concurrent oxaliplatin users  as of December 2018. Four patients were lost to follow-up. There were no deleterious effects of GM1 on survival . The results showed that two out of eight domains of health  in the GM1 group were improved when compared with those in placebo group -bound oxaliplatin accounts for nearly 40% of the total oxaliplatin and erythrocytic platinum's elimination half-life is close to that of RBC's 2 and 665mg/m2 in GM1 group and placebo group, respectively. Both doses are nearly equal to 8 cycles biweekly oxaliplatin treatment . Moreover, our study showed that persistent chronic OIPN was a feasible indicator for treatment. It is an easily understood criterion that can avoid discrepancies between clinicians and patients. In our study, 91·7% of the patients with persistent OIPN were NCI-CTCAE grade 2, a proper grade to begin medical intervention. Because nearly half of the patients would not develop ≥ grade 2 chronic OIPN, treating patients with persistent chronic OIPN is more economical than prevention [Because no drug has been effective in preventing chronic OIPN, it is important to address when GM1 should be administered. The cumulative oxaliplatin doses at enrollment were 680mg/mevention ,13.Good safety is another important advantage of GM1. It had no impact on tumour response and patient survival. Moreover, the long-term  safety of GM1 has been proven in patients with Parkinson's disease To adapt to the characteristics of oxaliplatin, EORTC QLQ‐CIPN20 was modified as MCIPN with most items identical to that in EORTC QLQ‐CIPN20. The results also showed that MCIPN scores correlated with NCI-CTCAE grades and patients’ QoL. Although MCIPN had not been validated, these results showed that it can be used in chronic OIPN assessment.Our items analysis showed that GM1 benefited 3 of all 14 items . Most other items showed the trends favour of GM1 group. The reason may be that we enrolled patients who were experiencing daily paresthesia and/or dysesthesia and only few patients had symptoms other than numbness. The test powers were not enough to evaluate these differences.P = ·01, data not shown). Based on the fact that the time from chronic OIPN diagnosis to receive study drug were 0-3 months in GM1 group and 0-4.8 months in the placebo group  The optimal dosage and treatment duration of GM1 as a therapy for chronic OIPN are still unknown. Whether a higher dosage and/or longer prescription will bring additional benefits are still unknown; (2) Multivariate logistic regression showed that the time from persistent chronic OIPN diagnosis to receiving the study drug was an influencing factor of efficacy  are available by sending requirement to e-mail: zhoubaling123@163.com from 2021-9-30 to 2026-9-30.Tianjin Medical University Cancer Institute and Hospital (No.C1706).This work was supported by clinical trial development fund of All authors declare no competing interests.


Diabetes is considered one of the major causes of chronic kidney disease (CKD), affecting renal blood vessels and nerves. Diagnosis of CKD by traditional biochemical serum and blood analyses is insufficient and insensitive, thus requiring the development of a more robust technique. This novel study aims to propose a new method for the accurate diagnosis of CKD, quantification of kidney damage, and its prognosis by physicians by measuring the kidney volume on computed tomography (CT). In total, 251 patients were enrolled in this retrospective study. They were divided into four groups: control, patients having diabetes, patients having CKD, and patients having both diabetes and CKD. Results showed that kidney volume correlated negatively with both GFR and HbA1C on CT images, in addition to decreasing faster in males than females. Moreover, HbA1C was shown to correlate positively with creatinine and negatively with GFR. Finally, GFR was more robust than creatinine when correlated with age. The association between kidney volume with GFR and HbA1c can be used to accurately anticipate kidney volume in established CKD on CT scan, especially in resource-poor settings. Furthermore, HbA1C can serve as a powerful biomarker for studying renal function in diabetic CKD patients as it correlates with creatinine and GFR. CKD is a serious, widespread, global disease that has dramatically increased over the past few years, affecting around 697.5 million people and resulting in 1.2 million deaths around the globe in 2017. It is ranked as the 12th leading cause of death . Since tIn addition to laboratory testing, medical imaging techniques have been proposed to assess renal functional and morphological abnormalities . In patiCKD has various risk factors that play a significant role in disease development and advancement . Additionally, CKD may also occur as a complication of various other diseases. Diabetes mellitus is considered one of the leading causes of CKD; accordingly, glucose control plays an important role in controlling diabetic nephropathy. Based on this, assessing the time-averaged mean of glycemia, through monitoring the glycosylated hemoglobin (HbA1C) level, is the main criterion for maintaining normal glycemia levels and decreasing the risk of diabetes-associated complications . The 201While CKD may be asymptomatic at its early stages, it was reported that it might develop various symptoms such as anemia, damage to glomerular capillary walls, gastrointestinal disturbances, itch and cramps, hematuria, dyspnea, fatigue, poor appetite, hypertension and peripheral edema at its end-stages. CKD may also cause a series of fatal complications, including bone diseases, metabolic disorders, cancer, as well as cardiovascular diseases .This study aims to facilitate the diagnosis of CKD at its early stages and monitor its progression by assessing kidney size on CT scan. It also aims to uncover a correlation between HbA1C and kidney volume in diabetic patients having CKD for better disease management and prevention of complications using CT, especially when the results are reinforced by clinical and laboratory data.This retrospective study was carried out over a period of 6 months, from 1 September 2020 to 28 February 2021. Data were collected from Ain Wazein Medical Village according to the International Classification of the Diseases Tenth Version (ICD 10), a system used by researchers and physicians to code and classify symptoms, diagnosis and diseases for CKD. It involves specific codes for diabetes and diabetic kidney disease (DKD), in addition to patients’ ID, age, gender, GFR, HbA1C and CT scan images. Patients having previous CT scan and laboratory test results in the hospital information system were included in the study. It is important to note that patients with incomplete data, acute kidney injury/failure, renal malignancy, obstruction, congenital anomalies  and polycystic kidney disease, in addition to those who underwent unilateral nephrectomy, were excluded from this study.p < 0.05 was considered to indicate a significant difference.A total of 251 participants were included in this IRB-approved study (CRU263). They were divided into four groups, with the lowest age being 45, since CKD is rare before this age and its presence increases with age, especially after age 65. Group 1 was classified as a control group including healthy patients without CKD or diabetes; Group 2 comprised patients having diabetes without CKD; Group 3 involved patients having CKD without diabetes; and Group 4 involved patients having both CKD and diabetes. Creatinine was measured by the AU480 chemistry analyzer system  according to the manufacturer’s protocol. GFR was calculated using the Cockcroft–Gault formula and HbA1C was measured by the Tosoh Automated Glycohemoglobin HLC-723G8 Analyzer . The identification of CKD and diabetic patients was performed based on GFR and HbA1C results after obtaining previously collected pathological data. CT images were acquired using a 64 multi-detector computed tomography (MDCT) Siemens Somatom Perspective scanner . The CT scan protocol incorporated the following technical parameters: 38.4 mm detector width; 0.6 to 20 mm reconstructed slice width, 80, 110, and 130 kVp ranges; 20 to 345 mA range; 17.5 lp/cm spatial resolution; 50 to 70 cm scan field of view (FOV); and 512 × 512 matrix size. CT images were analyzed independently by two observers with more than 10 years of experience in image data processing and analysis. Inter-observer reproducibility was assessed using intra-class correlation coefficients (ICC). 3) = length × width × depth × π/6.Since diabetes affects both kidneys equally, and in order to simplify the data, quantification was performed on the right kidney only. Renal length was measured using pole-to-pole kidney length distance on the coronal CT plane; kidney width was the diameter measured from the renal hilum to the opposite side on the transverse plane, and renal depth (anteroposterior diameter) was the longest distance on an axis perpendicular to the kidney width. Kidney volume, the most accurate measurement of renal size , was comThe collected data, including the demographic characteristics, were analyzed using MegaStat 10.1 add-in for Excel . To model the relationship between dependent variables such as kidney volume, GFR and creatinine and independent variables such as age and HbA1C, a linear regression model was constructed for each group. All correlations were made at a 99% confidence level and 90% power level. The minimum sample size needed for the whole study was calculated using Cochran’s formula and was found to be 166.Kidney volume measured on CT images, the levels of creatinine, GFR and/or HbA1C, along with patients’ age were correlated in the four different patient groups and regression coefficients were calculated. Scatter plot graphs were reported when there was either a positive or a negative correlation.r = −0.597) in males and (r = −0.308) in females  included 85 patients  with a mean age of 63.85 for females (minimum 48 and maximum 91) and a mean age of 62.36 for males (minimum 47 and maximum 92). A negative correlation was observed between kidney volume and age with Pearson correlation coefficient  and a negative correlation between GFR and age (r = −0.676)  .r = −0.031) while a weak positive correlation was seen between kidney volume and HbA1C (r = 0.063) (Diabetic patients (Group 2) included 111 patients  with a mean age of 67.97 for females (minimum 50 and maximum 86) and mean age of 64.78 for males (minimum 47 and maximum 95). There was a very weak negative correlation between HbA1C and age (= 0.063) .r = −0.594) while a positive correlation was noted between GFR and kidney volume (r = 0.371) (Chronic kidney disease patients (Group 3) included 24 patients  with a mean age of 72.60 for females (minimum 53 and maximum 88) and mean age of 74.36 for males (minimum 49 and maximum 95). A negative correlation was observed between creatinine and kidney volume (= 0.371) .r = −0.031) and a positive correlation between creatinine and HbA1C (r = 0.118) (r = 0.178).Patients having both CKD and diabetes (Group 4) included 31 patients  with a mean age of 75.21 for females (minimum 61 and maximum 86) and a mean age of 72.08 for males (minimum 59 and maximum 86). A negative correlation was found between GFR and HbA1C (= 0.118) . InteresThe positive correlation between HbA1C and kidney volume prompted further investigations as it contradicted the study’s expected result. Therefore, Group 4 was divided into two subgroups, controlled diabetes (included 24 patients) versus uncontrolled diabetes (included 7 patients), as controlling diabetes is known as the best way to prevent or slow down kidney damage . The divr = 0.9333), and a similarly positive correlation between the same variables but in uncontrolled diabetic CKD patients for 20 years and above (r = 0.996) (In uncontrolled diabetic CKD patients (below 20 years), there was a positive correlation between HbA1C and kidney volume (= 0.996) .Advanced glycation end-products, often caused by long-term, persistent hyperglycemia in diabetic patients, can trigger toxic mechanisms that can adversely impact health, especially the kidneys, resulting in diabetic nephropathy. The growth factor that manufactures extracellular proteins can increase significantly, thus leading to disposition of these proteins and, in turn, leading to renal mesangial extension or glomerular sclerosis . In addiHence, this study was conducted with the aim of expanding the screening and diagnosing tools on one hand, and since HbA1C is similarly efficacious as GFR in studying CKD  on the oInterestingly, the present study derived several correlations. In healthy patients, the correlation coefficient was greater between age and GFR than between age and creatinine. Consequently, the use of GFR was found to be more powerful when correlating with age, thus supporting the fact that creatinine revealed a weak correlation with age in normal, healthy patients .When correlating between kidney volume and age, males showed a stronger negative coefficient than females. Therefore, based on these results, kidney volume declines faster with age in males than in females. This is not surprising since gender, similar to many other factors, has its own effect on the age-related renal function decline . Piras eThis study also showed a very weak, insignificant correlation between HbA1C and age in diabetic patients. However, in patients having both CKD and diabetes, HbA1C showed a positive correlation with creatinine and a negative one with GFR. At first, a positive correlation was observed between kidney volume and HbA1C; consequently, this group was divided into two subgroups, taking into consideration diabetes onset and duration. Consequently, this positive correlation reappeared in controlled diabetic patients for less than 20 years, while it became a negative correlation in controlled diabetic patients for 20 years and above. The correlation between the same variables was positive in uncontrolled diabetic patients (below 20 years) (r = 0.9333) and with 20 years and above with (r = 0.996), respectively. It is important to note that a larger sample size is needed for better evaluation and conclusive results, as only three uncontrolled diabetic patients for 20 years and above were enrolled in this study.3, or an increase in GFR by 20 mL/min causes an increase in kidney volume by 20 cm3 approximately. On the other hand, an increase in HbA1C by 1% leads to a decrease in kidney volume by 13 cm3.Finally, the correlation between kidney volume with GFR (r = 0.371) and HbA1C (r = −0.577) on CT scan as reported in this study is of high interest as it can be used as a valuable biomarker to easily diagnose, predict and assess CKD. For instance, an increase in creatinine by 4 mg/dL results in a decrease in kidney volume by 50 cmThe current study had several limitations. First, it was conducted in one single hospital; therefore, intrinsic selection bias was present. Additionally, only right kidney measurements were taken into consideration, affecting the generalizability of the study. Moreover, renal volume measurement is not automatically segmented and depends entirely on the operator’s skills and protocol, leading to measurement and/or detection bias. Finally, there was a small sample size in the second and fourth groups.In this novel study, we have reported for the first time the correlation between both GFR and HbA1C with kidney volume measured using CT scan. This study aimed to facilitate the diagnosis and quantification of kidney damage and its prognosis by physicians by simply measuring the kidney volume on CT images rather than sending the patient for ultrasound exams and correlating the ultrasound measurements with laboratory GFR and HbA1C. GFR was more powerful than creatinine when correlated with age. Kidney volume was shown to decrease faster in males than females, in addition to revealing a negative correlation between GFR and HbA1C on CT images, and thus can be used as a powerful tool to predict CKD, especially in resource-poor settings. Moreover, the positive and negative correlations of HbA1C with creatinine and GFR, respectively, provide concrete evidence that HbA1C can serve as a good biomarker in studying renal function in diabetic CKD patients. This remarkable association created a potential “link” or “formula” that can help physicians to predict variations in kidney size in newly diagnosed CKD patients, in addition to assessing treatment efficiency and outcome via laboratory testing, thus eliminating the need for repeating the CT scan.However, further investigation should be performed, initiating standards regarding GFR, HbA1C and kidney volume correlations, shedding light on various different categories including diabetes duration and medications taken in diabetic kidney disease patients, as well as relating HbA1C results to intervals of age, different CKD stages and kidney volume.


Aim: Little is known about the cardiovascular effects of oral water intake in shock patients. This study was designed to assess the effect of oral water on stroke volume and blood pressure during a 1-h time period.Method and Results: This open-label, randomized clinical trial included patients admitted to intensive care with acute circulatory failure. Three ICU units at the anesthesia and critical care department of the Dijon Bourgogne University Hospital. Patients were randomized 1:1 to an intervention or standard care group. The intervention group received 500 ml of oral water while the standard care group received intravenous administration of 500 ml of physiological saline solution. Baseline SV did not differ between the two groups . The number of patients who were fluid responders did not differ between the two groups . The median change in stroke volume during the three time points did not differ between the two groups (p < 0.05). In the intervention group, blood pressure increased up to 60 min. In the control group, blood pressure quickly increased at the end of fluid expansion, then returned close to baseline value at 60 min.Conclusion: Shock patients who were administered oral water experienced improvements in blood pressure and blood flow up to 60 min when compared with patients who received intravenous saline solution. Further studies are warranted to confirm these effects.Clinical Trial Registration:www.clinicaltrials.gov, identifier: NCT03951519. Volume expansion remains a daily challenge in critically ill patients . There iBefore the development of the intravenous route, oral rehydration solutions were widely used. Oral rehydration was demonstrated to be associated with positive clinical effects such as an improvement in blood pressure, a lower fluid balance and a shorter hospital stay , 7. The Despite an abundant literature on oral feeding, we do not have data on the cardiovascular effects of oral intake of tap water in shock patients. Water is an easily obtained, natural product that can be administered orally, even in shock patients. Because we do not have data on the cardiovascular effects of oral water in shock patients, we designed a longitudinal randomized study over a 60 min period. This study aimed at describing the cardiovascular effects of oral water in patients with acute circulatory failure.The study was approved by an Independent Ethics Committee . This study is a second part of an investigation aimed at describing the value of oral water in shock patients , with stroke volume change following passive leg raising over 10% (preload dependency), and with no contraindication to a nasogastric tube. The exclusion criteria included permanent atrial fibrillation, hypothermia, concurrent participation in another study, and pregnant women.Inclusion criteria were participants who were aged 18 years or older, suffering from acute circulatory failure  at room temperature (22°C). Over a period of 15 min, 500 ml of this water was administered to the patient through the nasogastric tube by using a pump. Standard care consisted of intravenous administration of 500 ml of physiologic saline solution (NaCl 9%) over a period of 15 min.The intervention consisted of oral tap water with a low mineral content , immediately after administration (time 2), 30 min after administration (time 3), 60 min after administration (time 4).All patients had been sedated by continuous infusion of propofol and opioid, and were fully adapted to volume-controlled mode with a tidal volume (Vt) set at 7-9 ml/kg of ideal body weight, and a positive end-expiratory pressure (PEEP) of 5-15 cmHEchocardiography was performed by a physician with echocardiographic certification . Tissue 2, gap CO2/oxygen arteriovenous difference ratio, oxygen delivery (DO2), oxygen consumption (VO2), arterial lactate, hematocrit, sodium, and chloremia over a period of 60 min.The main outcome was the kinetic of stroke volume change between baseline (time 1) and 60 min after the end of fluid expansion (time 4). The secondary outcomes were the change of mean arterial blood pressure , the kinetics of arterial blood pressure, gap CO* (Hctpre/Hctpost – 1)/(1 – Hctpre) at time 2, time 3, and time 4 . The randomization procedure was stratified by stroke volume change following passive leg raising with a 1:1 ratio. Although the research staff who collected data could not be blinded to group assignments, much attention was given to ensuring strict blinding during the data collection and echocardiography data analysis.Study participants were randomly assigned to one of two groups using a computer-generated randomization code  were recorded by physicians affiliated with the hospital's clinical research division.p-value of 0.05. The normality of the data distribution was assessed using the Shapiro–Wilk test. Quantitative data were expressed as means ± standard deviation or medians [interquartile range], as appropriate, and qualitative data were expressed as numbers (percentages). Quantitative variables were analyzed by using bi-variate mixed linear modeling. The response variable was modeled depending on the group of randomization and the time of sampling (used as fixed effect) and the individual . Normality of the random effect and of residuals distribution was checked graphically. When the fixed effect was significant for between group comparisons, a pairwise testing was carried out with Bonferroni post hoc correction. Statistical analysis was adjusted to baseline amount of fluid before randomization. Qualitative variables were analyzed by using Wilcoxon test or Chi-2 test. All hypothesis tests were two-sided, and the threshold for statistical significance was set at P < 0.05. All analyses were performed using R software (Version 1.1.447).In absence of data, we performed a pilot study. The sample size calculation was based on volume expansion, where 500 ml of saline is usually associated with a mean SV change of 25% (+/−10%) for a mean baseline of 40 ± 10 ml . The inc−1  vs. 25 ml Kg−1 , p = 0.290). The number of patients with fluid responsiveness  did not differ between the two groups .Fifty patients were included; there were no exclusions. The baseline characteristics were similar between the two groups . Patientp = 0.952). The intervention and standard care groups exhibited significant differences in blood pressure over time . Then plasma volume decreased in the control group and increased in the intervention group .Oral water slightly increased hematocrit whereas saline infusion decreased hematocrit; both groups returned to baseline values at 60 min. After fluid administration, plasma volume changes differed between the two groups [8% (2-18%) vs. −2% (−5-4), p > 0.99) died during their stay in the ICU. Natremia and chloremia did not changed.The incidence of adverse events did not differ between the two groups . 18 patiThe main result of the present study is that oral tap water increases CO and blood pressure up to 60 min. These effects do not differ in term of amplitude, but they are longer with administration of oral water than with the infusion of a saline solution.These results may be explained by several known physiological mechanisms of oral water. The first and main effect is related to the pressor effect of tap water , 18, 19.The second mechanism may be in relation to the absorption of water and its effect on plasma volume . Water w2 up to the final time point of the study, and this effect was not observed in the control group. It may be explained by several factors: DO2-VO2 dependency, the effect of oral water on gut oxygen balance, or body thermogenesis following water ingestion (2 that can be diminished by decreasing the amount of enteral nutrition (b-adrenergic stimulation, as observed with intravenous infusion of epinephrine (Since water increases CO and blood pressure, we observed an increase in oxygen delivery. Oral water was associated with an increase in VOngestion . It was utrition . Oral wanephrine . IncreasThe present results demonstrated the effectiveness of oral water to improve blood flow and tissue perfusion. But these effects differ in term of duration from those observed with saline infusion. To date there are countless literature on fluid therapy, with a focus on renal effect and acid-base disturbance. No ideal fluid solution has been demonstrated. Interesting most of the literature has focused on fluid during shock resuscitation but maintenance fluid therapy and creep fluid may account for 30% of fluid balance . Oral waOral water may be harmful in specific subgroup such as acute heart failure, hemorrhage, or digestive ischemia. Few of the included patients were suffering of acute heart failure. Because the main underlying mechanism is the mobilization of the unstressed volume though pressor effect, giving oral water in hemorrhage shock may not be associated with fast hemodynamic effects. On contrary it could be associated with opposite effects , 30. Hea2 calculated from hemodynamic data is a valid alternative to VO2 derived from respiratory gas measurements.We did not perform a double-blind study. This study must be considered as a preliminary study that provides data on cardiovascular effects of oral water. We assessed hemodynamic changes by using echocardiography and not cardiac output device. Echocardiography has already used in several studies to evaluate the hemodynamic effect of intravenous solutions with good accuracy , 32. We In conclusion, the administration of oral tap water is associated with a sustained improvement in blood pressure when compared with patients who received intravenous saline solution. These results may be mainly explained by the vasopressor effects of oral water. Further studies are warranted to confirm these effects.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 Comité de Protection des Personnes Nord-ouest 3, Centre hospitalier universitaire de Caen. The patients/participants provided their written informed consent to participate in this study.Mohamed Radhouani, Tiberiu Constandache, Sandrine Grosjean, Pierre-Alain Bar, Pierre Voizeux, Emel Rafrafi, Audrey Martin.P-GG, MN, and VB contributed to the conception and design. P-GG and MN searched the associated data and drafted the manuscript. BB provided the supervision support. MN performed data analysis. All authors contributed to the critical revisions and final approval of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Coronary artery disease (CAD) is one of the most significant cardiovascular diseases that requires accurate angiography to diagnose. Angiography is an invasive approach involving risks like death, heart attack, and stroke. An appropriate alternative for diagnosis of the disease is to use statistical or data mining methods. The purpose of the study was to predict CAD by using discriminant analysis and compared with the logistic regression.This cross-sectional study included 758 cases admitted to Fatemeh Zahra Teaching Hospital  for examination and coronary angiography for evaluation of CAD in 2019. A logistics discriminant, Quadratic Discriminant Analysis (QDA) and Linear Discriminant Analysis (LDA) model and K-Nearest Neighbor (KNN) were fitted for prognosis of CAD with the help of clinical and laboratory information of patients.Out of the 758 examined cases, 250 (32.98%) cases were non-CAD and 508 (67.22%) were diagnosed with CAD disease. The results indicated that the indices of accuracy, sensitivity, specificity and area under the ROC curve (AUC) in the linear discriminant analysis (LDA) were 78.6, 81.3, 71.3, and 81.9%, respectively. The results obtained by the quadratic discriminant analysis were respectively 64.6, 88.2, 47.9, and 81%. The values of the metrics in K-nearest neighbor method were 74, 77.5, 63.7, and 82%, respectively. Finally, the logistic regression reached 77, 87.6, 55.6, and 82%, respectively for the evaluation metrics.The LDA method is superior to the Quadratic Discriminant Analysis (QDA), K-Nearest Neighbor (KNN) and Logistic Regression (LR) methods in differentiating CAD patients. Therefore, in addition to common non-invasive diagnostic methods, LDA technique is recommended as a predictive model with acceptable accuracy, sensitivity, and specificity for the diagnosis of CAD. However, given that the differences between the models are small, it is recommended to use each model to predict CAD disease. Cardiovascular diseases are of the leading causes of death worldwide. One of the most critical heart diseases is coronary artery disease (CAD). Coronary arteries include Left Anterior Descending (LAD), Left circumflex (LCX), and Right Coronary Artery (RCA), divided into left main artery (LMA) including LCX and LAD and right coronary artery (RCA). Suffering from CAD means that at least one of these arteries narrowness is more than 50% . ExaminaExercise testing, echocardiogram, nuclear scans of the heart and angiography are the ways to diagnose the disease, where angiography is the most accurate way to detect it , 8. In aThe literature review showed that different algorithms such as clustering, classifications, regression and association rules, decision trees, Bayesian network, neural network, multi-layer perceptron with error back propagation algorithm, scaled conjugate gradient (SCG) and support vector machine (SVM) have been used for predicting CAD –32. HoweGiven the importance of the issue of prediction prognosis of CAD and the fact that, up to now, no comprehensive comparative study has been conducted in Iran to predict CAD, this study tried to predict the prognosis of CAD using discriminant analysis and compared with the logistic regression model.The rest of this paper was organized as follows. In Sect. This diagnostic study was carried out as cross-sectional. The population study was all the patients with cardiovascular disease who were admitted to Fatemeh Zahra Teaching Hospital,  and underwent angiography of coronary arteries. The indication for angiography for patients were clinical indication including chest pain/ chronic coronary syndrome or unstable patients with myocardial infarction with or without ST segment elevation. The sample size in this study, according to the study of Kurt et al.  and consThis study contained the records of 758 patients, each of which has 19 variables. All variables can be considered as indicators of CAD for a patient, according to medical literature –38. The The inclusion criteria were patients who were admitted to the hospital for angiography due to cardiovascular disease with indication for angiography, and the exclusion criteria were patients who had received angiography before angiography or received any treatment after angiography. Diagnostic cases of CAD or non-CAD were recorded in the patient's file based on the results of angiography and physician's opinion. The study protocol and experimental protocols was approved by the Ethics Committee of Golestan University of Medical Sciences (IR.GOUMS.REC.1398.031). All methods were carried out in accordance with relevant guidelines and regulations, and a consent form was obtained from all the participants.DA is one of the multivariate statistical methods for classifying a set of observations and discriminant analysis is a statistical technique that allows the researcher to distinguish between two or more groups according to several independent variables simultaneously. This technique is one of the multivariate statistical methods used to classify a set of observations as well as assign new observations to predefined categories. In other words, with DA technique, one can combine the linear composition of the independent variables as a discriminant function and divide the observations into two or more categories .DA is one of the oldest and most well-known classification techniques proposed by Ronald Fisher in 1936 and generalized by others in later years , 41. OveLDA uses linear combination of independent variables to create the maximum intergroup ratio to intragroup changes in discriminant scores. Among the most popular functions used in DA is the Fisher discriminant function. In another method, the ranking rule is obtained by minimizing the average cost function (ECM) .DA examines the relationship between several independent variables and the class response variable. The easiest type of analysis is when the response variable has two groups. In this case, the discriminant linear function, which passes through the average of the two groups (centers), can be used to separate the two groups, and when there are several prediction groups, k-1, where k is the number of classes, is required for classification. Imagine there are two groups:If i is the member of group one if:Xi is the member of the second group if:XMultivariate normalization, homogeneity of variance–covariance matrix, linearity and the absence of multicollinearity between independent variables are of the assumptions of LDA , yet TabQDA is another DA technique that like LDA creates classification functions with independent variables. However, the functions are not linear in QDA. In some cases, linear functions may not create the best group separation, and using Quadratic Discriminant Functions (QDFs) may be more appropriate. However, in selecting the type of model, one must pay attention to the assumptions. Multivariate normal of the variables are independent of QDA method assumptions, but it does not assume variance–covariance homogeneity .Thus, QDA is a more appropriate analysis in case of variance–covariance heterogeneity.1 and S2 are variance–covariance matrix of the first and the second groups, respectively.QDA assigns the case i to group one if the following equation holds; otherwise, case i belongs to group two. Here, whereConsider the Mahalanobis distance (MD). This function is as follows:The function , 46. As LR is the commonest method used to examine the relationship between independent variables and qualitative response variables, especially the dichotomous response variable. LR is a multivariate statistical method where the dependent variable (response) is a nominal or ranked variable, and the independent variable or variables can be continuous, discrete, nominal, or ranking .Pi (probability of response) to n independent variables X1, X2,… and Xn. The name “Logistics” is derived from the word “Logit,” which is actually a variable change as follows.In LR, independent variables that can be continuous or discrete are used. This model is basically used to identify the relationship between two or more independent and dependent variables. LR model is for βi,s are the parameters estimated and Pi are the probability of the response. In using logistic regression to predict CAD, βo is the y-intercept and βi coefficients of the independent variables [In other words, Logit is a probability equal to the log of the ratio of chance or fraction whose numerator is the probability of an accident and its denominator is the probability of an accident. Converting P to ariables .In the data analysis, while examining the assumptions, to fit the discriminant analysis model, its assumptions were examined, and the results showed that according to the Mardia's Skewness test, the multivariate normality assumption is not established due to high Skewness and according to Breusch-Pagan test, variance–covariance matrix homogeneity assumption was not established in the two groups either. Tolerance and Variance Inflation were used to examine the multicollinearity between the independent variables. As the tolerance values were less than 0.1 and Variance Inflation less than 10, multicollinearity assumption was not violated. In this case, given the capability of DA, LDA techniques, QDA, discriminant analysis with KNN were used and compared, the value of k = 15 was obtained using cross-validation method in KNN.In order to fit the logistic regression model, the Hosmer–Lemeshow test was used to confirm the fit of the model, indicating that the logistic regression model can be used for this data set. In addition, the stepwise LR test is used to determine the predictor variables and perform multivariate analysis to adjust the effect of the variables. Odds Ratio (OR) and 95% confidence interval (95% CI) were calculated for the variable and the p. values less than 0.05 were considered as statistically significant. For model goodness of fit and to determine the accuracy, we used the diagnostic test indicators of receiver operating characteristics (ROC), accuracy, sensitivity and specificity. The statistical software package SAS  was used to perform a variety of DA and logistic regression.KNN is the first nonparametric DA presented by Fix and Hodges in 1951 , 50. ThiThe distance between the two observations is calculated from the following equation:Of the 758 subjects with suspected CAD who underwent coronary angiography, 409 (54%) were males and 349 (46%) females. The mean age and standard deviation were 59.11 ± 11.11 years with the lowest and highest age 27 and 90 years, respectively. Moreover, 250 (32.98%) subjects were non-CAD and 508 (67.02%) subjects were diagnosed with CAD.men vs women = 3.50, 95% CI: 2.55–4.82). Smoking  and illicit drug abuse  were similarly associated with the risk of CAD. Age , FBS , BUN , Cr , systolic blood pressures  and diastolic blood pressures  were directly associated with a greater risk of CAD. Conversely, according to the results, body mass index  and HDL  associated with a lower risk of CAD , in people with illicit drug abuse were 2.17 times higher than others , and in families with a history of cardiovascular disease were 1.93 times higher than in families without a history  . The level below the ROC curve in four modelling techniques was very close and estimated to be between 81 and 82%. According to the Delong test , there wIn general, all models converged in similar results. All methods estimated the same statistically significant coefficients. The overall classification rate for all was good, and either can be helpful in classifying the class membership of CAD. LDA slightly exceeds discriminant function in the correct classification rate but when taking into account sensitivity, specificity and AUC the differences in the AUC were negligibly, thus indicating no discriminating difference between the models.Accuracy, sensitivity, specificity and AUC indices of LR Models, LDA, QDA and KNN presented in Table Cardiovascular disease is the most important cause of death in Iran and the rest of the world. The most important recent epidemiological study of the Iranian population indicates that CAD is common among young people in this population . CardiovWe found that age, gender, illicit drug abuse, family history of heart disease, systolic blood pressure, as well as FBS, HDL, LDL, and BMI all play an important role in CAD risk. So that, in the study of Bidel et al. , gender,Subsequently, we report on a study in which we developed several predictive models to predict CAD. In particular, we used LR, KNN, LDA, and QDA. In addition, we evaluated the performance of the model based on SEN, SPE, Accuracy, and AUC. We tested the statistical significance of the difference in the area under the ROC curve in pairwise. Comparison of the results of evaluation indices showed that the accuracy of LDA was higher than logistic regression. In terms of sensitivity indicators, QDA is the highest and KNN is the lowest. In addition, their AUCs are very close in almost all models.According to the literature review, numerous studies have been conducted to predict CAD by using diagnostic models. In the study of Dwivedi et al. , data miWe suggest that gender, family history of heart disease, illicit drug abuse, age, BMI, FBS, HDL, LDL and Systolic blood pressure variables may be used as reliable indicators to predict presence of CAD. In our study, we compared methods by using a real data set in order to provide information on general tendency of data structures in data sets and help researchers to select best method for solving problems of classification. On the basis of these considerations, the linear discriminant analysis method is superior to the QDA, KNN and LR methods in differentiating CAD patients. Therefore, in addition to common non-invasive diagnostic methods, LDA technique is recommended as a predictive model with acceptable accuracy, sensitivity, and specificity for the diagnosis of CAD.There are a few limitations with this study. First, this was a cross sectional study design with the documented data that abnormalities in biologic characteristics such as laboratory values we do not know whether they preceded the disease or were a result of the disease. Second limitation, we only collected data from one hospital which may limit the generalizability of the developed models, so data collection from more hospitals or population based should be considered. We also need more data from patients e.g., clinical symptoms and electrocardiogram (ECG). However, consistent with the purpose of the current research, considering only the routine clinical features of the patients while being admitted would suffice. Another limitation of our study was the low number of samples to compare different models.In this study, several models were applied on the dataset and the results were discussed. The variables included in this dataset are possible indicators of CAD, according to our medical knowledge. The accuracy value achieved in this study is, to the best of our knowledge, higher than currently reported values in the literature.In future, we aim to consider predicting state of each artery independently. Moreover, it is obvious that true diagnosis of diseased people is more important than true identification of healthy ones. Finally, larger datasets, more variables and also broader data mining approaches, could be used to achieve better and more interesting results, and these models need to be compared with the artificial neural network and machine learning models as well.


Coronary artery tortuosity (CAT) is regarded as a variation of vascular anatomy, and its relationship with coronary artery calcification (CAC) score is still not well clarified. Studying the correlation between coronary artery calcification scores and CAT to determine specific prevention and intervention populations seems to have more meaningful.The study is a cross-sectional retrospective study, including 1280 patients. CAT is defined as the presence of at least three consecutive curvatures of more than 45°measured during systole or diastole of a major epicardial coronary artery. Multivariable regression analysis was used to adjust the clinical parameters directly affecting CAT.P = 0.025) revealed significantly associated with CAT on univariable analysis. However, multivariable analysis after adjusting for confounding factors only indicated that CAT was positively correlated with female , hypertension , and age , while was negatively associated with body mass index (BMI) 24–27.9, and BMI > 28 . Further analysis stratified by gender showed that compared with non-CAT, CAT was significantly linked with moderate CAC score , hypertension , and high-density lipoprotein (HDL) , while was negatively related to BMI > 28  in female patients.Of these individuals, 445 (35%) were evaluated having CAT, of which females are higher than males (59.1% vs. 40.9%). Moderate CAC score (101–400) (odds ratio (OR) 1.49, 95% confidence interval [95%CI] 1.05–2.10, CAT is more likely to be found in females, connected with hypertension, age, and BMI. No significant correlation is found between the presence of tortuosity and calcium score or diameter stenosis on multivariable analysis. Whereas the CAT is associated with moderate CAC score in correlation analysis when women are selected as the main group.The online version contains supplementary material available at 10.1186/s12893-022-01470-w. Vascular calcification is the active deposition process of bone-specific hydroxyapatite crystallization in the blood vessel wall caused by multiple pathogenic factors . VasculaFurthermore, CAT is a common phenomenon found in coronary angiography . The etiThis is a cross-sectional retrospective study registered in the China Clinical Trial Registration Center (ChiCTR1800020259). The study included patients with suspected coronary artery disease and stable hemodynamics who underwent coronary CTA examinations using 320-row-detector dynamic volume CT from January 1, 2020 to March 9, 2021.The patients with a past history of coronary stent implantation, coronary artery bypass graft, prosthetic valve or pacemaker implantation, pregnancy, chronic renal insufficiency, and those presenting any contraindication for iodinated compounds were excluded.Coronary CTA images were reviewed by two experienced radiologists who were blind to all clinical profiles of the participants. CAC score was calculated by dedicated software and quantified as the Agatston score . AccordiVenous blood samples were collected from all participants after a 12-h overnight fast. Biochemical parameters were determined in the Department of Clinical Laboratory, Zhong Da hospital affiliated Southeast University.Hypertension was defined as systolic blood pressure ≥ 140 mmHg or/and diastolic blood pressure ≥ 90 mmHg, or taking antihypertensive drugs. Diabetes was diagnosed according to the WHO criteria. Smokers were defined as those smoking in the past 1 month.t test if normally distributed or the Mann–Whitney test if not normally distributed. Categorical variables were described as percentages and compared by χ2 testing. Multivariable logistic regression was used to assess the association of CAT with calcification score. The final model was adjusted for sex, age, BMI, hypertension, diameter stenosis, uric acid, TG, and HDL. Univariable and multivariable analysis were performed to identify clinical parameters directly affecting coronary tortuosity. All tests were 2-sided and P values < 0.05 were considered statistically significant.IBM SPSS software  was used for statistical analysis. All data were accomplished a normal distribution test before analysis. Continuous variables were expressed as the mean ± standard deviation (SD) if normally distributed, otherwise as median (interquartile range); in addition, comparisons between groups performed by the P < 0.001), age (P < 0.001), BMI (P < 0.001), hypertension (P = 0.014), uric acid (P = 0.018), triglycerides (TG) (P = 0.047), and high-density lipoprotein (HDL) (P < 0.001) were similar in both groups.Baseline characteristics of participants in the study were presented Table . A totalP = 0.025) in unadjusted analysis  (Table P < 0.001). Participants with hypertension were more possible than those without to be CAT . Compared with patients without lumen stenosis, patients with moderate lumen stenosis were associated with CAT . In addition, overweight (BMI 24–27.9)  and obese patients (BMI > 28)  were less likely to coexist with CAT than normal weight patients (BMI 18.5–23.9) on univariable analysis.On univariable analysis, female was more likely to have CAT than male , age , and hypertension  remained significantly associated with CAT (Table P = 0.044) and obese  were less likely to have CAT than those with normal weight.On multivariable analysis, after adjusting for the parameters that affect CAT, female , while this correlation was not found in male patients (Table P = 0.024), and after full adjustment  . Moreover, CAT in female patients was positively correlated with hypertension  and HDL , and negatively correlated with obesity , while it in male patients was positively associated with age  and negatively associated with overweight  and obesity  (Tables In order to explore the correlation between coronary tortuosity and CAC score in special populations, gender was stratified and further analyzed. Univariate analysis revealed that in female patients, compared with patients with an Agatston score of 0, patients with a high Agatston score were significantly associated with CAT (1–100, OR 1.49, 95% CI 1.01–2.18, In this study of 1280 participants, it is documented that age and hypertension may be the main factors for the occurrence of CAT, which is consistent with the results of other researchers . It shouThe results of the study on the correlation between gender differences and CAT are also consistent with the findings of other current works , 24. It We did not find a negative correlation between CAT and atherosclerosis described by Li et al. , which mThis study is a single-center cross-sectional study, which limits the comparability of our findings to the general population. In addition, there is a lack of classification in CAT severity, which is uniformly defined as at least three consecutive curvatures greater than 45 degrees in a major epicardial coronary artery. Moreover, there may be some differences between the two methods of coronary angiography and CTA in the assessment of coronary artery stenosis.Tortuous arteries are common in humans. Although slight tortuosity is asymptomatic, severe tortuosity may cause an ischemic attack in remote organs. Our results show that tortuous arteries are related to aging, hypertension, BMI, and gender. However, little is known about the mechanism of its formation and development. In the future, more research is needed to explore the mechanism and provide new technologies to prevent and treat vascular curvature.Additional file 1. Univariable analysis of variables associated with CAT.


Health-related quality of life was assessed by self- and parent-rated German-language KINDL-R questionnaires , while mental problems were analyzed using the Strengths and Difficulties Questionnaire (SDQ). Our findings confirmed that blood pressure was significantly lower in adolescents reporting episodes of headache than in those without headache . Logistic regression models adjusted to sex, age, body mass index, contraceptive use, and serum magnesium concentration demonstrated that headache was significantly associated with self-rated KINDL-R (Exp(B) = 0.96, 95% confidence interval (95% Cl) = 0.96–0.97, p < 0.001), parent-rated KINDL-R (Exp(B) = 0.97, 95% CI = 0.96–0.98, p < 0.001), as well as self-rated SDQ (Exp(B) = 1.08, 95% CI = 1.07–1.10, p < 0.001), and parent-rated SDQ (Exp(B) = 1.05, 95% CI = 1.04–1.06, p < 0.001). There was evidence that quality of life and mental problems mediated the effect of blood pressure on headache, as revealed by mediation models. Our results from the nationwide, representative KiGGS survey showed that low blood pressure is a significant predictor of headache, independent of quality of life and mental problems. However, these psychosocial factors may mediate the effect of blood pressure on headache in a still unknown manner. Studies have reported controversial results on the relationship between headache and blood pressure. The aim of this post hoc study was twofold: first, to further investigate this relationship and, second, to assess the impact of psychosocial factors on this association in a population-based study of German children and adolescents. The analysis was conducted on study participants aged between 11 and 17 years ( Headache is one of the most common health problems in children and adolescents worldwide ,2, and aThis post hoc analysis is based on data from the public use file of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). The KiGGS study was a national survey conducted by the Robert Koch Institute , between 2003 and 2006 following a one-year pretest that collected data to provide information about the mental and physical health of children and adolescents in Germany . The datn = 5221) since, for these study participants, information on blood pressure as well as data from both self- and parent-rated psychosocial assessments were available. Using a standard interview question, study participants were asked whether they had experienced none, one, or more than one episode of headache within the last three months. The sample was categorized based on the presence of recurrent headache into those who reported suffering from headache (n = 2238) and those who did not (n = 2983) [The KiGGS baseline survey had a 66.6% response rate, producing a total cohort of 17,641 study participants aged between 0 and 17 years (8656 girls and 8985 boys) ,17. A we = 2983) . All accompanying parents, and the adolescents themselves if over 14 years of age, provided their written informed consent to participate in the survey prior to each interview and examination. The study protocol was approved by the Institutional Review Board of the Charité Universitätsmedizin Berlin as well as the German Federal Data Protection Office.The local study teams at each sample point, which consisted of five trained members led by a physician experienced in pediatrics, performed clinical interviews and physical examinations, and took blood samples for laboratory analyses. From each study participant, systolic and diastolic blood pressure was recorded using a two-time oscillometric determination with an automatic sphygmomanometer , according to the manufacturer’s algorithm . The twoFor laboratory measurements, blood samples were taken with evacuated EDTA and gel tubes after venipuncture. The samples were refrigerated at 4 °C and transported to a university hospital laboratory  for central analysis. Commercial tests were performed according to the specifications given by the manufacturers . MagnesiThe Strengths and Difficulties Questionnaire (SDQ) is a widely used psychometric instrument that detects possible psychiatrically relevant issues such as emotional and behavioral problems ,22. The To assess health-related quality of life, the German-language Children’s Quality of Life Questionnaire (KINDL-R), available as a self- and parent-rated version, was used ,25,26. T2 tests for categorical variables and Student’s t and Mann–Whitney tests for continuous measures. Pearson’s correlation coefficients were calculated to establish the associations between systolic blood pressure and self- and parent-rated SDQ and KINDL-R scores. Sampling weights were used to account for unequal sampling probabilities in terms of age, sex, region , and nationality. The study cohort was characterized based on the occurrence of headache by means of descriptive statistics. Means and standard deviations were calculated for continuous variables; percentages and standard deviations are given for categorical variables. Group comparisons between probands with and without headache were performed using χ2 were used as indicators for the amount of explained variance in the regression models. Odds ratios (Exp(B)) and results from Wald tests are also reported. Similar models were adjusted to the same confounders by substituting quality of life with either the self- or parent-rated SDQ score. To test whether health-rated quality of life independently predicted the occurrence of headache, logistic regression models were calculated by entering age, sex, body mass index, contraceptive use, mean systolic blood pressure, and serum magnesium levels as confounding variables. Cox and Snell Rp value of <0.05 was considered statistically significant. Statistical analyses were performed with the software Statistical Package for Social Science  from IBM Deutschland, Ehningen, Germany.Mediation models were computed using the SPSS macro PROCESS v2.10 created by Preacher and Hayes  to studyp < 0.001), more frequently female . Oral contraceptive use was more frequently observed in adolescents with versus without headache . Although socioeconomic and migrant status did not significantly differ with respect to headache, systolic blood pressure was slightly and significantly lower in the headache group than in their counterparts who did not report headache , whereas 2983 did not . Study pp < 0.001; p < 0.001). Similarly, self- and parent-rated SDQ values were both significantly higher in the headache group  and negatively related to the respective SDQ scores  [In the total study cohort, systolic blood pressure was positively associated with both self- and parent-rated quality of life (r = 0.030 and ctively) . A detaip < 0.001 and parent-rated KINDL-R Exp(B) = 0.97, 95% CI = 0.96–0.98, p < 0.001). In both models, systolic blood pressure (p < 0.001) and magnesium (p ≤ 0.039) remained associated with headache. A series of logistic regression models were computed to confirm whether headache was associated with either health-related quality of life or mental distress, when adjusted for sex, age, body mass index, contraceptive use, blood pressure, and serum magnesium . The datp < 0.001, and Exp(B) = 1.05, 95% CI = 1.04–1.06, p < 0.001). In these two models, blood pressure was again associated with headache (p < 0.001), whereas magnesium lost its role in predicting the occurrence of headache.Similarly, self-rated (Model 3) and parent-rated SDQ (Model 4) were significant predictors of headache (Exp(B) = 1.08, 95% CI = 1.07–1.10, Mediation models were created to test for possible interactions of either quality of life or mental distress on the relation between systolic blood pressure and headache. Data showed that quality of life was a significant partial mediator of the relation between blood pressure and headache, as the 95% CI for the indirect effect did not include zero. These results were observed for both self- or parent-rated KIND-R scores (Our analyses, based on data from the nationwide, representative German KiGGS study in children and adolescents, showed that the prevalence of headache was inversely related to systolic blood pressure, while it was positively linked to lower quality of life and higher mental distress. The main finding of the present post hoc study is that low blood pressure, reduced quality of life, and high distress are independently associated with the occurrence of recurrent headache. Moreover, psychological parameters such as quality of life and distress seem to mediate the effect of blood pressure on headache, irrespective of whether psychometric data from self- or proxy-rated questionnaires were used in these regression models. Several studies have analyzed the relationship between headache and blood pressure and have reported contradictory results. Even though some studies showed a positive relation between hypertension and an increased prevalence of tension-related headaches and migraines ,5,6,7, iThe inverse association between headache and blood pressure possibly results from a phenomenon termed hypertension-associated hypalgesia, in which the baroreflex system modulates nociception via endorphinergic and noradrenergic neurons present in the brain and spinal cord ,12. In hPreviously, low systolic and diastolic blood pressure were linked to different psychological disorders such as depression and anxiety in adults . LikewisOur regression models adjusted for quality of life showed a significant relationship between lower serum magnesium levels and headache problems in German adolescents. The finding of a link between serum magnesium and the prevalence of headache, which was independent of quality of life, is in accordance with data from other studies, showing that juvenile and adult migraineurs had significantly lower serum and red blood cell magnesium concentrations ,36. In aOur observations should be interpreted in light of several limitations that are inherent in this post hoc analysis and prohibit any causal interpretation of our findings. The evidence level of our findings is definitively lower compared with randomized controlled trials or with prospectively designed case-control studies, as the survey was not originally designed to assess the specific research question addressed here. Whether blood pressure and the psychological parameters tested have any causal relationship for the development of recurrent headache cannot be conclusively determined from this cross-sectional analysis. Although the large sample size allows for the detection of even weak associations, the correlation coefficients and the effect sizes are very small and, by far, not clinically relevant. However, the study also has distinct strengths, which include the large sample size and the method of sampling, which was random selection to ensure nationwide representativeness. The use of validated, clinically accepted assessments in a standardized and blinded manner should also be mentioned as a crucial strength of this analysis. Other strengths result from the clinical interviews and examinations being performed by trained physicians and laboratory measurements conducted under standardized conditions by experienced personnel blinded to the identity of the study participants.In summary, in this representative, nationwide, and large sample of German adolescents, we demonstrate that headache is inversely associated with systolic blood pressure, and is also linked to lower quality of life and higher mental distress. Psychological parameters may mediate the effect of blood pressure on headache. However, considerably more research is required to confirm these findings and decipher possible physiological mechanisms that may underlie these relationships.