Diabetic foot ulcer (DFU) is one of the serious complications of diabetes. It is the result of a joint effect of lower extremities vascular lesions, neuropathy, and infection, which require amputation and even threaten the life of the patient. At present, the conventional treatment for DFU includes infection control, wound care, wound reduction, reduction of foot pressure, use of dressings that are beneficial to wound surface healing, etc, but the effectiveness is not satisfactory. Recombinant human growth hormone and alginate dressing have been used in clinical, but there is lack of the relevant evidence of its effectiveness and safety, so this study evaluates the clinical effectiveness and safety of recombinant human growth hormone combined with alginate dressing in the treatment of DFU by systematic evaluation, the purpose is to provide a theoretical basis for the treatment of diabetic foot ulcer.This study mainly retrieves the randomized controlled trial of recombinant human growth hormone combined alginate dressing in the treatment of DFU in 7 electronic databases, such as PubMed, EMbase, Cochrane Library, SinoMed, CNKI, WANGFANG database, and VIP database. All the retrieval dates of database are from the establishment of the database until May 31, 2020. At the same time, searching the related degree papers, conference papers, and other gray literature by manual. The original literature data are independently screened and extracted by 2 researchers on the basis of inclusion and exclusion criteria and literature information sheets, and cross-checked and resolved through group discussions and consultations when there are differences of the opinion. Assessing the methodological quality of inclusion in the study based on the “Bias Risk Assessment Form” of the Cochrane Collaboration Network. Using the software of RevMan 5.3.3 and STATA 13.0 for statistical analysis.This study compares the main and secondary outcome indicators by systematic evaluation and it will provide strong evidence of recombinant human growth hormone combined alginate dressing in the treatment of DFU.All data in this study are obtained through the web database and do not involve humans, so ethical approval is not suitable for this study.DOI 10.17605/OSF.IO/W6P24.This study will give positive conclusions about the effectiveness and safety of recombinant human growth hormone combined alginate dressing in the treatment of DFU. With a prevalence rate of 9.7%, China has become the fastest growing region of diabetes in the world and the world's largest diabetes country.,3 The harm of diabetes is mainly reflected in complications, it has reported that the risk of cardiovascular complications in diabetic patients is 2 to 4 times higher than that in normal people, and diabetes is the leading cause of non-traumatic amputation, blindness, and advanced kidney disease.,5 As one of the serious complications of diabetes, diabetic foot ulcer (DFU), its high incidence, high hospitalization rate and high disability rate seriously threaten the quality of life of diabetic patients. According to statistics, diabetic patients have a 12% to 25% chance of developing DFU, and the recurrence rate within 5 years after ulcer healing is 50% to 70%. About a quarter of people hospitalized with diabetes are associated with DFU complications, and there is 1 amputation due to DFU every 30 seconds in the world has a 50% increased risk of losing another leg after 3 years, the leading cause of non-trauma amputation, with a death rate of 13% to 17%.,8 DFU not only affects the quality of life of diabetic patients, but also brings a heavy burden to their families and society. In the United States, the total cost of treating a final amputation due to a severe DFU infection is already as high as $190,000; in China, the cost of treating non-severe DFU is $1673; in India, a patient's total income of 5.7 years can only treat a foot ulcer surface. It can be seen that DFU has become a public challenge, the development and prognosis of foot ulcer is the result of multi-factor interaction, and it is closely related to neurological dysfunction, exovascular lesions, and infection. It is necessary to study the causes of foot ulcer healing and perfect its treatment plan to explore effective early prevention and treatment methods.Diabetes is a group of metabolic diseases characterized by high blood sugar and it causes by insulin secretion or deficiency of action, or both. Diabetes is becoming a public health problem as the improvement of people's living standards and the changes of their lifestyles. Growth hormone (GH) is a protein hormone secreted by the pituitary frontal leaves, controlled and regulated by the hypothalamus, which consists of 191 amino acid residues, the relative component is about 2.2 × 104, and it contains 2 pairs of disulfide bonds, no glycosylation, with a high degree of species specificity. GH is regulated by the GH secretion receptor in the human body, the main biological function is directly involved in the body metabolism and indirectly promote the growth of the body. Recombinant human growth hormone (r-hGH) is produced by recombinant gene technology and its chemical composition includes amino acid sequence and amino acid composition determined to be identical to pituitary growth hormone. In the 1980s, r-hGH was made and officially listed through gene recombination technology, which initially mainly treated patients with growth hormone deficiency (GHD), and it was then widely used in the fields of pituitary degeneration, bone and cartilage repair, burns, surface repair, plastic surgery, and so on. After long-term clinical research and practice observation, a better therapeutic effect has been obtained. In recent years, with the further study of GH, its application in the field of DFU repair has gradually increased.,15 Dressing is widely used in wound care, protecting wounds and promoting wound healing, and it is a key material for treating DFU, of which alginate dressing is the most representative. Alginate dressing has high water absorption, exists in the form of calcium sea alginate or sodium sea alginate, and it can be combined with collagen. Alginate comes into contact with the surface of the wound to form a gel that can be removed with the dressing or rinsed with sterile saline. Alginate dressing contains calcium alginate or sodium sea alginate is highly hydrophilic and can absorb large amounts of wound oozing, so it is commonly used to treat very wet wounds, absorb excess water, and avoid skin impregnation. International guidelines for DFU treatment suggest that DFU should choose a dressing that keeps wounds moist, so alginate dressing has gradually been used in the treatment of DFU in recent years.The clinical treatment of DFU is difficult, long course of illness, high cost of treatment, poor quality of life, so surgical treatment has become the main method of diabetic foot ulcer, but how to improve the quality of preoperative surface foundation, reduce preoperative preparation time, improve the rate of wound healing after surgery has been listed as the common problem need to be solved urgently by the world's major health organizations.At present, recombinant human growth hormone and alginate dressing have been used in clinical treatment of diabetic foot ulcer, but due to the lack of high quality, multi-level, and multi-angle clinical trial supporting, so the effectiveness and safety of recombinant human growth hormone and alginate dressing in DFU patients is still controversial. This study evaluates the randomized controlled trials of recombinant human growth hormone combined alginate dressing in the treatment of DFU by systematic evaluation.2The purpose of this study is to find evidence-based medical evidence for the effectiveness and safety of recombinant human growth hormone combined alginate dressing in the treatment of DFU, so as to provide new clinical ideas and theoretical basis for the diagnosis and treatment of DFU in the future.33.1https://osf.io/w6p24).OSF registration number: DOI 10.17605/OSF.IO/W6P24  ≥ 0.9.3.2.2Collecting the randomized controlled trials published in Chinese or English on recombinant human growth hormone combined with alginate dressing in the treatment of DFU.3.2.3Patients with type I or type II diabetes and open DFU wounds. There are no restrictions on the cause of DFU in this study, and randomized controlled trials in DFU patients with neurotic or ischemia or ischemia are eligible for inclusion.3.2.4Patients in the control group were treated with alginate dressing for external use and basic treatment of diabetes.Patients in the experimental group were treated with recombinant human growth hormone + alginate dressing for external use + basic treatment of diabetes. The specifications, dosing, and treatment time of the drug are unlimited.3.31.Persons with severe cognitive impairment and non-cooperation.2.Persons with apparent necrosis and osteomyelitis.3.Patients with malignant tumors.4.Persons suffering from cellular tissue inflammation who have not been treated.5.Drugs that interfere with this study have been used in the last 1 month.6.Exclusion of diabetics who are pregnant.7.Patients using drugs that affect wound healing: for example, glucocorticoids, chemotherapy, anticoagulants, immunosuppressants, etc.8.Literature with incomplete reviews, animal studies, and data reports.3.43.4.11.Total effective rate: it is evaluated by healing, effectiveness, and ineffectiveness. Healing: ulcer or gangrene have fully healed, or scarred. Effectiveness: ulcer or gangrene surface reduction, significant reduction of local secretions, gangrene shows a large area of shedding state, and some new granulated tissue. Ineffectiveness: ulcer or gangrene invasive surface aside, secretions does not significantly reduce, or even increase. Total effective rate = healing + effectiveness/total number of cases × 100%.2.Local symptom scores: the total score is 36 points, the higher the score, the more serious local symptoms.(1)Wound surface depth: Healing (0 points), <0.5 cm (2 points), 0.5 to 1 cm (4 points), >1 cm (6 points).(2)The coverage rate of rotten meat: none (0 points), <30% (2 points), 30% to 70% (4 points), >70% (6 points).(3)The range of red and swollen: none (0 points), from the edge of the wound <1 cm (2 points), from the edge of the wound 1 to 3 cm (4 points), from the edge of the wound >3 cm (6 points).(4)Meat buds: healing (0 points), red shoots, small particles (2 points), granules light red or slightly red (4 points), granules edema, meat color is not fresh (6 points).(5)Secretions: none (0 points), serum-like secretions (2 points), pus thick (4 points), pus thick, skunk (6 points).(6)Pain level: none (0 points), occasional or sustained minor pain (2 points), pain is tolerable, does not affect normal life (4 points), pain is unbearable, need to use analgesics (6 points).3.4.21.Occurrence of adverse reactions: including bleeding, edema, infection, dermatitis, etc.2.Coagulation function: active partial clotting enzyme time and fibrinogen content.3.High value of ankle brachial index, ABI, high value of systolic pressure of the ankle artery (back artery or back artery)/high value of systolic pressure of the artery.4.The healing time of wound surface.5.Cumulative number of drug changes.3.5The computer fully retrieves PubMed, EMBASE, Cochrane Library, CNKI, SinoMed, WANFANG Database, VIP Database, and the retrieval time range is from the establishment of the database until May 31, 2020. Collecting the randomized controlled trials of recombinant human growth hormone combined alginate dressing in the treatment of DFU, the search method is to combine the subject word with the free word, and try to search for synonyms, and determine the search strategy after many pre-retrievals, according to the specific situation of strategic, different databases will be adjusted. In addition, the references to all relevant articles are screened to ensure full documentation. Results of literature search using PubMed database ; the details of treatment plan of control group and experimental group; the details of the same interventions in both groups of participants; the data on main and secondary outcome indicators: the sample size of counting data, the average and standard deviation of measurement data.3.7The quality of included studies is evaluated by using the bias risk assessment tool recommended by the Cochrane System Reviewer Manual. A total of 7 evaluation entries, including:(1)Random method.(2)Allocation concealment.(3)Implementation bias.(4)Follow-up bias.(5)Measurement bias.(6)Reporting bias.(7)Other bias.Each evaluation entry has a “High,” “Unclear,” and “Low” 3 levels of bias risk. “High” refers to the failure to implement a group of allocation concealment, the intervention is not uniform, and the subjects withdraw from the trial research, random method is error, measurement results method is not uniform, blind method is not used, the outcome data is incomplete, or failure to report the main key outcomes that should be included, etc; “Unclear” means that the specific situation or incomplete information is not stated in the text; “Low” means that the random method describes it in detail and correctly, using the appropriate blind method, or whether or not the use of blind method does not affect the results of the trial, the outcome data is complete, or the missing data does not affect the outcome analysis, there are no other problems.3.8I2 tests, the test level α is 0.05. The counting data is represented by odds ratio (OR) or relative risk (RR) and 95% CI, and the metering data is represented by a standardized mean difference (SMD) and 95% CI. The heterogeneity between the results of each study is tested by using Cochrane Q. When the studies with better homogeneity , the fixed effect model is used, while the meta-analysis is carried out by using the random effect model for the studies with more obvious heterogeneity. In the forest map, the point estimate of each study effect is expressed in square, the weight of each study is represented by the square, the line extending on both sides of the square represents the confidence interval of the effect amount, the length of the line is inversely compared with the confidence interval of the effect amount, and the longer the segment, the wider the confidence interval, the less accurate the result is, and vice versa. When the 95% CI horizontal line of the study RR intersects the invalid vertical line , it is not statistically significant to indicate the difference between the occurrence rate of the experimental group and the control group, when the 95% horizontal line of the study RR falls on the right side of the invalid line, the occurrence rate of an event in the control group can be considered to be greater than the occurrence rate of an event in the experimental group, the experimental factor can increase the occurrence of an event, and it clinically considers the effectiveness of the experimental group to be better than the control group; otherwise, it is the opposite conclusion.The RevMan 5.3.3 software provided by Cochrane Collaboration Network is used for meta-analysis. Heterogeneity tests are based on forest maps and 3.9If there is obvious statistical heterogeneity between the included studies, it needs to conduct the analysis results for the sensitivity analysis.(1)Excluding studies of lower quality, excluding studies with less stringent designs, excluding studies with large or small sample sizes, excluding unresolved studies, and then conducting meta-analysis again to observe whether the conclusions have changed.(2)After changing the study type and selecting different effect models for the same data, it is observed whether the effect merge value and confidence interval have changed.If the results of meta-analysis do not change significantly before and after the sensitivity analysis, indicating that the results of this meta-analysis are reliable, and if the results of meta-analysis change significantly before and after the sensitivity analysis, indicating that the reliability of the meta-analysis results is poor, it is important to clearly use heterogeneity sources, the results and conclusions need to be careful.3.10P > .05, indicating that there is no publication bias, on the other hand, indicating that there is publication bias, which can be used to further clarify the symmetry of the funnel plot by linear regression, and to find out the intercept of regression equation and 95% CI, and to analyze the possible causes of publication bias.Using funnel plot to indicate publication bias, the horizontal coordinates of funnel plot to represent the effect size, ordinates represent the sample size by using the scatter plot. If the effect points of the included study on the axis of the collection is an inverted funnel shape, the left and right is basic symmetry, indicating there is no publication bias, and using Egger's test to detect the specific situation of publication bias. If 3.11This study uses the method of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) to evaluate the evidence quality and recommended strength of the study results, and it is divided into high (A), medium (B), low (C), and very low (D). The starting of RCT is high quality, and studying the bias risk, insistency, inexactness, indirectness, and publication bias that will be considered to downgrade and indicating the downgrade factors in the study results. The process of evaluation is conducted independently by the 2 researchers after the training, and discussing and resolving with the third researcher in case of disagreement.4The mechanism of diabetic foot ulcer is complex, including the result of a combination of vascular lesions, neuropathy, and accompanying infection. The occurrence of DUF mainly includes 2 aspects:(1) In addition, patients with DM disease have narrow blood vessels, rough blood vessel walls, increased fibrinogen and globulin, high blood viscosity and slow blood flow, which cause changes in the patient's hemodynamics. The change of hemodynamics can further increase the risk of foot ulcer, and patients often have no conscious symptoms until ulcers occur. The reduction of blood supply at the extremity of DFU patients hinders the wound healing, thus increasing the risk of foot lesions and infection.Vascular lesions are the main factors in the emergence of DFU, diabetes mellitus (DM) patients’ high blood sugar can aggravate the endothelial damage of blood vessels. In addition, its anti-agglutination effect is weakened, thus aggravating the formation and development of atherosclerosis. Atherosclerotic plaque is formed after atherosclerosis, so that it deposits a large amount of calcium in the patients’ blood vessels, thus affecting the formation of collateral circulation of blood vessels in the distal part of the body. DM patients are often accompanied by vascular spasms, which cause blood movement disorders at the end of the limb, most of which are associated with insulin resistance in DM patients.(2) In addition, the infection is the direct cause of amputation of DFU patients, due to peripheral neuropathy, the normal sweating ability of the sweat glands weakened, making it easier for bacteria to plant deep tissue. In addition, the inflammatory chemotaxis of DFU patients is weakened and the resistance is reduced. It is highly susceptible to cause infection and infection migration, which can seriously lead to amputation or even death.Neuropathy and excessive mechanical force are the starting factors that cause ulcer in the lower extremities of DM patients. Neuropathy in DFU patients includes sensory neuropathy and mild peripheral neuropathy. Among them, sensory neuropathy makes patients lack of neuroprotective mechanism, resulting in sensory paralysis, and significantly reducing the patient's ability to protect themselves. Peripheral neuropathy causes the skin's blood regulation and control of perspiration to weaken, resulting in decreased elasticity of the foot tissue, thereby increasing the incidence rate of ulcer.:At present, the mechanism for recombinant human growth hormone in the treatment of DFU may have(1)The effect of promoting cell proliferation and growth: the injection of growth hormone can stimulate the continuous proliferation of endoblast cells, endocrine cells, etc in wound tissue, thus accelerating the deposition of wound collagen, so that accelerates the re-epithelialization process of the ulcer wound and reduces the healing time of the wound.(2)Immunomodulation effect: DFU patients are prone to cause infection and infection migration, may be due to the long-term high blood sugar of DFU patients, the tending effect of body inflammatory weakened, the decreased resistance. GH is a strong inducer of the immune system and a hormone that promotes the protein synthesis, which plays an important role in regulating the production and function of immune cells. It stimulates the synthesis of lymphocyte DNA, enhances the proliferation of macrophages and lymphocytes, and stimulates the production of immunoglobulins. In addition, growth hormone has been found in in-body experiments to improve the function of the immune system, which can promote the chemicalization effect, stimulate monocytes to enhance their phagocytic function, and improve the reactivity of T lymphocytes.(3)Angiogenesis: Studies have confirmed that GH is an angiogenesis factor, which stimulates the division of endothelial cells and angiogenesis, and helps to promote the production of vascular growth factors and the expression of their function. Alginate dressing plays a role in wound healing to provide a moist environment for the wound, absorbing oozing, reducing pain in patients, reducing the infection risk in the wound, and helping the wound stop bleeding.It has the following advantages:(1)It is easy to use, and it is safe. The dressing uses sterile sealed envelope. It can be used after opening the protective film. The soft gel formed by the dressing will not adhere to the fragile tissues of the wound bed and can be easily removed from the wound.(2)Wetting wound healing environment, allowing gas exchange, which is the wound bed surface healthy growth of the necessary conditions, so as to prevent the formation of eschar and reduce the formation of scar.At present, due to the lack of evidence-based medical evidence, the effectiveness and safety of recombinant human growth hormone and alginate dressings in DFU patients is debatable. In this study, the clinical effectiveness and safety of recombinant human growth hormone combined alginate dressing in the treatment of DFU are analyzed by systematic evaluation. Through this study, it will provide a positive evidence-based medical evidence to help the treatment of DFU and benefit more patients with DFU.Conceptualization: Deng-Rong Zhou, Feng-Ling Wang.Data curation: Deng-Rong Zhou, Hai-Yan Deng, Lin-Li Pu.Formal analysis: Deng-Rong Zhou, Hai-Yan Deng, Feng-Ling Wang.Funding acquisition: Feng-Ling Wang.Methodology: Deng-Rong Zhou, Lin-Li Pu, Shao-Lan Lin.Software: Hai-Yan Deng, Lin-Li Pu, Rong Gou.Writing – original draft: Deng-Rong Zhou, Hai-Yan Deng, Lin-Li Pu, Shao-Lan Lin, Rong Gou.Writing – review & editing: Feng-Ling Wang.


P < 0.01). A significant negative correlation was found between baPWV and high-density lipoprotein levels (P < 0.05). Multivariate regression analysis showed that the hs-CRP level and duration of diabetes most strongly influenced baPWV. baPWV may be a convenient, noninvasive, and reproducible method for detecting early diabetic nephropathy.Brachial-ankle pulse wave velocity (baPWV) has been shown to correlate with a host of disorders associated with arterial stiffness. Type 2 diabetes is associated with the involvement of both small vessels and large vessels. Studies on the relevance of baPWV to early diabetic nephropathy are scarce. This retrospective observational case-control study enrolled 120 patients with type 2 diabetes from our medical records. We classified patients into two groups depending on the magnitude of albuminuria: 60 patients with microalbuminuria were classified as the early diabetic nephropathy group (EDN group) and 60 patients without albuminuria were classified as the diabetes without nephropathy group (DWN group). An additional 30 nondiabetic age- and sex-matched controls were also enrolled. Data regarding the lipid profile, blood pressure, baPWV, high-sensitivity C reactive protein (hs-CRP) level, anthropometric measurements, urine albumin/creatinine ratio (UACR), serum creatinine level, and glycemic control indices , postprandial glucose (PPG), and glycosylated hemoglobin ) were recorded for all enrolled participants. baPWV was significantly higher in the EDN group than in the DWN group. Moreover, baPWV was positively correlated with age, duration of diabetes, obesity, poor glycemic control, and high serum levels of triglycerides (TG), hs-CRP, creatinine, and uric acid as well as a high UACR (all  The prevalence of type 2 diabetes mellitus (T2DM) is rising globally, which is partly due to rapid urbanization and partly due to increased awareness and early diagnosis , 2. The According to various studies from China, 20%–40% of patients with type 2 diabetes have concomitant DN, and a significant portion of these have end-stage renal disease (ESRD) –11. DN wPulse wave velocity (PWV) is the measurement of the speed of transit of the pressure wave along the arterial wall between two specified arterial end points. It is a good index of arterial stiffness; with higher stiffness, the velocity increases . BrachiaWe undertook this case-control observational study to elucidate the utility of baPWV measurement in patients with early DN (EDN) diagnosed on the basis of microalbuminuria detected as an elevated urine albumin/creatinine ratio (UACR). We also performed correlation and regression analyses of baPWV with other confounding risk factors for arterial stiffness.From our medical records, we selected 120 patients with type 2 diabetes , diagnosed according to the World Health Organization criteria published in 2018, who had visited the First Affiliated Hospital of Dalian Medical University between July 2014 and January 2015. The study protocol was in accordance with the Declaration of Helsinki and was approved by the ethics committee of the First Affiliated Hospital of Dalian Medical University. Written informed consent was obtained from all participants after enrollment in the study. Thirty nondiabetic control participants were also recruited.2) or hepatic dysfunction  were also excluded from enrollment. According to the UACR estimation, patients were divided into two groups: the EDN group (UACR 30–300 μg/mg) and the DWN group (UACR < 30 μg/mg).Patients between 35 and 70 years of age were included in the study. Patients with a duration of diabetes exceeding 15 years and patients with a past history or present evidence of coronary heart disease, cerebrovascular disease, or peripheral arterial disease were excluded from the study. Patients with type 1 diabetes or other forms of diabetes were excluded. Patients with acute complications of diabetes, such as diabetic ketoacidosis, hyperglycemic hyperosmolar status, lactic acidosis, and hypoglycemic coma within the previous 6 months were also excluded from the study. Patients with severe renal failure (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 cmAnthropometric data including height, weight, waist circumference, and body mass index (BMI) were recorded. Systolic blood pressure and diastolic blood pressure were recorded to calculate pulse pressure (PP) and mean arterial pressure (MAP). Glycemic control was assessed by measuring fasting plasma glucose (FPG), postprandial glucose (G-6-PDH method), and HbA1c. Lipid profile (direct method), ALT , AST (IFCC method), uric acid (urase method), and creatinine (HMMPS (N-(3-sulfopropyl)-3-methoxy-5-methylaniline) method) estimation were done using routine laboratory techniques. Serum fasting C peptide (FCP) and 2-hour postprandial C peptide (2hCP) were examined by electrochemiluminescence assay . Levels of high-sensitivity C-reactive protein (hs-CRP) were measured by the immunoturbidimetric method . HbA1c was determined by high-performance liquid chromatography .Second-pass morning urine specimens were collected for 3 consecutive days. Urinary albumin excretion was measured by the immunoturbidimetric method, and urinary creatinine was determined by an enzymatic method. These parameters were used to calculate the UACR , 18. ThebaPWV was calculated by dividing the distance (in centimeters) between two arterial end points  by the transit time (in seconds) the pressure waveform took to travel. The distance between the peripheral arterial end sites was calculated using a height-based algorithm, as required by the Colin waveform analyzer . TransitP < 0.05.The normality of continuous variables was verified by the Kolmogorov-Smirnov test. Normally distributed variables were expressed as mean ± standard deviation (SD), and differences among the three groups were analyzed by one-way analysis of variance (ANOVA). The nonnormally distributed variables were expressed as median ± interquartile range (IQR), and differences in such variables among the three groups were identified by the nonparametric Kruskal-Wallis test. The Levene test was used to verify the homogeneity of variance. Correlation between baPWV and continuous variables was analyzed by Pearson linear correlation  or Spearman rank correlation (for skewed data). Multiple regression analysis was performed to identify variables that had an independent effect on baPWV. Receiver operating characteristic (ROC) curve analysis was done to identify a specific cut off with the help of Youden's index that gave the best specificity and sensitivity for detection of diabetic nephropathy defined by the presence of albuminuria. SPSS 25.0 software was used for all statistical analyses, and the level of statistical significance was set at The baseline clinical and laboratory data are presented in ROC curve analysis was performed to evaluate the effectiveness of baPWV for detecting DN . The areCorrelation analysis showed that baPWV was correlated significantly with age and duration of diabetes. baPWV also showed positive correlations with anthropometric parameters such as BMI and waist circumference. Mean arterial blood pressure, HbA1c, FPG, and postprandial plasma glucose values also were significantly positively correlated with baPWV. Moreover, baPWV correlated positively with hs-CRP, serum creatinine, microalbuminuria, and TG levels. Conversely, HDL-C showed a significant negative correlation with baPWV .Multiple regression analysis  showed tDN is an insidious, gradually progressive chronic complication of diabetes, which has a multifactorial pathogenesis influenced by glycemic control, blood pressure control, lipid parameters, genetic factors, and environmental and inflammatory factors. Internationally, microalbuminuria detection by UACR determination has been accepted as the gold standard for early detection of DN . Spot saUACR however has certain limitations as well; for example, conditions such as accelerated blood pressure, heart failure, fever, urine infection, and systemic illness may result in falsely positive results. To minimize these confounding variables, two positive readings 3 months apart are needed to diagnose DN . This leMeasurement of baPWV is a new, noninvasive, and reproducible method for assessing arterial stiffness . PreviouSmulyan et al. claimed that age and blood pressure were the strongest independent determinants of baPWV . Yiming Increased arterial stiffness plays a key role in the progression of chronic kidney disease . A serieThe present study has several limitations. First, the sample size was small, and hence, further multicenter clinical trials are needed to collect robust data across different ethnic populations to assist in clinical decision making. Second, other arterial stiffness indices, such as carotid-femoral PWV and central pulse wave analysis, were not investigated in this study . More stIn summary, baPWV measurement has the potential for wide-scale application for detection of EDN, and further studies are warranted to establish its role in predicting future risk of DN.


Therefore, we aimed to characterise patients with hypocapnia compared to patients with normocapnia (PaCO2 > 35 mmHg). Data concerning demographic and anthropometric variables, clinical symptoms, hospitalisation, lung function and gas-analysis were collected. Our study comprised 81 patients, of whom 19 (24%) had hypocapnia as compared to the remaining , and defined by lower levels of PaCO2, serum bicarbonate (HCO3−), carbon monoxide diffusion capacity (DLCO), and carbon monoxide transfer coefficient (KCO) with an increased level of pH and arterial partial oxygen pressure (PaO2). KCO was directly correlated with PaCO2 and inversely with pH. In our preliminary report, hypocapnia is associated with a residual lung function impairment in diffusing capacity. We focus on ABG analysis’s informativeness in the follow-up of post-COVID patients. Patients who have recovered from COVID-19 show persistent symptoms and lung function alterations with a restrictive ventilatory pattern. Few data are available evaluating an extended period of COVID-19 clinical progression. The RESPICOVID study has been designed to evaluate patients’ pulmonary damage previously hospitalised for interstitial pneumonia due to COVID-19. We focused on the arterial blood gas (ABG) analysis variables due to the initial observation that some patients had hypocapnia (arterial partial carbon dioxide pressure-PaCO CO) has been evident at discharge [CO) alterations might better characterise the gas exchange efficiency [2). Any technical bias has been excluded, and several patients repeated blood sample to confirm the results. Aim of our study was, therefore, to characterise patients with hypocapnia (PaCO2 ≤ 35 mmHg) in comparison to patients with normocapnia (PaCO2 > 35 mmHg). A total of eighty-seven percent of patients who have recovered from COVID-19 show persistent symptoms at 60 days, particularly fatigue and dyspnea [ischarge  and duriischarge ; the carficiency . Few datAt our tertiary hospital , we have organised a dedicated outpatient clinic for adult patients previously hospitalised for interstitial pneumonia due to COVID-19, with or without respiratory failure. The RESPICOVID study, a prospective observational trial, has been designed to comprehensively evaluate the prevalence, clinical impact, and predictive factors of pulmonary damage in patients recovered from COVID-19. Due to the explorative nature of our study and the feasibility of observations derived, here we report some aspects related to preliminary data. For this reason, no formal sample size calculation was made and we had not a comparison group of not exposed (controls without COVID-19). The study has been described according to a cross-sectional design, following the STROBE guidelines. The local Ethics Committee approved the study protocol (No. 2785CESC), according to the Good Clinical Practice recommendations and the requirements of the Declaration of Helsinki. Written informed consent was obtained from all participants.All consecutive patients discharged were considered, excluding those unable to reach the outpatient service  or perform tests . All measures were collected prospectively beginning on 6 July 2020, 4 months after patients’ discharge . The ABG analysis has been performed in all patients enrolled, at rest, in-room air and quiet condition. 2) were also standardised (stPaO2) according to the lower levels of PaCO2 (<40 mmHg) by the following formula: We recorded demographic and anthropometric variables, clinical symptoms, laboratory, and gas-analysis. Values of arterial partial oxygen pressure , and total lung capacity (TLC) were recorded. FEV1/FVC ratio was taken as the index of airflow obstruction. DLCO and KCO were measured by the single breath method. FEV1, FVC, TLC, DLCO and KCO were expressed as percentages of the predicted values [Lung function was performed according to the international recommendations ; a flow-d values ,8. 2 test or the Fisher exact test, while continuous variables were assessed by the independent t-test or the non-parametric Mann–Whitney test. Pearson (r) and Spearman (ρ) correlations have been carried-out between variables. All analyses were performed using IBM SPSS, version 25.0 , with p values of <0.05 considered statistically significant. Data are reported with numbers (percentages) for categorical variables, mean (SD) or median  for continuous variables with a normal or non-normal distribution, respectively. A preliminary Shapiro–Wilk test was performed. Categorical variables were compared by the χn = 62, 76%), and defined by lower levels of PaCO2, serum bicarbonate (HCO3−), DLCO, and KCO with an increased level of pH and arterial partial oxygen pressure (PaO2). Comparing data from hospitalisation, hypocapnic patients had lower PaCO2 and HCO3−  had hypocapnia as compared to the remaining  mismatch are the most frequent causes of hypoxaemia, diffusion limitation may cause hypoxemia also in the absence of VA/Q mismatch [2 the respiratory drive increase the minute ventilation primarily by increasing tidal volume (hyperpnea) and respiratory rate (tachypnea) [2/FiO2 ≤ 300) but with no residual hypocapnia differences. Similarly, the correction of oxygen pressure by the stPaO2, such as other data concerning oxygenation at hospitalisation and in the recovery phase seems to be little associated with hypocapnia. Mechanical adaptation to the increased elastic work of breathing or a reflex-mediated originating from the chest wall receptors may be a resting hyperventilation mechanism, which probably starts in our patients from hospitalisation. However, we cannot exclude the possibility of an increased virus-induced respiratory drive stimulation, explaining the long-time persistence of hypocapnia. Notably, hyperventilation has no impact on clinical symptoms perceived from patients and concerning in particular extensional dyspnea; other causes of symptom perception will probably have to be sought. Several pulmonary disorders such as pneumonia, pulmonary embolism, asthma or interstitial lung disease (ILD) may produce hypocapnia; the leading physiologic cause of the reduction of PaCOtilation . Severe tilation . Althougmismatch . Moreovemismatch : as a cochypnea) ,11. At hIn other ILD conditions, not COVID-19, the association of hypocapnia regardless hypoxemia has been reported. Hypocapnia induced by resting hyperventilation has been observed in asbestos-exposed subjects with a restrictive disorder related to mild pleural plaques . MoreoveOur major strengths are the originality of considerations, the prospective and consecutive data collection. As limitations, we should mention the relatively small sample size and controls missing: our considerations need to be confirmed in a large study cohort with matched-controls without COVID-19. In conclusion, our report highlights the hypocapnia as a marker of residual lung function impairment of patients recovered from hospitalised COVID-19; moreover, we focus on ABG analysis’s informativeness in these patients’ follow-up.


To investigate the clinical value of non-invasive ultrasound imaging in the evaluation of brain death caused by traumatic brain injury.Thirty-four patients with acute severe traumatic brain injury were admitted to hospital within 48 h after injury. All patients were monitored intracranial pressure, transcranial Doppler, echocardiography examination, collection intracranial pressure, MCA-Vs, MCA-Vd, MCA-Vm, EF, LVMPI, RVMPI and other indicators, and combined with clinical conditions and other related data for comparative study and statistical analysis.P < 0.05). For the parameters of echocardiography, there were statistically significant differences in EF, LVMPI, and RVMPI between clinical brain death group and normal control group (P < 0.05).The blood flow spectrum was characterized by diastolic retrograde blood flow spectrum pattern and nail waveform spectrum shape when the patient had clinical brain death. For the parameters of transcranial Doppler, there were significant differences in MCA-Vm and PI between clinical brain death group and normal control group (Non-invasive dynamic monitoring of cerebral hemodynamics and cardiac function parameters in patients with severe craniocerebral injury can provide a high accuracy and reliability for the preliminary diagnosis of brain death in patients with severe craniocerebral injury. It is helpful for early evaluation of prognosis and provides effective monitoring methods and guidance for clinical treatment. With the rapid development of economic construction, urbanization and transportation, the incidence of traumatic brain injury increasing gradually and the number of patients who died due to craniocerebral trauma are also increasing gradually. However, the mortality rate of patients with severe traumatic brain injury is extremely high. In clinical work, we found that many patients with severe traumatic brain injury have been in the state of spontaneous breathing arrest, deep coma, dilation and fixation of double pupil due to intracranial hypertension or other reasons, and they are completely dependent on the ventilator to maintain breathing, that is, the brain function has been completely irreversible damage. In this case, the maintenance of respiration and drug circulation by ventilator often can maintain the heart rate and circulation for a long time until the organs of the whole body fail. This not only wastes valuable medical resources, but also limits the development of organ transplantation. Brain death will produce a series of pathophysiological changes including hemodynamics, endocrine, metabolism, inflammatory reaction, among which the most prominent manifestation is hemodynamic disorder. Non-invasive dynamic monitoring of cerebral hemodynamics and cardiac function parameters in patients with severe traumatic brain injury by ultrasound imaging is conducive to early evaluation of the prognosis of patients, providing effective monitoring means and guiding methods for clinical treatment, so as to provide a favorable opportunity for organ transplantation.Thirty-four patients with acute severe traumatic brain injury were admitted to hospital within 48 hours after injury. There were 30 males and 4 females, aged 26–53 years old. The injury mechanism included 17 cases of accelerated injury, 13 cases of deceleration injury and 4 cases of mixed injury. Among them, 18 cases were injured by traffic accidents, 8 cases were caused by falling, 5 cases were injured by striking, and 3 cases were injured by other reasons. All cases were diagnosed by CT examination before or after admission. According to CT diagnosis, brain injury was classified. The main injury types included: 15 cases of cerebral contusion and laceration combined with acute subdural hematoma, 11 cases of cerebral contusion and laceration with intracerebral hematoma, 6 cases of acute epidural hematoma, and 2 cases of extensive brain contusion and brain swelling. According to the state of consciousness, 19 patients with GCS score of 6-8 and 15 patients with GCS score less than 6. Among them, 9 patients with multiple injuries, 5 patients with closed fractures of extremities  and 4 patients with pulmonary contusion were treated conservatively .All the patients were monitored intracranial pressure and dynamic cerebral hemodynamic indexes of transcranial Doppler after admission. According to the prognosis of the patients, they were divided into clinical brain death group  and survival group. Another 20 healthy subjects were selected as the control group, and laboratory, transcranial Doppler and echocardiography were performed respectively. All measurements were performed by a physician with 5 years of experience in ultrasonography.Inclusive criteria: Admission within 48 h after injury; age 20–60 years old; GCS ≤ 8 points at admission.Exclusion criteria: Patients with severe multiple trauma, combined injury and shock; those who have been transferred to our hospital after craniotomy in another hospital; patients with heart, lung, liver, and kidney dysfunction; patients with stenosis of internal carotid artery system and vertebrobasilar artery system; patients whose temporal window was completely closed and could not detect blood flow signals; patients whose family members gave up treatment.The patients were clinically diagnosed as brain death. The criteria for brain death were referred to the criteria for brain death (adult) (Revised Version) drafted by the drafting group of the Ministry of Health in 2003 and the criteria and technical specifications for brain death  in 2013. (i) Deep shock; (ii) disappearance of the papillary light reflex and corneal reflection; (iii) absence of spontaneous respiration; (iv) electroencephalogram displaying resting potential; (v) negative atropine test; (vi) no change in all of these conditions for 12 h after initial observation, then brain death was determined .Intracranial pressure detection monitoring was carried out by intracranial pressure monitor , with an intracerebral probe, and the patients who needed outdoor drainage used intraventricular probe. ICP monitoring lasted for 1 week, and some patients were slightly prolonged according to their needs. Head wounds should be cleaned and disinfected daily to prevent intracranial infection. If the baseline of intracranial pressure monitor is shifted due to the patient’s turning over or other nursing work, the baseline should be adjusted to zero according to the situation.2, Germany). The middle cerebral artery was examined from the temporal window with a 2 MHz probe at a sampling depth of 45–60 mm. When the spectrum shape is smooth and the sound in the frequency window is loud was taken as the parameter index. All patients were placed in supine position with the head of bed raised 30 degrees. The detection time was 9:00 a.m. (before mannitol) and 4:00 p.m. (1 h after mannitol) for 7 days. After reaching the standard of clinical brain death, the patients were checked every 2–6 h according to their circulatory system. In order to exclude the influence of human subjective factors and technical factors on the experimental value, the cerebral blood flow detector was relatively fixed. The indexes included pulsatility index (PI), resistance index (RI), systolic blood flow velocity (MCA-Vs), diastolic blood flow velocity (MCA-Vd), and mean middle cerebral artery velocity (MCA-Vm).The cerebral hemodynamics was detected by transcranial Doppler (TCD)  with a S4 probe at a frequency of 1–4 MHz. The patient was in supine position. The weight, height and blood pressure were recorded and BSA was calculated. The indexes of echocardiographic parameters included left ventricular end diastolic diameter (LVDd), left ventricular end systolic diameter (LVDs), and ejection fraction (EF). The myocardial performance index (MPI) was calculated by the ratio of the sum of isovolumic systolic (ICT) and isovolumic diastolic (IRT) to ejection time (ET), MPI = (ICT + IRT)/ET. The blood flow spectrum of mitral valve, tricuspid valve, aortic valve, and pulmonary valve was clearly displayed to calculate left ventricular (LVMPI) and right ventricular (RVMPI) according to the formula. In order to reduce the error of echocardiography as much as possible, the average value of three consecutive cardiac cycles was taken for each index. All examinations were completed by one doctor and the images were stored at the same time.t test. The correlations were analyzed using Spearman’s correlation analysis, and the correlation coefficients (r) were calculated. A two-sided P-value < 0.05 was considered to indicate statistical significance.Statistical analysis was performed using SPSS Version 19.0 . Continuous variables  were expressed as the mean ± standard deviation (SD). The differences between the two groups were compared by independent sample r = 0.872, P < 0.001) and MCA-Vm . With the increase of ICP, the amplitude of cerebral blood flow spectrum gradually decreased, and the MCA-Vm gradually decreased, showing a low flow rate and high resistance spectrum morphology. When the patient had clinical brain death, the blood flow spectrum was characterized by diastolic retrograde blood flow spectrum pattern and nail waveform spectrum shape   .P < 0.05)  .Severe craniocerebral trauma patients die because of the sharp increase of intracranial pressure and the formation of cerebral hernia, which is the difficulty of clinical treatment in neurosurgery. With the continuous development of Neurosurgery, the effect of rescue treatment has been improved, but the effect is not satisfactory . The maiBrain death refers to the irreversible stop of whole brain function due to persistent and severe cerebral ischemia, hypoxia or other reasons . The diaTranscranial Doppler can monitor the cerebral hemodynamic status of patients with severe traumatic brain injury, describe the cerebral hemodynamic state combined with mean arterial blood pressure, and evaluate the cerebral perfusion and intracranial pressure . InvasivThe results showed that, with the slight increase of intracranial pressure, the condition was aggravated, MCA-Vd decreased in the early stage, while MCA-Vs increased slightly, and MCA-Vm was normal; with the moderate and severe increase of intracranial pressure, the condition was further aggravated, MCA-Vd and MCA-Vs decreased, MCA-Vd decreased more significantly, and PI increased gradually. When the blood pressure reaches the mean arterial blood pressure level and continues, diastolic regurgitation or nail spectrum may appear finally. The changes of parameters of cerebral blood flow state were significantly corresponding to the changes of intracranial pressure and disease condition. When patients with complete diastolic reverse blood flow or nail waveform, clinical brain death will occur in a short period of time. This indicates that the brain function of the patients has undergone serious and completely irreversible changes when the above-mentioned manifestations of cerebral blood flow state detected by non-invasive detection, indicating that the patient is about to or has suffered from clinical brain death.Therefore, in the process of clinical treatment, before the typical spectrum of complete diastolic reverse blood flow or nail spectrum appears in TCD detection, active treatment should be taken as soon as possible to effectively control and reduce the improvement of cerebral perfusion and cerebral ischemia and hypoxia, which is of great significance for improving the prognosis and reducing the mortality of patients.As an important organ to maintain hemodynamics, the heart can cause secondary heart injury in severe brain injury, especially in brain death . The lowAs a non-invasive and rapid technique, ultrasound can dynamically monitor the structure and function of the heart. Myocardial performance index (MPI) as a comprehensive index to evaluate the overall systolic and diastolic function of the heart can be used to evaluate the overall ventricular function . When leTherefore, once the typical spectrum of complete diastolic reverse blood flow or nail spectrum appear in TCD detection, EF decreases and LVMPI, RVMPI increased in Echocardiography, that the patient has entered the state of brain death, and it is of no medical significance to continue treatment. With the informed consent of patients’ families, we should improve the systematic examination methods of brain death as soon as possible, such as EEG and brainstem evoked potential, to further diagnose brain death and save limited medical resources. Whether the patients who died of non-traumatic brain injury also have the characteristic blood flow changes of the above mentioned brain death needs further data collection and research. Non-invasive dynamic monitoring of cerebral hemodynamics and cardiac function parameters in patients with severe craniocerebral injury can provide a high accuracy and reliability for the preliminary diagnosis of brain death in patients with severe craniocerebral injury. It is helpful for early evaluation of prognosis and provides effective monitoring methods and guidance for clinical treatment. With the development of medical image data, it is helpful to further dig out the biometrics and other information in the image, which will further improve the accuracy of prediction ,b.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Medical Ethics Committee of the Tianjin First Central Hospital. The patients/participants provided their written informed consent to participate in this study.YT contributed to the conception of the study and helped perform the analysis with constructive discussions. XH, NN, and JW performed the experiment. NN contributed to the data analysis and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Syncope usually lasts less than a minute, in which short time arterial blood pressure temporarily falls enough to decrease brain perfusion so much that loss of consciousness ensues. Blood pressure decreases quickest when the heart suddenly stops pumping, which happens in arrhythmia and in severe cardioinhibitory reflex syncope. Loss of consciousness starts about 8 s after the last heart beat and circulatory standstill occurs after 10–15 s. A much slower blood pressure decrease can occur in syncope due to orthostatic hypotension Standing blood pressure can then stabilize at low values often causing more subtle signs  but often not low enough to cause loss of consciousness. Cerebral autoregulation attempts to keep cerebral blood flow constant when blood pressure decreases. In reflex syncope both the quick blood pressure decrease and its low absolute value mean that cerebral autoregulation cannot prevent syncope. It has more protective value in orthostatic hypotension. Neurological signs are related to the severity and timing of cerebral hypoperfusion. Several unanswered pathophysiological questions with possible clinical implications are identified. Two key features of syncope are that is a form of transient loss of consciousness and that it is due to cerebral hypoperfusion , 2. The This paper provides an overview of the timing of cardiovascular and neurological events in syncope. The discussion of reflex syncope will address some general aspects that apply to all forms of syncope. These will not be repeated in the discussion of cardiac syncope and syncope due to orthostatic hypotension. Some unanswered questions will be identified.Transient loss of consciousness (TLOC) in syncope is the result of a temporary low blood pressure. As arterial blood pressure (BP) is the product of cardiac output and total peripheral resistance (TPR), and as cardiac output is the product of stroke volume (SV) and heart rate (HR), BP is the product of all three: BP = SV·HR·TPR. This simple equation means that a decrease of any one of these three parameters can in principle cause syncope, provided the decrease is severe enough, lasts long enough and is not compensated for sufficiently by an increase of any of the other parameters.The terms “reflex syncope” and its synonym “neurally mediated syncope” indicate that syncope is evoked by a trigger setting afferent nerve impulses in motion. However, reflex syncope does not only involve the nervous system. Hormonal factors are likely to play a role as well. There are obvious similarities between neuronal reflex and endocrinological mechanisms of regulation: both involve the detection of a disturbance and a corrective response. The sections below focus primarily on autonomic nervous system responses, and provide a short overview of humoral influences.The array of possible triggers in reflex syncope comprises extremely diverse elements; examples are thinking unpleasant thoughts, eating a heavy meal, stretching, stopping with running, coughing, being stuck with a needle, or simply standing still. It is hard to understand why such diverse impulses would all evoke a very similar response, and yet they do. Clinical experience suggests reflex syncope is more likely to occur when several risk factors occur at the same time. It seems likely that a low circulating volume or an already low blood pressure feature in this set of common factors, but it is unknown whether any one factor is obligatory in triggering reflex syncope.The neuronal efferent responses in reflex syncope can be identified with more confidence because their specific efferent circulatory effects are also involved in normal baroreceptor blood pressure control. The nuclei transmitting the efferent impulses are the dorsal vagal nucleus and the nucleus tractus solitarii. These control two effector mechanisms that are normally involved in blood pressure control. In reflex syncope these two mechanisms can both lower blood pressure: they are the cardioinhibitory (CI) and vasodepressive (VD) pathways.CI concerns an increase of vagal stimulation of the heart, resulting in a decrease of HR. The severity of CI ranges from a slight HR decrease to long asystole. Asystole during tilt table testing (TTT) may last about 1 min, but that is not the typical duration. Asystole, defined as a pause of at least 3 s. duration, occurred in 21 of 69 TTT cases 30.4%) selected for the occurrence of full syncope; the mean duration of asystole was 9.1 ± 6.4 s % selecte. In contA decrease of HR can lead to a quick decrease of BP, as is evident from the sudden cardiac standstill that occurs in complete AV-block. BP may then be halved in just 3 s. after the last beat; after about 10–15 s. of persistent asystole, BP becomes stable at 10–20 mmHg . At thisVasodepression (VD) can be interpreted as any mechanism in reflex syncope apart from CI that causes blood pressure to decrease. As explained below, a decrease in venous return is one such cause. The other is a decrease of sympathetic vasoconstriction of arterioles, and some authors restrict VD to this mechanism. This decrease allows arterioles to dilate, resulting in a decrease of Total Peripheral Resistance (TPR). The shortest time in which sympathetic effects can affect BP through this mechanism is probably a few heart beats, whereas vagal effects on HR can operate within one heartbeat.In reflex syncope, VD and CI may occur together to varying degrees, making it difficult to determine how much either contributes to the decrease of BP. Even so, it is safe assumed that asystole, if it lasts long enough, will always cause the circulation to come to a halt and cause syncope; this will occur irrespective of any additional VD.The nature and severity of CI differs between types of reflex syncope. In swallow syncope asystole due to an AV-block has been frequently described , althougOver the last 15–20 years the concept that reflex syncope involves CI and VD in the shape of reduced arteriolar vasoconstriction had to be revised substantially for VVS. As these studies mostly concerned TTT, the results hold for VVS induced by standing (“orthostatic VVS”). The existence of CI remained undisputable in view of obvious bradycardia and asystole. But a decrease of TPR was not consistently present. In many of these studies Modelflow was used, a technique relying on analysis of the arterial pressure waveform of individual heart beats . TPR didInstead of the expected decrease in TPR, a decrease in SV emerged as a consistent finding in the minutes before syncope in tilt-induced VVS , 25–28. While it has become clear that venous pooling acts as the starting point of orthostatic VVS, it is not clear why this occurs at some times, and its place in the “reflex” concept is not clear. It may be seen as the triggering process rather than as part of the response. If it is a trigger, then the neuronal reflex may in fact only become active at the moment when CI starts. Whether the reflex then also has a component of a reduction of arteriolar vasoconstriction (low TPR), is not yet clear.At any rate the question may be asked whether the term “vasodepression” should be limited to a sympathetically mediated release of arteriolar vasoconstriction. A wider concept of VD, comprising both arterial and venous components, has already been proposed . The artIn tilt-induced VVS, BP may start to decrease several minutes before syncope, while CI typically starts later, a minute or less before syncope. As said, CI may be triggered by a secondary abnormality related to the ongoing venous pooling. Putative secondary triggers may be sought in consequences of venous pooling, such as a reduction of blood volume in the thorax, likely to alter the filling, flow or pressure in thoracic blood vessels and in the heart itself. The “empty heart hypothesis” sought to explain the origin of CI in mechanoreceptors in the walls of the near-empty ventricles ; howeverIt should be understood that a lowering of HR at a time when BP is decreasing contradicts the normal behavior of the baroreflex. This reflex normally aims to keep BP constant by manipulating HR as well as TPR. Normally a lowering of BP elicits a rise in HR, and a BP increase will evoke a HR decrease. After CI sets in, BP and HR decrease together, showing that normal baroreflex control is lost . BarorecWhile tilt-induced VVS appears to be a good model for orthostatic VVS , its finCI and VD can each cause syncope on their own: VD can cause LOC in the absence of any decrease of HR , and canThe relative strength of CI and VD is not the only important factor in determining whether syncope will occur; their time of onset also determines the outcome . The timFor a detailed review of the possible roles of neurohormones in VVS we refer to Benditt et al. . Here, aVarious other hormones and circulating agents have been investigated, such as vasopressin and natriuretic peptides. At present it remains to be seen whether hormonal alterations are a response to a circulation that is slipping out of autonomic control, or whether they contribute to it .Blood will only flow through an organ if two conditions are met: firstly, there must be a pressure difference between the arteries and veins supplying the organ. Secondly, the vessels in between must be open . For flaThe comparison of opening with closing forces helps explain brain perfusion in abnormal conditions. A surprising consequence of this is that cerebral flow in imminent brain death resembles that in syncope. In brain death intracranial pressure is so high that the closing forces gain the upper hand. A reflex increase of systemic blood pressure counters the high intracranial pressure in part, but beyond a certain point intracranial pressure will approach blood pressure. Transcranial Doppler (TCD) then shows that diastolic flow velocity decreases before systolic velocity does; this is because the opening forces are at their weakest in diastole. In syncope BP is so low that the closing forces again win, but now because the opening forces are very weak. Again, TCD shows that systolic flow velocity remains nearly normal while diastolic velocity is markedly reduced.Cerebral autoregulation describes the ability of brain perfusion to counteract changes in arterial BP: when BP decreases, the forces that close vessels decrease to keep cerebral perfusion constant. Likewise, when BP increases, vessels must constrict to increase the closing forces in parallel with the increase in the opening force. Cerebral autoregulation has a lower limit of regulation of about 60 mmHg. If B falls below this level, cerebral perfusion will decrease in parallel with BP . CerebraThe time scale of autoregulation is critical for reflex syncope. In case of a sudden asystole, BP will fall below the lower level of autoregulation before that autoregulation has had the time to exert its full effect. When BP decreases slowly, as may happen with pure VD, autoregulation has more time to counteract the effects of decreasing BP. An elegant study found that cerebral resistance to flow was markedly reduced at syncope, meaning that autoregulation indeed opened vessels to compensate for low BP , confirmNot all symptoms and signs associated with syncope are due to cerebral hypoperfusion . Some syIn tilt-induced VVS, the first observable signs of LOC were motor ones, i.e., a vacant expression or dropping of the head and jaw . From thSome syncopal signs indicate a loss of neuronal function whereas others can only be interpreted as abnormal excessive neuronal activity, probably due to a lack of inhibition. Examples of the latter are mumbling, pointing to cortical disinhibition, and roving eye movements, suggesting brainstem disinhibition . Both th“Cardiac syncope” is usually taken to comprise both specific cardiac causes as well as disorders of the great vessels, such as pulmonary embolism . The twoStructural heart disease concerns heart diseases, other than coronary heart disease, of a mechanical nature, including valvular disease, septum defects, and cardiomyopathy. Structural heart disease impairs the mechanical efficiency of the heart. This becomes most problematic when there is a discrepancy between the demands for a high cardiac output and a failure to deliver it. This helps explains why syncope in relation to exercise is a cardiac danger signs. However, if low cardiac output were the only mechanism, patients might be expected to experience a slow inability to perform physical work. Instead, the typical history is a sudden LOC with little or no warning. The explanation for the latter pattern may be a susceptibility to respond to hypotension with syncope, so the mechanism in structural cardiac syncope may in fact partly be reflex syncope , 37, 50.In many cases cardiac syncope develops very quickly, resulting in the same clinical signs as in sudden complete CI in reflex syncope: patients may only have a few s. to become aware of a problem before they lose consciousness. But the situation may be more complicated when the pumping action is not lost entirely, so cardiac output is decreased but not nil. We have noted patients becoming aware of “weakening” or “dizziness” without LOC, even in cases of ventricular tachycardia.The term “convulsive syncope” appears to be used to indicate a perceived high severity of syncope, and suggests that it is based on the presence of myoclonic jerks. However, jerking of the arms did not occur significantly more often with severe cerebral hypoperfusion, i.e., EEG flattening, then without such flattening , so therThere are recent observations of sudden cardiac death, taken from publicly available video records of sports players –55. One There are three types of orthostatic hypotension (OH); the initial, classical and delayed types: iOH, cOH, and dOH . Note thThe definition of cOH , 59 descThe causes of cOH are a failure to control arteriolar vasoconstriction, hypovolemia or both. The most common cause of cOH is medication. When the cause concerns structural damage to the sympathetic nervous system, the resulting cOH is often labeled “neurogenic OH” . The daThe central defect of nOH is an inability to bring about arteriolar vasoconstriction . In termBP measurements in patients with cOH/nOH exhibit two features that point to even more complicated processes: supine hypertension  and a BPOne unexpected finding in nOH was a decrease of TPR in the upright position, measured from a baseline supine position –67. ThisPatients with nOH may be fully conscious at remarkably low BP values, suggesting excellent autoregulation . CerebraAs said, signs and symptoms in syncope may either be related to the cause of syncope, or to cerebral perfusion. In nOH, examples related to the cause of syncope include the absence of “autonomic activation” as occurs in reflex syncope. Another example is the occurrence of complaints in the standing position, often exacerbated during exercise or just after it , 79. SomThe signs of cerebral hypoperfusion in syncope are in principle irrespective of the cause. Whether they are perceived and reported depends critically on the speed of the blood pressure decrease. When this is very fast, patients often report either no awareness of anything amiss at all, or a non-descript yet recognizable feeling for a few seconds. In cOH, the BP decrease can be quick initially, but the rate of decrease typically diminishes and BP tends to become stable at a lower level. If that level is below that needed to maintain consciousness, syncope ensues; if it is higher, there may be no symptoms or signs. Because BP decreases slowly in cOH, most patients learn to heed the warning signs and learn to prevent syncope. One sign occurs fairly often in nOH: an “inability to act.” In nOH, BP is then too high to cause unconsciousness, but too low to allow higher cortical functions such as deciding to sit down  81). Th. Th81). The above discussion shows that the speed and timing of circulatory and neurological events is of prime importance to understand the signs and symptoms of syncope. Syncope concerns a change from fully functional alertness and awareness to, in the most severe forms, one in which cortical functions have stopped altogether while the brainstem is on the way to equal that state. The quickest natural way to reach that state is probably a sudden asystole, leading to LOC in about 8 s., in which patients may only realize that something was wrong when they regain consciousness after the fact. At the other end of the spectrum lies the slow BP decrease in nOH, in which patients may perceive a slow progression of symptoms over minutes, in which an inability to rectify the situation may precede a loss of vision and finally LOC. Important factors in the equation are the occurrence of bradycardia or asystole on the cardiovascular side, and cerebral autoregulation on the cerebral end.The timing and speed not only have consequences for the clinical presentation of syncope, but also for therapy. Whether attempts to rectify CI with a pacemaker will prevent syncope in reflex syncope will critically depend on simultaneous VD. The fact that CI started too late to cause LOC in one third of cases with tilt-induced reflex syncope, suggests that pacing will fail at least that same rate, if started at the onset of asystole .The above overview helps delineate a number of gaps in the understanding of the processes that lead to LOC in reflex syncope.The first is limited knowledge concerning the pathophysiology of emotional VVS and other forms of syncope. The reason is very likely that orthostatic VVS can be evoked with relative ease with a TTT, while the other forms, in particular emotional VVS, are difficult to evoke. TTT studies on VVS have clarified that the original scheme of a dual parasympathetic and sympathetic reflex action, respectively causing bradycardia and too little arteriolar vasoconstriction, is at best incomplete. Instead, venous pooling causing a reduction in SV seems to be the prime abnormality starting the complex process of orthostatic VVS. As other forms of reflex syncope are triggered much swifter, these may not rely on the slow process of venous pooling. Hence, studying other forms of reflex syncope may clarify pathophysiological differences between the various types.A second problem is why and how excessive venous pooling occurs in orthostatic VVS. This reflects an excessive shift of blood from the thorax to lower regions of the body. At present the assessment of venous pooling relies mostly on indirect deductions of its presence from a reduction in SV, i.e., it relies on measurements that concern the arterial system. Instruments that would allow direct measurements of venous filling or the distribution of blood across body regions might yield as much new information regarding the venous system as continuous blood pressure measurements did for the arterial system. Impedance measurements should help fill his gap, and have shown important results, but are not used widely , 83.A third and fundamental problem is why the autonomic nervous system seems incapable of countering venous pooling in orthostatic VVS. The reduction in SV leads to a slow decrease in BP, meaning that this decrease is for some reason not countered by adequate increases in sympathetic arteriolar vasoconstriction nor heart rate. Are there conflicting demands on the autonomic nervous system that prevent it from acting normally, or is there perhaps a mismatch between humoral and nervous actions?Fourth, it is difficult to assess which of the processes CI and VD affect BP the most when both act together. In the well-known equation BP = SV·HR·TPR, HR represents CI, and SV and TPR may represent venous and arterial VD. The multiplicative nature of this relation suggests that it should be possible to determine how much each parameter contributes to a given decrease in BP. If such comparisons would for instance reveal that over half of a BP decrease is due to a HR decrease, pacing attempts become more promising then when CI hardly explains any BP decrease. Clearly, not only the relative severity of VD and CI, but also their relative time of onset is important for the occurrence of syncope: in about one third of cases of tilt-induced VVS, asystole occurred too late to cause syncope . TreatmeThe pathophysiological studies on nOH reveal that it is surprisingly complex, with an apparent mixture of primary defects and secondary reactions. The paradoxical occurrence of an apparent decrease in TPR in the standing position is a case in point. Studying it and its as yet unidentified mechanisms might help alleviate the orthostatic BP decrease.JD: main concepts, outline, writing, and revising. IR: critique and writing. RT: critique and writing.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.


Anterior ischemic optic neuropathy (AION) occurs due to hypoperfusion of the optic nerve and is a rare complication in patients receiving maintenance dialysis. To date, AION has only been reported in 22 children, all of whom were receiving peritoneal dialysis. We report the first case of AION in a 2-year 11-month-old child receiving chronic hemodialysis secondary to polycystic kidney disease from a phosphomannomutase 2 gene mutation. This case highlights the consideration for frequent blood pressure monitoring and ophthalmic screening in a certain cohort of children receiving chronic dialysis. Anterior ischemic optic neuropathy (AION) is characterized by hypoperfusion of the posterior ciliary arteries resulting in optic nerve infarction . AION haWe report a 2-year 11-month-old male on chronic hemodialysis secondary to polycystic kidney disease (PCKD) who underwent bilateral nephrectomy. He had a compound heterozygous phosphomannomutase 2 promoter and missense mutation, accounting for PCKD and congenital hyperinsulinism. His left kidney was removed in February 2017 due to respiratory insufficiency from mass effect. Seven months later, with significantly reduced kidney function, he underwent a left nephrectomy due to respiratory compromise and hypertension. Following his second nephrectomy, he began intermittent hemodialysis five days a week; decreased to four days a week after 6 months.9/L. His electrolytes were grossly normal  and his albumin was low at 30 g/L. Creatinine was elevated at 421 μmol/L. His echocardiogram showed normal biventricular function.Prior to his second nephrectomy, he was being treated for hypertension with an angiotensin-converting enzyme inhibitor, beta-blocker, and furosemide. After the second nephrectomy, his intradialytic systolic blood pressure used to be around 68 mmHg. For this reason, he was started on 2.5 mg midodrine during hemodialysis for systolic blood pressure below 90 mmHg. His ultrafiltration was minimized to avoid further hypotensive episodes during hemodialysis. Despite that, his systolic blood pressure stayed around 60 mmHg. Other medications included diazoxide, omeprazole, levothyroxine, and darbepoetin. He was G-tube fed without salt restriction. His blood work five days prior to presentation demonstrated normocytic, mild anemia (hemoglobin 95 g/L) with a reticulocyte count of 20 × 10μmol/L. Tox screen was negative, and AST, ALT, and INR were all normal. He had no history of trauma, toxin ingestion, sick contact exposure, or seizure activity.In June 2018, 9 months after initiating hemodialysis, he presented to the emergency department with an unsteady gait and difficulty focusing and following objects starting approximately two hours after completion of hemodialysis that day. Parents noted a pupil size change from small to large bilaterally, documented at 8 mm. On his initial neurological examination, his pupils were dilated but responsive, and he had poor visual acuity and an unsteady gait. He was otherwise alert, oriented, and comfortable. Vitally, his blood pressure was 59/33 mmHg, heart rate was 92 bpm, and he was afebrile. Laboratory findings on admission demonstrated a normocytic, mild anemia with a hemoglobin level of 101 g/L and an MCV of 92.7 fL. His sodium was found to be low at 127 mmol/L, with a potassium level of 4.4 mmol/L, and a chloride level of 98 mmol/L. Repeat blood work displayed a sodium level of 134 mmol/L, and thus, no hypertonic saline was administered. Creatinine was elevated at 166 Head CT displayed nonspecific findings of bifrontal subcortical white matter hypodensities. MRI displayed multiple foci of increased fluid-attenuated inversion recovery signal, mainly on bilateral subcortical white matter of the frontal lobes and corona radiata. Optic nerve size and signal intensity were normal . OphthalHe was discharged after steroid treatment with a diagnosis of bilateral AION. Ophthalmology follow-up two months after his acute presentation revealed his vision to be 20/800 in the left eye and 20/30 in the right eye . He contAION results from poor perfusion of the optic nerve and is a rare but serious condition that can occur in patients on chronic dialysis . The optTo date, 22 cases of AION have been reported in children, all of whom were on peritoneal dialysis. Similarities of our case with the previously reported 22 cases are the bilateral nature of vision loss in 95% 21/22) of patients and sudden presentation in all patients /22 of pa–5. As wiThis case emphasizes the importance of blood pressure control in children receiving chronic hemo- or peritoneal dialysis. Dialysis patients have frequent contact with the health care system, providing ample opportunity for blood pressure monitoring and management. All children with risk factors for AION, such as anemia, young age, chronic hypotension, bilateral nephrectomy, and polycystic kidney disease, should be regularly screened for AION with an early involvement of ophthalmology as needed. Adequate medical management of low blood pressure and early diagnosis of AION could reduce both the incidence of AION and the associated potential for complete vision loss in patients receiving chronic dialysis.


Similarly, by analyzing 158 rejection episodes, BPAR showed no correspondence with mean daily PPI intake. We conclude that prolonged PPI intake has no relevant adverse effect on kidney transplant function or rejection rates. Polypharmacy, however, remains a problem in renal transplant recipients and it is thus advisable to question the necessity of PPI prescriptions when clear indications are missing.Recently, proton pump inhibitor (PPI) intake has been linked to acute kidney injury and chronic kidney disease. The objective of this study was to assess the effect of PPIs on renal function and rejection rate in kidney transplant patients. We performed a single center, retrospective analysis of 455 patients who received a kidney transplant between May 2010 and July 2015. Median follow-up time was 3.3 years. PPI prescription was assessed in half-year intervals. Primary outcome parameters were the estimated glomerular filtration rate (eGFR), change in the eGFR, and >30% and >50% eGFR decline for different time periods (up to four years post-transplantation). Our secondary outcome parameter was occurrence of biopsy proven acute rejection (BPAR) in the first two years after transplantation. Except for >30% eGFR decline from half a year to two years post-transplantation ( With only a single transplanted kidney and oftentimes reduced renal filtration rates, kidney transplant (KTx) recipients are particularly vulnerable to the nephrotoxic adverse effects of drugs. Care is taken to avoid such drugs that could further impair kidney function. For this reason, recent epidemiological studies that have observed a relationship between acute kidney injury (AKI), chronic kidney disease (CKD) and proton pump inhibitor (PPI) intake have been of special interest for practitioners involved in the care of KTx patients ,2,3,4,5.Furthermore, in the setting of KTx, two medication interactions of possible relevance are the interaction between PPIs and mycophenolate mofetil (MMF) and between PPIs and tacrolimus. The first may lead to decreased blood levels of the active metabolites of MMF ,10,11,12In the face of surgical stress and long-term polypharmacy, upper gastrointestinal symptoms are frequent in KTx patients . Even inIn light of the mentioned studies and the possibility of adverse drug interactions between PPIs and mycophenolate mofetil or tacrolimus, we carried out this study. Previous PPI studies in KTx patients have focused on the possible interaction of MMF with PPIs ,24,25 orPrior to analysis, the data of all patients was anonymized. The local ethics committee  approved the study. Methods in this study were carried out in accordance with the current transplantation guidelines and the Declarations of Istanbul and Helsinki. Written informed consent was given by all participants at the time of transplantation for recording their clinical data.We herein performed an explorative, retrospective, single-center cohort study. We enrolled all patients receiving a KTx between May 2010 and July 2015 at the University Hospital Muenster. Inclusion criteria were patient age ≥18 years and PPI therapy at primary hospital discharge post-transplantation (pTx). Patients receiving multiple organ transplants remained included. The recipient and donor data was collected from the patients’ electronic files. The following data was collected and used: recipient and donor age and sex; recipient body mass index (BMI); prior renal transplants; transplant under European Senior Program; donor type (living or deceased); delayed graft function ; cold ischemia time; pre-transplant time dialyzed; pre-transplant arterial hypertension; pre-transplant diabetes; presence of peripheral arterial occlusive disease; cerebral arterial occlusive disease or stroke; coronary heart disease or myocardial infarction; anticoagulant prescription; antiplatelet drug prescription ); statin prescription; MMF dosage at primary discharge and two years pTx; cortisone intake at primary discharge and one year pTx; tacrolimus dose and blood level three months pTx; prior smoking history; continuation of smoking after KTx; number of human leukocyte antigen (HLA) mismatches; ABO incompatibility of transplant; induction therapy; pre-transplant donor specific antibody (DSA) occurrence; panel reactive antibodies; transplant rejection occurrence and type according to Banff criteria; eGFR from half a year to four years pTx; and data on PPI prescription. At primary discharge, none of the patients had any non-steroidal anti-inflammatory drug prescriptions, except for ASA. To improve adjustment for confounding through comorbidities, additional data was collected to calculate the Charlson comorbidity index  at transThe induction therapy was chosen according to the immunological risks of the patients. One gram of mycophenolate mofetil was given twice a day; the dosage was reduced in case of adverse events. Prednisolone was started at 500 mg intravenously (i.v.) before KTx, followed by 100 mg for three days; then reduced by 20 mg/day. A dosage of 20 mg/day was maintained until day 30 and then slowly reduced to 5 mg/day. Immunosuppressive maintenance therapy usually consisted of a calcineurin inhibitor (tacrolimus or cyclosporine A), mycophenolate sodium or mycophenolate mofetil and prednisolone.Data on the prescription of PPIs (agent and dose prescribed) were collected in half year intervals for all patients starting at primary discharge. PPI intake was assumed according to this prescription until the next interval. If data was not present for a certain interval, the prescription from the preceding interval was assumed.Due to the favorable drug interaction profile of pantoprazole in comparison to other PPIs , pantoprAt our center, patients are instructed to ingest tacrolimus and MMF on an empty stomach one hour before intake of PPIs. Both tacrolimus and MMF are usually taken twice daily, while PPIs are mostly taken once per day.n = 363) and non-intake (n = 82) at half a year pTx, two patient groups were formed. These were used for a direct comparison of GFR and change thereof.Based on PPI intake  is an elevated dose .Primary outcome measures were: the eGFR , change in the eGFR , eGFR decline >30% and eGFR decline >50% (from six months to two years and two years to four years). All eGFR-values were calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation .Our secondary outcome was biopsy proven acute rejection (BPAR) in months one to six, seven to twelve and in the second year pTx. For each time period, every patient with a rejection was counted (not only a patient’s first rejection). The usual indication for biopsy in our center is a rise in creatinine with no apparent cause.® Statistics 24 for Windows . Microsoft Excel was used for data collection, simple calculations, and graphing. Statistical analysis was performed using IBM SPSSp-values ≤ 0.05 were regarded as statistically noticeable. Normally distributed continuous variables are displayed as mean ± standard deviation (SD), non-normally distributed as median and interquartile range (IQR), and categorial variables as frequencies and percentage of total. Pairwise comparisons of independent samples were performed using student’s t-test or Welch’s unequal variance t-test for normally distributed data and the Mann–Whitney U test was used for non-normally distributed data. For categorial variables, groups were compared using Fisher’s exact test.This is an explorative study and no adjustment was made for multiple testing. For the group comparison of the eGFR and change in the eGFR, the Mann–Whitney U test and multivariable linear regression were performed. Further information on model building and the included variables is found in A possible relationship between >30% and >50% eGFR decline endpoints and mean daily PPI intake was investigated using Fischer’s exact test and multivariable logistic regression analysis. Mean daily PPI intake was calculated by averaging the prescribed PPI dose at half year intervals up to half a year before the final relevant eGFR value. Information on model building and the herein included variables can be found in Correlation of BPAR in months one to six, seven to twelve and in the second year pTx with mean daily PPI intake, respectively, was investigated univariably using Fischer’s exact test and multivariably using logistic regression analysis with forward selection of confounders (same procedure as for >30% and >50% eGFR decline endpoints). A list of the variables included and further information on the testing can be found in A total of 511 patients were transplanted in the study period. The following exclusions were made: 37 patients as they were <18 years of age, 13 as they did not receive PPIs at primary discharge, five due to non-onset of graft function after transplantation and one due to death before primary discharge. A final number of 455 patients were included; the median follow-up time was 3.3 years . In our cohort, 12 patients died and 10 experienced graft loss within the first year; seven died and eight graft losses occurred within the second year pTx. Most patients (96%) initially received pantoprazole as their PPI agent. Patient and donor characteristics are displayed in Lost to follow-up rates in the PPI group and no PPI group were 16/363 (4.4%) and 2/82 (2.4%) at one year, 64/363 (17.6%) and 6/82 (7.3%) at two years, 152/363 (41.9%) and 28/82 (34.1%) at three years, 229/363 (63.1%) and 54/82 (65.9%) at four years, respectively.The two groups differed noticeably regarding recipient age, donor type (living or deceased), time dialyzed before transplantation, active smoking, smoking history, cerebral artery occlusive disease or stroke, coronary artery disease or myocardial infarction and Charlson index at the time of transplantation. These characteristics were favorable for the no PPI group. A noticeable difference was also found in the number of fast tacrolimus metabolizers three months pTx. .p < 0.05) (multivariable). For the third and fourth year, the difference was not statistically significant . All other eGFR decline endpoints showed no relation to mean daily PPI intake. eGFR decline >50% from two to four years showed some tendency in the same direction (p = 0.056). However, here, only three events occurred. Tables with the results can be viewed in Multivariable logistic regression was only carried out for the outcome >30% eGFR decline from half a year to two years pTx. In all others, only univariable analysis was performed (due to the low number of events). eGFR decline >30% from half a year to two years showed statistical correlation with higher PPI doses in multivariable logistic regression (p = 0.027); multivariable (logistic regression) analysis was not feasible in this case due to zero events in one group. All other tests did not show any association.BPAR occurred in 96 patients in months one to six, in 32 patients in months seven to twelve and in 36 patients in the second year pTx. For the rejection analysis, patients who did not complete a follow up of at least 5/6 of the analyzed time points were excluded from analysis. Those with death or transplant loss with prior rejection, however, were included. Twelve patients were excluded from multivariable analyses due to missing data. The results of the analysis are presented in As the possible drug interaction of MMF with PPIs was of special interest, all rejection analyses were repeated, analyzing the data of patients who had MMF at primary discharge only. None of these tests showed any significant association.Our results demonstrate that prolonged PPI intake after KTx does not lead to any meaningful decline in kidney function within the first four years after transplantation. Additionally, our analyses of rejection rates are in line with recent studies showing no relevant association between rejection rates and PPI-intake after KTx ,24,25.Several large epidemiological studies observed a relationship between AKI, CKD, and PPI intake ,2,3,4,5.Following the Kidney Disease Improving Global Outcomes (KDIGO) guideline, a form of mycophenolate acid (MPA) together with the calcineurin inhibitor tacrolimus and low dose corticosteroid therapy is the preferred maintenance therapy after KTx at our center  43]. Th. Th43]. p = 0.07) to be higher in the PPI group (p = 0.035). However, the previously mentioned Dutch KTx magnesium study found no relevant interaction between PPI and tacrolimus in their observational study [Tacrolimus and PPI potentially interfere e.g., at the cytochrome P450 system (CYP3A) ,18. AnotPI group . Furtheral study . Thus, tIt may also be worth mentioning that we did not investigate a possible effect of PPIs on the intrapatient variability of tacrolimus. It has been shown that the intrapatient variability of tacrolimus correlates with poor long-term outcomes in kidney transplant recipients . It may Mycophenolate mofetil is a prodrug that is hydrolyzed to the active metabolite MPA. It acts as a selective uncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and thus inhibits de novo guanosine synthesis . PharmacPrevious PPI studies in KTx patients relevant to our investigation have focused on the possible interaction of MMF with PPIs. Van Boeckel and colleagues compared 125 patients taking pantoprazole with 77 patients using ranitidine . The priOur study adds to the existing literature as we extended the analyses of the eGFR and changes thereof to a longer time period  than previous studies .A simple comparison of the eGFR reflected differences in patient characteristics . These dMoreover, similar rejection rates in the groups taking different doses of PPI, namely 0 mg, 1–20 mg, 21–40 mg and >40 mg pantoprazole equivalent, led us to conclude that the relevance of PPI intake for MMF efficacy is at best minimal. This is in line with the previously mentioned observational studies that used different methodologies. Correction for various potentially relevant confounders did not change the results with regards to kidney function or rejection rates. In line with our observations is a recently published meta-analysis that evaluated the data of 6786 KTx patients. The authors found that PPI use was linked to hypomagnesemia, but not associated with acute rejection, graft loss, or one-year mortality [One limitation of our study is the retrospective study design analyzing a limited number of patients from one center. For part of the rejection analysis and >30% and >50% eGFR decline, the inclusion of covariables in the multivariable logistic regression analyses was limited due to the low number of events. Confounding by indication proved a serious difficulty in this study. Patients with longer, higher PPI intake showed a tendency to higher comorbidity and risk factors . To copeFor the statistically observed relation of second year AMRs and >30% eGFR decline  with PPI average intake, we presume residual confounding to be the reason because in a post-hoc comparison of the groups used for the >30% eGFR decline analysis, we found significant differences for the following patient characteristics: recipient age and BMI, pre-transplant dialysis time, prior renal transplant, donor type (living or deceased), pre-transplant diabetes, ABO transplant incompatibility, cerebral arterial occlusive disease or stroke, coronary heart disease or myocardial infarction, statins, prior smoking history, continuation of smoking after KTx, and Charlson comorbidity index. All of these, apart from prior renal transplant and ABO incompatibility, showed an unfavorable tendency with higher PPI intake.We conclude from our data that prolonged PPI therapy is safe in regard to KTx function. However, further studies into a possible interaction between PPIs and tacrolimus may be of interest. In addition, our findings highlight the importance of examining changes in the eGFR rather than single eGFR measurements in similar studies. Polypharmacy is a relevant problem in the transplant population  and it i