Falls from a height are a common cause of polytrauma care in Level I Trauma Centers worldwide. The expected injury consequences depend on the height of the fall and the associated acceleration, as well as the condition of the ground. In addition, we further hypothesize a correlation between the cause of the fall, the age of the patient, and the patient’s outcome. A total of 178 trauma patients without age restriction who were treated in our hospital after a fall >3 m within a 5-year period were retrospectively analyzed. The primary objective was a clinically and radiologically quantifiable increase in the severity of injuries after falls from different relevant heights . The cause of the fall, either accidental or suicidal; age and duration of intensive care unit stay, including duration of ventilation; and total hospital stay were analyzed. Additionally, the frequency of urgent operations, such as, external fixation of fractures or hemi-craniectomies, laboratory parameters; and clinical outcomes were also among the secondary objectives. Sustaining a thoracic trauma or pelvis fractures increases significantly with height, and vital parameters are significantly compromised. We also found significant differences in urgent pre- and in-hospital emergency interventions, as well as organ complications and outcome parameters depending on the fall’s height.  Falls from great heights, either accidentally or intentionally, are common traumatic circumstances in major trauma centers and are often associated with challenging long-term treatment. According to the World Health Organization (WHO), falls are the second-leading cause of accidental injury deaths worldwide, while more than 80% of falls occur in low- and middle-income countries . A fall is defined as a downward movement of the body associated with a high kinetic energy, which ends in a sudden vertical deceleration . The heiThey are mostly associated with multiple complex injuries regarding the skeleton and trunk. Depending on the height, life-threatening injuries are more likely to be expected and falls greater than 18 m are usually fatal . Adults Although quite a few studies on falls from heights have been published since the late 1960s, there are only a few that presented specific clinical and laboratory parameters throughout the complete hospital stay. Earlier investigations mostly focused on specific body regions or operative treatments. A few, mostly forensic studies, have presented some age-related differences in injury patterns and influences of height and landing position ,6. OtherHeight affects the expected injuries directly by acceleration and therefore by the landing impact and indirectly by influencing the orientation of the body. Suicidal jumpers tend to sustain more lower extremity fractures, since most of them jump with their feet first .Emergency physicians need to have an understanding of the potential injury patterns in order to be prepared and organized to treat these patients in an often multidisciplinary approach. We hypothesize that there is a correlation between the height of the fall, age of the patient, cause of the fall and related injuries and outcome of the patient. One aim of this study is to identify specific injury patterns that are increasingly occurring with greater fall height to further sensitize treatment teams to these injuries in often complex overall injury patterns.The charts of all patients that were admitted to our university Level 1 Trauma Center located in the city center of a German metropolitan region with suspicion of severe multiple injuries between January 2015 and December 2019 were screened for falls from a great height as the mechanism of injury.® (ATLS) and received a full body CT scan, as well as additional conventional X-rays, if necessary.All patients were admitted to our emergency room after a fall from a great height, defined higher than 3 m (ICD-10 code: W09-W17) and were treated as inpatients. All individuals were treated according to the standards of Advanced Trauma Life SupportThe height of the fall was taken for all patients from the ambulance reports, which were available in all presented cases. Patients were then assigned into three groups depending on their fall height: 3–6.99 m (low), 7–9 m (intermediate), and a fall height of >9 m (high). If the number of floors from which an individual fell were recorded instead of meters, the height of each floor was assumed to be the average value of 3 m based on international standards. The trauma mechanism “fall from a staircase/escalator“ was excluded, independent from the estimated altitude. No age restriction was made, and a sub-analysis of children and adolescents younger than 18 years of age was provided in this study.Clinical and radiological data were obtained from the patients charts and diagnostic imaging. The cause of the fall, either accidental or suicidal; age and duration of intensive care unit stay, including duration of ventilation; and total hospital stay were analyzed. Additionally, frequency of urgent operations, such as, external fixation of fractures or hemi-craniectomies (Damage Control Surgery: [DCS]); laboratory parameters; and clinical outcomes were also among the secondary variables. Severity of injury was given by the Injury Severity Score (ISS). Base excess (BE), hemoglobin (Hb), and number of thrombocytes were analyzed, and coagulopathy was determined based on partial thromboplastin time (PTT) or INR value, PTT  ≥  40 s or INR  ≥  1.4. Patients’ outcome was graduated into 5 categories: good recovery, minor disability (patient independent), severe disability (patient awake but needs support), persistent vegetative state, and dead.The study was approved by the ethics committee of Frankfurt University Hospital: Grant Number: 20-712. p values for categorical variables were derived from Chi-square or two-sided Fisher’s exact test and for continuous variables from Student’s t-test or the Mann-Whitney U-test.Values are reported as the mean ± standard deviation (SD) for continuous variables and as percentages for categorical variables. All analyses were performed using the Statistical Package for Social Sciences (SPSS for Mac) version 25.0 . Demographic and clinical parameters comparing the different height groups were evaluated using bivariate analysis. A total of 178 patients whose admission to the clinic was caused by a fall from a height of at least 3 m were analyzed. Overall, 77% (n = 137) of patients were male, and the mean age was 33.7 ± 17.37 years. The mean ISS was 19.58 ± 15.26 points, whereas the thorax , extremities (AIS: 1.63 ± 1.39 points), and the head (AIS: 1.53 ± 1.74 points) were most severely injured: 74.2% (n = 132) if falls happened accidently, while 25.8% (n = 46) of falls were due to intended suicide. The mean length of intensive care unit stay was 6.41 ± 8.78 days and overall mortality was 4.5% (n = 8) .p < 0.001), respectively. In terms of fall height, no differences in terms of gender distribution or age were found . ISS was the highest for patients from the high group (33.77 ± 19.81 points), as compared to that in the intermediate (24.58 ± 15.51 points) and low (15.48 ± 12.03 points) groups, respectively (p < 0.001). No differences between the groups were found with regard to the AIS of the head (p = 0.738), but significantly higher scores were recorded for the thorax, abdomen, and extremities for patients from the high group (p < 0.001) (p < 0.001) (p = 0.6).The patients were then divided into three groups depending on their fall height; 120 patients were assigned to a fall height 3–6 m (low), 36 patients were assigned to a fall height between 7–9 m (intermediate), and 22 patients were assigned to a fall height of > 9 m (high). The mean fall height was 4.4 ± 1.1 m (low), 8.3 ± 0.8 m (intermediate), and 14.1 ± 4.1 m (high) (< 0.001) . The pro< 0.001) . Of thesp = 0.017), heart frequency , and the Glasgow Coma Scale (GCS) were lower for (higher for HF) patients from the high group . Furthermore, initially determined Hb values were lower in the “high” group (p = 0.004), and the highest BE deviation was present for falls from the highest altitude group (p < 0.001)  .p < 0.001) and pre-clinical implantation of chest tubes , as well as higher ratio of circulatory support by administration of catecholamines   .p < 0.001). In addition, chest trauma was more common, the higher the height of the fall was described . In total, three patients suffered from deceleration of the thoracic aorta (intermediate: 1 vs. high: 2). One of these patients deceased during the initial treatment in the trauma bay. The remaining two patients underwent emergent surgery with implantation of an endovascular prothesis. Traumatic brain injuries were distributed equally between the groups  (p = 0.59) (p < 0.001). Kinetic therapy due to severe chest trauma was established during the intensive care unit course in 40.9% of the patients from the high group, 25% from the intermediate group, and 11.8% from the low group respectively (p = 0.002)  , as well = 0.59) . On the = 0.002) .p < 0.001). Nevertheless, no significant differences were detected with regard to the duration of mechanical ventilation (p = 0.533). Mortality was higher for the intermediate (11.1%) and high (9.1%) groups when compared to the low group   .p = 0.026). All falls from a height in children under 6 years of age were accidental, whereas five children from the older group jumped from a height intentionally (p = 0.031), where the youngest patient was 14 years old.In this study, 34 (19.1%) patients were younger than 18 years of age. In a subgroup analysis, these patients were further divided into two groups, whether they were younger (n = 15) or older (n = 19) than 6 years of age. Injuries related to body region were comparably distributed between these groups, except for Traumatic Brain Injury (TBI), which were significantly more frequent in the younger patients  in the TR-DGUThe results of this study extend the knowledge from currently available literature. With increasing fall height, the overall injury severity is higher. This appears to be due to a significantly higher severity of thoracic and pelvic injuries, whereas the severity of head injuries and fractures of the spine were not significantly more severe as a function of fall height. As a consequence, emergency stabilization of the pelvis had to be performed significantly more often in the high fall group, which emphasizes the requirement to “clear the pelvis” in patients jumping from the greatest height.This study has some limitations. First of all, its retrospective character with all accompanying restrictions due to the study design. Thus, the data about the height of the fall could be taken from the rescue service protocols, and in most cases, no valid information was available about the nature of the ground—which must be considered when interpreting the results. Furthermore, it can be assumed that the rate of prehospital deaths is relatively high, especially with increasing height. Against this background, the data on lethality should be interpreted with caution, as there is a clear selection bias due to a presumably high rate of preclinical patient deaths. Therefore, this study does not provide any information on injuries that directly cause death.


MSNA/HFMSNA) and the gain and coupling of the sympathetic baroreflex function in HFrEF patients. In a sample of 139 HFrEF patients, two groups were selected according to the level of LFMSNA/HFMSNA index: (1) Lower LFMSNA/HFMSNA  and (2) Higher LFMSNA/HFMSNA . Heart rate (ECG), arterial pressure (oscillometric method), and muscle sympathetic nerve activity (microneurography) were recorded for 10 min in patients while resting. Spectral analysis of muscle sympathetic nerve activity was conducted to assess the LFMSNA/HFMSNA, and cross-spectral analysis between diastolic arterial pressure, and muscle sympathetic nerve activity was conducted to assess the sympathetic baroreflex function. HFrEF patients with lower LFMSNA/HFMSNA had reduced left ventricular ejection fraction , gain  and coupling of sympathetic baroreflex function  and increased muscle sympathetic nerve activity  and heart rate  compared with HFrEF patients with higher LFMSNA/HFMSNA. Further analysis showed an association between the LFMSNA/HFMSNA with coupling of sympathetic baroreflex function  and left ventricular ejection fraction . In conclusion, there is a direct association between LFMSNA/HFMSNA and sympathetic baroreflex function and muscle sympathetic nerve activity in HFrEF patients. This finding has clinical implications, because left ventricular ejection fraction is less in the HFrEF patients with lower LFMSNA/HFMSNA.Sympathetic hyperactivation and baroreflex dysfunction are hallmarks of heart failure with reduced ejection fraction (HFrEF). However, it is unknown whether the progressive loss of phasic activity of sympathetic nerve bursts is associated with baroreflex dysfunction in HFrEF patients. Therefore, we investigated the association between the oscillatory pattern of muscle sympathetic nerve activity (LF Heart failure is a complex syndrome and considered the leading cause of hospitalization in patients over the age of 60 years, which accounts for about 30–40% of the mortality of these patients . AccordiHFrEF patients have increased sympathetic activity as shown by the enhanced sympathetic nerve discharges , and a pIn healthy individuals, spontaneous fluctuations in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) are strongly coupling in the LF band both at rest and during physiological maneuvers  . Based oOn the other hand, the increase of burst frequency with a shift from LF fluctuations toward HF bands (∼0.20 Hz) are linked with a marked reduction in the linear relationship between systolic arterial pressure (SAP) and MSNA oscillation in the presyncope phase during a tilt test maneuver . These dMSNA/HFMSNA)  . The eff/HFMSNA) . Curious/HFMSNA) , and a pThis study was approved by the Scientific Commission of the Heart Institute (InCor), University of São Paulo Medical School (#3946/13/071) and Human Subject Protection Committee of the Clinical Hospital, University of São Paulo, Medical School (# 22255213.2.0000.0068). Signed informed consent was obtained from all patients during the screening visit.2) < 20 ml.kg–1.min–1 were included in the study. The exclusion criteria were recent myocardial infarction or unstable angina (<3 months), HFrEF duration (<3 months), and permanent pacemaker dependence. According to the level of the LFMSNA/HFMSNA index, patients were placed into two groups: (1) Lower LFMSNA/HFMSNA  and (2) Higher LFMSNA/HFMSNA .Patients were selected from a database of randomized studies performed at the Unit of Cardiovascular Rehabilitation and Exercise Physiology of the Heart Institute (InCor), University of São Paulo Medical School. Initially, 139 HFrEF patients, age ranging from 30 to 65 years, New York Heart Association functional class II to III, left ventricular ejection fraction (LVEF) < 40%, and peak oxygen uptake  .2 peak) was averaged from the last 30 s interval and was considered the maximal exercise capacity  on a beat-to-beat basis. Simultaneously, HR was monitored through lead II of the ECG and respiratory rate was monitored with a piezoelectric thoracic belt  placed around the upper abdomen.AM, with the patients in a supine position in a quiet air-conditioned room (22–24°C). After obtaining an adequate sympathetic nerve recording site in the leg and after stabilization of the autonomic and cardiovascular variables, baseline recordings of arterial pressure, HR, MSNA, and respiratory rate were taken for 10 min.On the day of the experiment, all patients abstained from caffeine or other types of stimulants for 12 h. The protocol experiment was performed at approximately 8:00 i-th heart period were defined as SAP and DAP values, respectively, where i is the cardiac beat counter. Thereafter, the beat-to-beat variability of MSNA, RRi, systolic and diastolic arterial pressure , and respiratory activity were analyzed by an autoregressive frequency domain approach. On stationary segments of 200–300 beats, autoregressive spectral decomposition of times series were calculated based on the Levinson–Durbin recursion with the order of the model chosen according to Akaike’s criterion. This procedure automatically quantifies the center frequency and the power spectral density of oscillatory components in very low (VLF: 0.003–0.04 Hz), low (LF: 0.04–0.15 Hz), and high frequency (HF: 0.15–0.40 Hz) ranges in absolute (abs.) values as well as in normalized units (n.u.). However, only the normalized units were used of the LF and HF components of RRi and MSNA variability due to the variances in data. According to the international guidelines, the RRi spectral component quantified in the LF band representing cardiac sympathetic modulation predominance, and the HF band synchronized with respiration, representing cardiac parasympathetic modulation (RRi/HFRRi) and oscillatory pattern of MSNA (LFMSNA/HFMSNA), respectively  was used by a trained investigator (ET-D) to process the MSNA, ECG, arterial pressure, and respiratory activity signals and to extract the time series of MSNA, R-R interval (RRi), systolic and diastolic arterial pressure , and respiration on a beat-to-beat basis. The sympathetic bursts were sampled once per cardiac cycle synchronously with the peak of the R-wave of ECG and automatically detected considering an amplitude threshold of 30% of baseline and rejection ratio of 3%. The maximum and minimum values of arterial pressure inside the dulation . Spectradulation , becausedulation . Finallydulation . Furtherectively .To evaluate sympathetic baroreflex function, transfer function analysis by means of the bivariate autoregressive model was used with model order fixed to 10. As previously described in detail , this pr2) test was used to assess categorical data differences. For each continuous or discrete variable, Lèvene and Kolmogorov–Smirnov tests were used to assess the homogeneity and normality of distribution, respectively. Demographic data and baseline physical characteristics and hemodynamic and autonomic data were compared using Student’s t-tests or Mann–Whitney tests when appropriate. Spearman correlation was used to test the association between LFMSNA/HFMSNA, LVEF, VO2, gain and coherence of sympathetic baroreflex function. Probability values of P < 0.05 were considered statistically significant.The data are presented as mean ± standard error. A chi-square  than the higher LFMSNA/HFMSNA group had , someone could argue about the influence of the menstrual cycle of these women on our results. We did not control the menstrual cycle and the use of hormonal contraceptives or hormone replacement therapy of the women participating in our study. However, because few women were under 50 years of age  our sample was mainly composed of postmenopausal women, who were similarly distributed between the groups. Thus, it is unlikely that menopause, the use of hormonal contraceptives, or hormone replacement therapy could be a confounding variable in the present study. Finally, considering our strategy for the composition of the HFrEF groups, it is possible that some differences in autonomic control markers could be expected due to the interdependence of cardiovascular parameters. Further analysis will be needed in future studies to address this issue.Our study has some limitations that need to be addressed. First, the experimental protocol considers only recordings obtained with the patient in the resting position to evaluate autonomic nervous system in HFrEF patients. Some authors have suggested that the autonomic nervous system needs to be evaluated both at rest and during physiological maneuvers to examine the complexities of neural regulation. Therefore, it is difficult to generalize our findings to HFrEF patients during a physiological challenge . Second, even considering that female participants in the present study were a smaller proportion  or Dr Toschi-Dias (edgar.dias@metodista.br).The data, analytic methods, and study materials are available to other researchers at the Heart Institute (InCor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, with Dra. Rondon (The studies involving human participants were reviewed and approved by the Scientific Commission of the Heart Institute (InCor), University of São Paulo Medical School (#3846/13/071) and Human Subject Protection Committee of the Clinical Hospital, University of São Paulo, Medical School (# 22255213.2.0000.0068). The patients/participants provided their written informed consent to participate in this study.ET-D, NM, ET, and MR conceived and designed the research. ET-D, PT, RG, LA-C, TN, DL, AS, LU-P, LM, PO, AB, MA, CN, and MR performed the experiments. ET-D, ET, and NM analyzed the data. ET-D, NM, ET, CN, and MR interpreted the results of the experiments, and edited and revised the manuscript. ET-D and MR prepared the figures. ET-D and ET drafted the manuscript. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hypertension is a risk factor for generalized periodontitis (GP) and chronic kidney diseases (CKD). However, the role of isolated systolic blood pressure as one of the major risks for these inflammatory diseases has not been explored. Very limited studies exist identifying the red-complex bacteria in association with the isolated systolic blood pressure. Hence, the main objective of this study was to assess the isolated systolic blood pressure and the red-complex bacteria along with the demographic variables, periodontal parameters, and renal parameters in patients with generalized periodontitis and chronic kidney disease. One hundred twenty participants (age 30–70 years) were divided into four groups—Group C: control , Group GP: generalized periodontitis, Group CKD: subjects with CKD with good periodontal health, Group CKD + GP: subjects with both generalized periodontitis and CKD. Demographic variables and periodontal parameters were measured and recorded. Blood pressure measurements and a detailed history and renal parameters such as serum creatinine, eGFR, and fasting blood sugar were recorded. The red-complex bacteria (RCB) were assessed in the subgingival plaque samples of all four groups using RT-PCR. Older participants (above 50 years) showed worse periodontal scores in the CKD + GP group along with elevated isolated systolic blood pressure, higher serum creatinine, and fasting blood sugar. eGFR was significantly decreased compared to the other groups. Bacterial counts were higher in the GP + CKD group, suggesting that they may be at a higher risk for generalized periodontitis and chronic kidney disease. Isolated systolic blood pressure (ISBP) and RCB were significantly correlated with the renal and periodontal parameters. A log-linear relationship exists between periodontal disease, CKD, RCB, and isolated systolic hypertension levels. Clinical hypertension and impaired regulation of arterial blood pressure and are two major systemic conditions associated with inflammation and immune dysfunction ,2. It isChronic kidney disease is a complex multifactorial pathogenic disorder. The main risk factors are reduced physical activity, increased body mass index (BMI), elevated blood pressure and increased blood cholesterol levels. Periodontal disease has recently been identified as an important potential risk factor for CKD . StudiesTanerella forsythia (Tf), Treponema denticola (Td), and Porphyromonas gingivalis (Pg), are most commonly seen in the diseased periodontitis sites of the patients [Periodontitis is a chronic inflammatory disease associated with gram-negative bacteria leading to the destruction of the tooth-supporting structures and ultimately tooth loss. It affects nearly one in two adult individuals worldwide . The redpatients . The asspatients .Periodontitis and hypertension share common risk factors of older age, male gender, smoking, overweight/obesity, diabetes, and low socioeconomic status. Recent studies have revealed that the association between periodontitis and hypertension extends beyond the sharing of common risk factors. Epidemiological studies reveal periodontitis to be an independent risk factor for hypertension ,12,13.When considering the association of complex multifactorial diseases, two distinct scenarios are possible: a particular genetic background predisposes to the two diseases, or one complex disease predisposes to the other, or both predispose to each other. CKD and periodontitis are two diseases, with hypertension being a common risk factor. Few studies have explored the association between isolated systolic blood pressure and the RCB in generalized periodontitis and systemic disorders such as chronic kidney disease ,13. KeepThe study was conducted between January 2018 to February 2020 in Thrissur, Kerala, India. Two hundred patients were recruited from PSM College of Dental Science and Research, Thrissur, India. Both male and female participants aged 30 to 70 years were included in the study. Study participants who were unwilling or did not meet the inclusion criteria were excluded. Subjects who had periodontal treatment in the past 6 months, with smoking/tobacco/alcohol habits, patients with carcinoma, sarcoidosis, immunosuppressive conditions, rheumatoid arthritis, and tuberculosis were excluded from the study.One hundred twenty subjects were selected as the study population. This study was approved by Institutional Ethical Review Board, PSM College of Dental Science and Research, Thrissur, India . The study was conducted according to the guidelines of the Helsinki Declaration of 1975, revised in 2013. The study protocol was explained in detail to the patients, and written informed consent was obtained from all participants.The study subjects were divided into four equal groups:Group C: Control group of 30 subjects who were systemically and periodontally healthy;Group GP: 30 subjects with Generalized Periodontitis (group GP) with at least 10 remaining natural teeth and generalized periodontitis;Group CKD: 30 patients with chronic kidney disease alone. Periodontally healthy CKD patients who were not on CKD stage 5 and dialysis were selected. Patients without CKD presented an estimated glomerular filtration rate >90 mL/min, estimated according to CKD-EPI equation 2009 ;Group CKD + GP: 30 subjects with both and periodontitis (CKD + GP) . PatientThe parameters assessed in the study included the demographic, periodontal, and renal parameters.2), and sex.Demographic variables included age (30 to 70 years), body mass index  Plaque Index (PI) , (2) GinCriteria for diagnosis of the generalized periodontitis: Participants were diagnosed with generalized periodontitis if they had at least 30% of tooth sites: (1) with probing depth (PD) ≥ 5 mm at one or more sites; (2) CAL ≥ 3 mm at the same site with positive bleeding on probing, with stage II grade B periodontitis patients, according to the recent 2017 World Workshop Classification of Periodontal and Peri-implant diseases were selected. For periodontally healthy subjects, PPD ≤ 3 mm in every site with no bleeding on probing was considered.Venous blood samples (5 mL) were collected in the morning after a 12 h fasting period. The samples were transported to the laboratory for biochemical analysis. The serum creatinine and fasting blood sugar were determined by an automated method, using a semi-automated biochemical analyzer –Italy). eGFR was calculated based on serum creatinine values using CKD—EPI equation 2009 .At the hospital visit, the participants were asked to complete questionnaires. A detailed case history, including a history of past medications and dental history, was taken, followed by a physical and oral examination. All relevant parameters were recorded. Before blood pressure examination, the patients were advised to take a rest for five minutes. Blood pressure (SBP and DBP) measurements were documented twice on the right arm using a stethoscope and a sphygmomanometer in a hospital room away from excessive workplace noise. Systolic and diastolic blood pressures were defined using the first and fifth Korotkoff sounds, respectively. Measurements were rounded upward to the nearest 2 mm Hg and recorded. Previous diagnosis and/or treatment of hypertension or high blood pressure by a physician was assessed via a questionnaire.Hypertension was defined as taking self-reported physician diagnosis or treatment for hypertension, blood pressure-lowering medication on medication inventory, having systolic blood pressure ≥140, or diastolic blood pressure ≥90 . SecondaThe study analyzed the potential confounders such as age, sex, BMI, and obesity as a part of demographic variables. Diabetes mellitus associated with CKD, generalized periodontitis and hypertension were also taken into account .Tanerella forsythia (Tf), Treponema denticola (Td), and Porphyromonas gingivalis (Pg) were quantified in subgingival plaque samples using real-time polymerase chain reaction. The diseased area was first isolated with the sterile cotton roles, and the supragingival plaque and calculus were removed. Subgingival plaque was then collected using periodontal curettes from the sites with the deepest periodontal pockets present in the entire dentition and transferred to the sterile vial for further molecular analysis.Molecular Analysis: Red-complex bacteria: DNA isolation from the subgingival plaque: A laboratory phenol extraction procedure was used to obtain plaque DNA . One hundred milliliters of buffer containing 10% sodium dodecyl sulphate solution (SDS) and 5 mL of Proteinase-K were used to incubate the samples for an hour at 37 °C. After incubation, 1 mL mixture of phenol and chloroform were added to the samples and centrifuged for 10 min at 10,000 rpm. The supernatant was collected, and the mixture was extracted. The supernatant was stored for 2 h at −200 °C before being treated with 0.5 mL isopropanol solution. The final product was centrifuged for 15 min at 10,000 rpm. The final fractions were rinsed in 0.5 mL of 70% alcohol and were liquified in 0.2 mL sterile milli-Q water. The quantity of DNA was measured with a spectrophotometer at a wavelength of 260–280 nm. The DNA was stored at −200 °C for subsequent examinations.‖ dye was utilized to identify microbial DNA. Species-specific primers were utilized for the quantification of Pg, Tf, and Td. § Melt curve analysis was used to assess the presence of nonspecific products, numerous amplicons, and impurities in each sample. CT technique (comparative cycle threshold units) was used to determine the number of a gene. The CT value represented the number of bacteria in the red complex. The comparative estimation of bacteria was obtained using the normal amplification curve produced from the typical genomic DNA. Lower CT values represented higher levels of red-complex bacteria in the subgingival plaque samples.Red-complex bacteria: The primers for red-complex bacteria were developed using 16S rRNA as a reference and were generated using NCBI-BLAST . In RT-PThe PCR results were seen using a 2% agarose gel electrophoresis with 100 base pair DNA. It was observed using a UV transilluminator in the gel documentation system at a wavelength of 260 nm. A solid PCR plate with 96 wells was used to prepare the mix, along with translucent seal plates. The plate edges and corners were sealed to prevent evaporation-related artifacts. The products were amplified using a real-time thermocycler. The real-time instrument’s SYBR Green channel was employed for quantification utilizing Luna Master Mix (BIORAD-CFX100).p-value ˂ 0.05 was considered statistically significant. The ternary SBP and DBP variables adopted the diagnostic criteria as suggested by the JNC7 report [The statistical analysis was performed using SPSS, v.17 in Microsoft Windows. The data were normally distributed. In each of the four groups, the mean ± SD was calculated for all the recorded parameters, and the level of significance was estimated. To measure metric data under normal distribution, Kolmogrov–Smirnov and Shapiro tests were used. For intergroup comparisons, a chi-square test and ANOVA were used for all parameters. Pearson correlation analysis was done to correlate all the variables in all four study groups and the red-complex bacteria with all periodontal and renal parameters. A 7 report .p = 0.0001 . Mean probing pocket depth was highest in the CKD + GP group, followed by the GP group. The percentage of sites with periodontal pockets was higher in the CKD + GP group, with a significant difference when compared to the GP group . The mean CAL was highest in the CKD + GP group compared to the GP group showing a statistically significant difference . The frequency of diabetic individuals was higher in the CKD + GP group, CKD, and GP group than in the C group   .On comparison of red-complex bacteria, CT values in C, GP, CKD, and GP + CKD group showed lower CT values in the GP + CKD group, indicating increased levels of bacteria. The results were statistically significant .Overall Systolic Blood Pressure showed a significant correlation with all the variables of age, missing teeth, creatinine values, eGFR, PI score, and mean CAL .Pg, Td, and Tf with PI, GI, PPD, CAL, number of teeth present, and eGFR  as compared to the remaining groups . This reThe Body Mass Index (BMI) was similar in all four study groups in our study. This result reflects those of Caula et al.  and MessConsistent with earlier literature , we founCKD + GP group showed higher plaque index (PI) and gingival index (MGI) scores compared to the other groups . This coThe percentage of periodontal pockets, mean PPD, and CAL values were statistically significantly higher in the CKD + GP group compared to the other groups . These rChronic kidney disease is associated with an increased prevalence of cardiovascular diseases in older, hypertensive and diabetic patients . InflammWe observed a lower range and mean of eGFR value in CKD groups compared to the other groups. This matches the results of Chen et al. 2011  Table 4Table 4. The number of diabetic individuals was higher in the CKD + GP group compared to the other three groups. These results mirror the findings of Sharma P et al.  and AlmeCKD + GP group showed higher systolic blood pressure (SBP) compared to the other groups . PeriodoThe percentage of individuals in normal, prehypertension, and hypertension stages were lower in C and GP groups as compared to the other groups . This waCKD + GP group showed higher counts of red-complex bacteria, with lower CT values correlating to higher bacterial counts . Kshirsap ≤ 0.05). Periodontitis-induced systemic inflammation may contribute to the severity of CKD [Pearson’s correlation coefficient analysis was used to correlate SBP with the demographic, periodontal, and renal parameters . Systoliy of CKD . Periodoy of CKD . Diseasey of CKD . Metaboly of CKD ,46. Infly of CKD . Both diy of CKD . These iy of CKD . Endothey of CKD .We correlated the periodontal bacteria present with other variables and found them to be statistically significant. An increased count of red-complex bacteria was correlated with the periodontal parameters, raised serum creatinine levels, and lower eGFR values . PersistThe sampling strategy and the data collection methods used in this study allowed minimization of selection or information bias. Confounding variables were analyzed to make the results credible. As the study participants were not asked to stop taking their prescribed medications before the assessment, the blood pressure measurements obtained from those on antihypertensive medication reflect the genuine degree of blood pressure control. Additionally, the present study had data on multiple covariates that allowed the control of potentially confounding factors. Hence, the results of the present study are reliable to test the hypothesis that increased isolated systolic blood pressure is associated with periodontitis and chronic kidney disease.A limitation of our study is its cross-sectional design. This temporally limits the assessment of periodontal disease and hypertension occurrence. Our sample size was limited, which could hamper the precise estimation of the true direction and degree of association of the diseases. This is an important issue for future research. Long-term longitudinal studies should be done to corroborate these findings and to develop a fuller picture of the association between red-complex bacteria, isolated systolic hypertension, and chronic kidney disease.Based on our findings, we concluded that isolated systolic blood pressure and RCB counts were significantly high in chronic kidney disease patients with generalized stage II grade B periodontitis. Hence isolated systolic blood pressure and the presence of red-complex bacteria may pose the potential risk factors for generalized periodontitis and chronic kidney disease, which may be associated with adverse outcomes in older adults. Thus the control of isolated systolic hypertension and reduction in the red complex bacterial counts becomes essential to limit the risk for generalized periodontitis and chronic kidney disease.


P = 0.014 and P = 0.003, respectively). Five of 32 eyes (15.6%) in the dipper group and 32 of 54 (59.3%) in the non-dipper group had macular ischemia. In a multivariate analysis, the night-to-day systolic BP ratio was associated with the degree of macular ischemia . Thus, a non-dipping pattern may be a risk factor for macular ischemia in patients with BRVO.Branch retinal vein occlusion (BRVO) is ocular vascular disease affecting approximately 14 million people worldwide, and is closely associated with high blood pressure (BP). Although macular ischemia is a critical factor in the visual prognosis of BRVO, the relationship between macular ischemia and different patterns of nocturnal BP is unknown. Here, we investigated whether a dipping pattern of nocturnal BP is associated with the development of macular ischemia in patients with BRVO. A total of 273 patients were reviewed; of these, 86 (86 eyes) patients were included. All recruited patients had a macular thickness map by optical coherence tomography and underwent 24-h ambulatory BP monitoring. According to their dipping patterns, the participants were divided into dipper and non-dipper groups. The non-dipper group had worse visual outcomes at the initial and 6-month visits ( The prevalence of branch retinal vein occlusion (BRVO) in patients with RVO is 4.42/1000 adults, an estimated 13.9 million adults worldwide2. It is the second most common vision-threatening retinal vascular disease3. The visual outcomes of patients with BRVO depend on their macular condition, which is affected by impaired blood circulation, such as macular edema and ischemia6. In particular, macular ischemia has been identified as one of factors for visual outcomes6.Retinal vein occlusion (RVO) is an ocular vascular disease affecting approximately 16 million people worldwide6. The damage of photoreceptor corresponded to area of capillary nonperfusion at the level of the deep capillary plexus can be detected by optical coherence tomography angiography6. In this background, macular ischemia is the most critical factor in determining the visual prognosis of BRVO8. However, it is not well known which factors contribute to the development of macular ischemia in patients with BRVO.Ischemia in macular area can damage the integrity of the foveal photoreceptor which was correlated with visual outcomes in the patients of BRVO9. Specifically, hypertension is closely associated with macular edema in patients with RVO10. It has been reported that successful treatment of systemic hypertension alone could be sufficient to resolve macular edema10. The reduction of macular edema following systemic hypertension treatment suggests that systemic vascular conditions are key factors for retinal vascular diseases11. In addition to the degree of blood pressure (BP), the patterns of circadian BP variation have been implicated in targeted organ damage, including cerebral blood vessels and cardiovascular systems12. The patterns of systolic BP can be classified according to the systolic night-day BP ratio. Clinical terms such as “dipper,” “non-dipper,” and “riser” have evolved to include people whose BP declines by over 10% during nighttime, those whose BP declines by less than 10% during nighttime, and those who have a higher BP during nighttime compared to that in daytime, respectively12. For assessing the patterns of BP, 24-h ambulatory blood pressure monitoring (ABPM), as opposed to clinical BP monitoring, is highly useful. The pattern of 24-h ABPM is associated with microalbuminuria and early diabetic nephropathy and is a key predictor of cardiovascular outcomes16.Systemic vascular diseases such as hypertension and arteriosclerosis are risk factors for BRVO19. In a previous study, a higher prevalence of hypertension was observed in patients with BRVO, and approximately half of the patients with hypertension were non-dippers19. RVO studies in North America have suggested that 24-h ABPM is a useful tool for detecting uncontrolled nocturnal hypertension, and patients with RVO have a higher prevalence of non-dipping patterns18. These studies have reported that nocturnal hypertension is a risk factor for BRVO. However, to the best of our knowledge, the effects of nocturnal BP pattern on the development of macular ischemia in patients with BRVO have not been investigated yet. Hence, we investigated the association between nocturnal BP patterns and the development of macular ischemia in patients with BRVO.In the ophthalmic field, several studies have investigated the patterns of ABPM in patients with BRVOA total of 273 patients were reviewed, and 86 patients (86 eyes) were included after the exclusion criteria were applied. These patients were followed up for a minimum of 12  months.p = 0.409). There were no significant differences in the distribution of right/left eye affected, follow-up time, baseline intraocular pressure (IOP), mean counts of anti-vascular endothelial growth factor (VEGF) injection and laser treatment sessions, axial length, smoking history, and alcohol history between the two groups.The clinical characteristics of the dipper and non-dipper groups are summarized in Table p = 0.163 and p = 0.145, respectively). The daytime systolic and diastolic BPs in the dipper group were 149.3 ± 2.9 mmHg and 93.2 ± 2.0 mmHg, respectively, which were significantly higher than those of the non-dipper group, 138.8 ± 2.3 mmHg and 86.4 ± 1.5 mmHg, respectively (p = 0.006). The nighttime systolic BP in the non-dipper group, 134.4 ± 2.1 mmHg, was significantly higher than that in the dipper group, which was 127.3 ± 3.0 mmHg (p = 0.048). The night-to-day systolic BP ratios in the dipper and non-dipper groups were 14.7 ± 0.9% and 3.0 ± 0.8%, respectively (p < 0.0001).The results of the 24-h ABPM characteristics between the dipper and non-dipper groups are shown in Table p = 0.017). However, the difference in baseline CMT between the two groups disappeared after 6 months . The extent of change in CMT from baseline to after 6 months was found to be significantly greater in the non-dipper group . A comparison of subfoveal choroidal thickness (SFCT) revealed no significant difference between the two groups (p = 0.737). The degree of macular ischemia between the two groups was significantly different (p = 0.001). There was macular ischemia in 15.6% and 59.3% of the dipper and non-dipper groups, respectively , choroidal thickness, and grade of macular ischemia of the dipper and non-dipper groups are listed in Table p = 0.014 and p = 0.003, respectively). However, the changes in visual acuity between the initial and final visits were not significantly different between the two groups (P = 0.364). Significant differences between the two groups at both the baseline and 6-month visits were also maintained in the multivariate linear regression analysis. .The mean visual acuity of the two groups from baseline to 6 months is shown in Table P = 0.003). However, the 24-h mean systolic and diastolic BP , daytime mean systolic and diastolic BP , and nighttime mean systolic and diastolic BP  showed no association with macular ischemia.Table p = 0.004). In logistic regression analysis of macular ischemia and dipping patterns, the non-dipper group was 8.25 times riskier in multivariate analysis than the dipper group , hypertension, hyperlipidemia, coronary artery disease, or hemorrhagic stroke, is well-known25. Several recent studies have found that a non-dipping pattern is more frequently seen in patients with RVO than in normal control patients27. These observations suggest that non-dipping pattern is related to RVO. However, previous reports did not present any data on how macular changes varied according to the dipping patterns. Therefore, in this study, the authors investigated whether the 24-h ABPM patterns affect the development of macular ischemia, which is a critical factor for the visual outcomes in patients with BRVO. In our study, the univariate and multivariate analyses demonstrated that a non-dipping pattern of systolic BP is strongly associated with the development of macular ischemia in patients with BRVO.In 2006, the Renin-Angiotensin System Study investigated the relationship between BP and the severity of diabetic retinopathy in normotensive individuals with type 1 DM but without clinical diabetic nephropathy27. Neurological clinical studies have shown that cerebral microbleeds are associated with reverse nocturnal dipping in hypertensive patients with ischemic stroke28. Considering these studies, the capillary endothelium around the macula affected by nocturnal hypertension is likely to be more vulnerable to inflammation, edema, and ischemia caused by BRVO than the normal endothelium is. Macular ischemia caused by capillary dropout is a key factor of visual outcome in BRVO29. In this study, perifoveal capillary dropout was significantly more likely to occur in the non-dipper group than in the dipper group, leading to worse visual outcomes in the non-dipper group. Considering the associations between nocturnal hypertension and microvascular damage of various target organs, our results suggest that the constant occurrence of a non-dipping nocturnal pattern could lead to damage the capillary endothelial cells of the macula. This implies that the nocturnal decline in BP is a protective mechanism of the target organ’s capillaries. The absence of a nocturnal decline in BP could make the macula of patients with BRVO vulnerable to hypoxic conditions caused by venous obstruction.The mechanism by which elevated BP at night leads to macular ischemia has not been determined yet. However, according to studies on capillaries of target organs, such as the kidney and cerebrum, a few mechanisms can be inferred. Oliveras et al. demonstrated that nocturnal hypertension is associated with an increase in microalbuminuria; this suggests that a continuously high BP that physiologically fails to fall during nighttime (dipping pattern) will ultimately lead to the destruction of a target organ’s capillary endothelium31. Macular edema can be controlled early through intravitreal injection of anti-VEGF, which is recently developed effective treatment, although recurrence of macular edema has been frequently noted following anti-VEGF therapy32. Therefore, the long-term visual prognosis of patients with BRVO depends primarily on the presence or absence of macular ischemia34. In this study, macular edema was improved using anti-VEGF treatment in the non-dipper and dipper groups. Considering that the reduction in macular edema was greater in the non-dipper group than that in the dipper group, the former demonstrated a lower visual acuity during the final visit. If macular edema disappears after treatment, vision should improve; however, in the non-dipper group, even after the edema disappeared, not much vision improvement occurred, which can be attributed to macular ischemia. Therefore, as observed in our study, the night-to-day systolic BP ratio may be a risk factor for macular ischemia, thus affecting the visual outcome.Macular edema is also a cause of decreased vision in patients with BRVO. However, macular edema can be improved through treatment or resolved on its ownThis study has several limitations. This study involved a relatively small number of patients (n = 86) and was designed retrospectively. Among the risk factors associated with BRVO, blood glucose and lipid levels related to blood tests could not be included due to data limitations. Further prospective studies are needed to measure BP at later stages in the course of the disease. Although the average values were measured through 24-h monitoring, there is a possibility of bias in the BP measurements. This is owing to variable activity patterns and sleep timings of individuals. In addition, patients with a history of hypertension or who have taken antihypertensive drugs were not included in this study, but patients with no symptoms due to latent hypertension may be included in this study. However, despite the limitations of this method, we believe that we proceeded with this study by carefully monitoring nocturnal BP in BRVO patients to identify patients with non-dipping BP patterns.In conclusion, to the best of our knowledge, this is the first study to evaluate the prognostic factors for visual outcome in patients with BRVO by investigating the association between nocturnal BP pattern and macular ischemia. The evidence from this study shows that patients with BRVO who have non-dipping patterns might be vulnerable to macular ischemia, leading to poor visual outcomes. In our opinion, the 24-h ABPM method should be used to assess nocturnal BP patterns in patients with retinal vascular disease.This was a multicenter, retrospective study conducted at a tertiary medical center in Busan, South Korea. All data were collected and analyzed after approval of informed consent waived by the Institutional Review Board of Kosin University Gospel hospital , and the study adhered to the tenets of the Declaration of Helsinki. All experimental protocols were approved by the Institutional Review Board of Kosin University Gospel hospital. A medical chart review was performed to identify patients who were diagnosed with BRVO between January 2015 and December 2018. All included patients had BRVO and a macular layer thickness within the 6 mm diameter circle of the Early Treatment Diabetic Retinopathy Study (ETDRS) map. The exclusion criteria were as follows: diagnosis of glaucoma, vitreous hemorrhage, retinal arterial occlusion, or diabetic retinopathy and prior history of focal/grid or panretinal photocoagulation, macular disease, or intraocular surgery. All patients who had taken systemic medications for hypertension in the past were excluded. A thorough ophthalmic examination, including color fundus photography, optical coherence tomography (OCT), fundus fluorescein angiography (FFA), and 24-h ABPM, was conducted for all patients at the initial outpatient visit. The clinical characteristics of the patients, including age, sex, systemic medical history, visual acuity, IOP, axial length, and follow-up period, were acquired from medical charts. Best-corrected visual acuity based on spectacle correction was measured using a Snellen chart. It was then converted to the logarithm of the minimum angle-resolution visual acuity.Retina evaluation, including FFA and OCT, was performed for all patients using the Heidelberg Spectralis  platform. CMT and SFCT were measured by enhanced depth imaging (EDI)-OCT. CMT was recorded using an automated software present in the line scan pattern of OCT. The thickness values were defined as the foveal central subfield (1 mm from the center of the fovea).SFCT was measured using the Heidelberg software caliper at a point under the fovea, from the base layer of Bruch’s membrane to the layer of the sclerochoroidal junction. Experienced reviewers who were blinded to the patients’ clinical data reviewed the choroidal thickness EDI-OCT scan data.Macular edema was defined as a radial cystic pattern in FFA images within a 3 mm diameter of the ETDRS grid. The degree of macular ischemia was assessed using FFA to evaluate macular perfusion state and foveal capillary ring loss, which was an outline of the foveal avascular zone (FAZ). And it was obtained in the initial outpatient visit. Patients with broken perifoveal capillary rings at the border of the FAZ, with a distinct area of capillary nonperfusion within the foveal center, were regarded as having macular ischemic BRVO. A quantitative assessment of the degree of macular ischemia was performed using the 3 mm zone of the ETDRS grid circle. The assessments were based on the four-quadrant area of capillary ring loss and FAZ outline breaks Fig. .Figure 2ABPM was performed for a full day (24 h). The BP of all patients with BRVO was measured at the initial outpatient visit with the same kind of instrument, and their data were analyzed using the same software . The monitoring device used in this study was programmed to measure BP at 30-min intervals from 6 AM to 10 PM (daytime) and at 60-min intervals from 10 PM to 6 AM (nighttime). When the BP values that exceeded certain limits  were not recorded, the device repeated the measurements. All BP values were measured automatically .14. The night-to-day systolic BP ratio was calculated as the ratio between the differences in mean daytime and nighttime systolic BP. The daytime systolic BP was calculated using the following formula: 15. For example, if a patient had a mean daytime systolic BP of 160 mmHg and a mean nighttime systolic BP of 140 mmHg, the mean Nocturnal hypertension was defined as nighttime systolic BP ≥ 120 mmHg or diastolic BP ≥ 70 mmHgP < 0.05.All patient data were collected using Microsoft Office Excel 2007  and were entered into the electronic data-processing systems as mean ± standard deviation. Bivariate comparisons between the dipper and non-dipper groups were performed using a Student’s t-test for continuous variables and Pearson’s chi-square test for categorical variables. Univariate and multivariate analyses were performed to identify the factors associated with macular ischemia. All statistical analyses were conducted using SPSS software . Statistical significance was set at


Clinicopathological characteristics and outcomes, as well as early graft function and long-term survival, were retrospectively analyzed. Results: Donor and recipient characteristics were comparable between both groups. Rates of postoperative complications were significantly higher in the <91 mmHg group than those in the >91 mmHg group (vascular thrombosis of the pancreas: 7 (14%) versus 2 (3%); p = 0.03; pancreatitis/intraabdominal abscess: 10 (21%) versus 4 (7%); p = 0.03; renal delayed graft function (DGF): 11 (23%) versus 5 (9%); p = 0.03; postreperfusion urine output: 106 ± 50 mL versus 195 ± 45 mL; p = 0.04). There were no significant differences in intraoperative volume repletion, central venous pressure (CVP), use of vasoactive inotropic agents, and the metabolic outcome. Five-year pancreas graft survival was significantly higher in the >91 mmHg group . No significant differences were observed in patient and kidney graft survival at 5 years between both groups. Multivariate Cox regression analysis affirmed MAP < 91 mmHg as an independent prognostic predictor for renal DGF  and pancreas allograft failure . Conclusions: A MAP > 91 mmHg at the time point of reperfusion was associated with a reduced rate of postoperative complications, enhancing and recovering long-term graft function and outcome and thus increasing long-term survival in SPKT recipients.Objectives: Adequate organ perfusion, as well as appropriate blood pressure levels at the time of unclamping, is crucial for early and long-term graft function and outcome in simultaneous pancreas–kidney transplantation (SPKT). However, the optimal intraoperative mean arterial pressure (MAP) level has not well been defined. Methods: From a prospectively collected database, the medical data of 105 patients undergoing SPKT at our center were retrospectively analyzed. A receiver operating characteristic (ROC) analysis was preliminarily performed for optimal cut-off value for MAP at reperfusion, to predict early pancreatic graft function. Due to these results, we divided the patients according to their MAP values at reperfusion into <91 mmHg ( Simultaneous pancreas–kidney transplantation (SPKT) represents the international gold standard treatment for patients with insulin-dependent diabetes mellitus type 1 (IDDM1) and end-stage kidney disease (ESKD) ,3,4,5. HThe aim of this study was to evaluate and validate the association of peri- and intraoperative hemodynamic parameters, with a special focus on the recipient’s blood pressure levels at the time of reperfusion on short- and long-term graft and patient outcomes in SPKT recipients.The study protocol was approved by the local ethics committee of the University of Leipzig (AZ: Nr: 111-16-14032016). From a prospectively collected electronic database, we retrospectively analyzed medical data of all 109 patients who underwent SPKT at the University Hospital of Leipzig between 2000 and 2017. We especially focused on the influence of peri- and intraoperative hemodynamic parameters on long-term graft function and outcome. Patients younger than 18 years, receiving kidney transplantation alone (KTA), pancreatic retransplantation, and patients with insufficient/missing data about preoperative, perioperative, and postoperative hemodynamic parameters and outcomes were excluded from our study. The mean follow-up period of the study was 121 ± 34.4 months.Standard demographic and clinicopathological characteristics were collected and analyzed before, at the time point of, and after transplantation in the follow-up period for each patient: the pretransplantation data included recipient and donor characteristics such as age, sex, body mass index (BMI), donor causes of death, and donor’s comorbidities/clinical course ). Recipient data included a history of diabetes mellitus, time on the waiting list for organ transplantation, history and duration of pretransplantation dialysis, data of metabolic endocrine and lipid metabolism, and information on special comorbidities  (%), peripheral arterial disease (PAD), blood pressure parameters/arterial hypertension, as well as the number of antihypertensive agents prescribed).Peri- and postoperative data included information on operative and postoperative clinical course , delayed renal graft function (DGF), surgical and infectious complications), immunological and immunosuppressive characteristics (human leukocyte antigen (HLA)-mismatches, cytomegalovirus (CMV)-state, induction therapy), as well as graft function and patient outcome.Acute graft rejection was presumed when a combination of the following was observed—namely, a sudden increase in serum amylase/lipase and/or serum glucose levels in combination with a decline of serum C-peptide level, increased serum creatinine, and a reduction in urine output diuresis and abdominal pain associated with graft edema in sonographic examination. Thus, suspected acute rejection was confirmed by endoscopic biopsies of the duodenal segment of the graft whenever possible. Transcutaneous biopsies of the kidney graft were performed to confirm rejection with the omission of pancreatic biopsies due to risk-benefit evaluation. Acute cellular rejection was treated with pulsed steroids or administration of 8 mg per kg bodyweight antithymocyte globulin (ATG), together with increased baseline immunosuppression. DGF of the kidney was defined as the requirement of dialysis in the first week following transplantation .General anesthesia was induced with intravenous propofol, fentanyl or sufentanil, and rocuronium, and maintained with isoflurane or desflurane in an oxygen-air mixture, with continuous administration of remifentanil or bolus administration of fentanyl or sufentanil and rocuronium as appropriate. Additionally, to standard monitoring, arterial pressure and central venous pressure (CVP) were continuously monitored. The arterial catheter was inserted into the radial artery, and the central venous catheter was inserted into the internal jugular vein.According to general standards, hemodynamic indices and parameters were evaluated to guide goal-directed fluid therapy in patients undergoing major invasive surgery, particularly high-risk patients with large expected blood loss and fluid shifts, such as SPKT recipients ,22.Our center protocol consists of providing volume repletion and use of vasopressors, as needed, to achieve optimal and appropriate blood pressure at the time of graft reperfusion, ideally a systolic blood pressure level of >140 mmHg/MAP of >70 mmHg. In this context, the volume of fluids administered included crystalloids (mL), fresh-frozen plasma (FFP), human albumin (HA), and transfusion of erythrocyte concentrate (EC).In the case of MAP < 70 mmHg, unresponsive to volume repletion, norepinephrine was used to maintain the targeted arterial blood pressure levels.For assessment of hemodynamic parameters in SPKT, the following data were collected and analyzed: central venous pressure (CVP), mean arterial pressure (MAP), and heart rate (HF) at the start of incision, at the time of clamping, at the time of completion of anastomosis (reperfusion), and thereafter.As described previously, pancreas and kidney grafts were procured and transplanted following the international standards and guidelines ,23,24,25®) or the interleukin-2 receptor antagonist basiliximab (Simulect®) was used. Maintenance therapy included calcineurin inhibitors  or tacrolimus (Prograf ®), and/or antimetabolites (Sirolimus (Rapamune®), mycophenolate mofetil (MMF); (Cell Cept®), mycophenolate sodium (Myfortic®), and tapered steroids (Prednisolone®).The immunosuppressive protocol consisted of induction therapy, followed by triple maintenance therapy, as described previously ,27. Short-test, χ2, analysis of variance (ANOVA), Kruskal–Wallis and Wilcoxon–Mann–Whitney test.With regard to baseline data, continuous variables are reported as mean values with standard deviation, whereas categorical variables are presented as whole numbers and percentages (%). For analysis of baseline data, we used the appropriate statistical significance tests, including Student’s To evaluate prognostic accuracy and find the appropriate cut-off values of MAP at the time of reperfusion for predicting early graft survival/failure (within the first 3 months after SPKT), a receiver operating characteristic (ROC) curve analysis for MAP and early pancreatic graft function was generated, and the area under the curve (AUC) was calculated.According to the results, patients were divided into two groups—MAP > 91 mmHg versus MAP < 91 mmHg—for analysis of primary and secondary endpoints.The primary endpoint of our study was long-term pancreas allograft failure following SPKT.In this context, pancreas graft failure was defined as resumed insulin therapy, removed pancreas graft, retransplantation, or patient death. Kidney graft failure was defined as the need for dialysis, removed kidney graft, retransplantation, or patient death.The secondary endpoint included the occurrence of renal delayed graft function, which was defined as a necessity of dialysis in the first week after transplantation or failure of creatinine to fall by 50% independently in the first week .p-value. For the estimation of survival rates, the Kaplan–Meier method was used, and the log-rank test was applied to test statistical significance between groups.A study of potential prognostic risk factors for the secondary endpoint was carried out using logistic regression models. In the final multivariable model, potential risk factors with significant values in univariate analysis and/or known risk factors from the literature were selected using a stepwise backward selection procedure with adjustment for potential confounders. Results of the regression analysis were presented as odds ratio (OR) with 95% confidence interval (CI) and corresponding Graft survival was calculated as the time from initial transplant to graft failure, censoring for death with a functioning graft, and grafts still functioning at the time of analysis. Patient survival was defined as the time from transplant to patient death, censoring for patients still alive at the time of analysis. If a recipient was alive or lost to follow-up at the time of the last contact, then survival time was censored at the time of the last contact.p value < 0.05 was considered statistically significant.Cox proportional hazard regression models were used to calculate hazard ratios (HR), with 95% confidence intervals (CI) for the primary endpoints. Variables to be entered into the multiple logistic regression analysis were chosen on the basis of the results of univariate analysis. A All statistical analyses were performed by using SPSS software .Between January 2000 and July 2017, a total of 105 patients following SPKT at the University Hospital of Leipzig could be included in the study.At ROC curve analysis, the optimal cut-off point for MAP at reperfusion to predict early pancreas graft failure was 91 mmHg.p = 0.017).The area under the curve was (AUC) was 0.63 (95%CI: 0.60–0.66), with a sensitivity of 39.9% and a specificity of 87.7%  an ad significantly higher EF rates (p = 0.04). No other significant baseline characteristics could be observed between both groups.Patients with >91 mmHg at reperfusion had significantly shorter durations of the intensive care unit (p = 0.04). Further, the amount of intraoperative administered fluids were higher in the MAP < 91 mmHg group  but showed no significant difference.In the MAP > 91 mmHg group, the total intraoperative urine output was significantly higher than that in the MAP < 91 mmHg group , warm ischemic time pancreas  and kidney , cold ischemic time of pancreas  and kidney , blood loss , transfusion of erythrocyte concentrates , or fresh-frozen plasma .There were no differences in operating time . No differences were seen in CVP  and heart rate (HF)  between both groups.The hemodynamic parameters were not statistically different at the time of incision. The MAP at the time of reperfusion was 104 ± 9.8 in the MAP > 91 mmHg group and 89 ± 3.4 in the MAP < 91 mmHg group (p = 0.03), higher rates of pancreatitis/intraabdominal pancreatic infectious fluid formations , and higher rates of vascular thrombosis of the pancreas  in the MAP < 91 mmHg group.Postoperative outcome parameters of the recipients according to their MAP values are illustrated in p = 0.481), rate of reoperations (p = 0.858), bleeding episodes (p = 0.756), and CMV infections (p = 0.974) between both groups.There were no significant differences with regard to acute rejection episodes (p = 0.032), 3 years , and 5 years  after transplantation.In terms of the metabolic outcome, recipients of the MAP > 91 mmHg group showed significant better HbA1c- values at 1 year  and three-month pancreas graft survival —as defined by the ROC analysis—were significantly lower in patients with MAP < 91 mmHg at the time point of reperfusion, compared with patients with MAP > 91 mmHg.Five-year pancreas graft survival  was an independent and significant predictor and risk factor of increased pancreas allograft failure in our study population  was intentionally included as a single univariate risk factor in the explorative multivariate Cox regression analysis to assess its validity and robustness see also . Here, mpulation .Furthermore, donor age and BMI, recipient BMI, donor cause of death, >12 h cold ischemia time (CIT) of the pancreas, as well as DGF, were also revealed as independent and significant predictors for pancreas graft failure in our study analysis.p = 0.08) and patient death , p = 0.568).No significant differences could be observed between MAP < 91 mmHg and kidney allograft failure (HR 1.90 (95% CI 0.93–3.84), p = 0.02), donor age , and duration of pretransplant dialysis . Multivariate logistic regression analysis revealed MAP < 91 mmHg, donor age, and duration of pretransplant dialysis as independent risk factors for DGF  at the time of reperfusion, was frequently associated with DGF in renal transplant recipients ,14,15,19 mmHg at Concerning the observed differences in baseline data, the MAP < 91 mmHg group had a lower EF before SPKT than patients with MAP > 91 mmHg at reperfusion. Of interest is the finding that the MAP < 91 mmHg group also showed a trend toward longer exposure to hemodialysis, as well as a trend toward a longer waiting time before transplantation. These findings may to some extent contribute to difficulties in achieving an adequate MAP during reperfusion due to decreased cardiac output and aggravated vasoplegia in the MAP < 91 mmHg group. However, despite some intraoperative efforts achieving an appropriate MAP at reperfusion, there were no significant differences between both groups in terms of CVP and administration of total fluid volume or catecholamine at the time point of reperfusion. Concerning major perioperative/surgical-related complications, the differences in incidence rates between both groups further highlighted the remarkable role of optimum blood pressure levels at the time of reperfusion. Though there were no differences in glomerular filtration rate (GFR) and metabolic factors post-transplant, securing adequate blood pressure and organ perfusion in the early postoperative phase seems to be vitally important for early recovery from DGF and to optimize adequate graft function and long-term survival.Optimum perioperative fluid administration with adequate intravascular volume maintenance is essential to improve outcomes in critically ill patients, prevent acute organ failure or dysfunction, and improve immediate graft function after KTA and SPKT ,33,34,35In this context, the use of extended hemodynamic monitoring—especially in high-risk patients such as SPKT recipients—may be a helpful tool to assess intravascular volume status and fluid responsiveness enabling an individualized perioperative volume and organ perfusion approach to reduce morbidity and mortality during SPKT and improve graft function and outcome ,19,32. Cp = 0.589), as well as administered total volume , were comparable between both groups at reperfusion. Thus, volume management was considered to have been performed appropriately and without significant differences between both groups.In our current study, CVP  were introduced in specific patient populations for optimal fluid management [Currently, several technologies and equipment for assessing dynamic preload and cardiac output variables of fluid response such as pulse contour analyses, arterial waveform derived variables , pulse pressure variation (PPV), stroke volume variation (SVV)), thoracic electrical bioimpedance, lithium dilution or partial COnagement ,43.However, prospective comparative clinical studies are lacking to check the reliability of these new techniques to guide the optimal fluid therapy in surgical cases during the clinical routine setting.To date, there are only sparse data on the use and effect of vaso-inotropic agents on postoperative graft function in renal transplant recipients, and no data on SPKT exist ,17. AlthSeveral limitations of our study are important to illustrate.Firstly, the low number of patients in each group and the retrospective non-randomized design need to be discussed. Thus, there is a possibility of insufficient power to detect small effects and although adjustments were made for some confounders, residual confounding effects could not be ruled out completely. Moreover, as the results of our ROC analysis showed that the AUC of MAP at reperfusion is only just above over 0.6 and thus represents a weak correlation, we included this parameter in an explorative multivariate Cox regression analysis to check its robustness and validity. In addition, we only observed that the differences in MAP at the time of reperfusion are statistically correlated with long-term graft function; therefore, it is completely unclear if an increase in MAP results in better graft function, and if so, which measures to increase MAP may translate into better graft function. Therefore, to test the hypothesis that therapeutically increased MAP might result in better graft function, prospective studies in this interesting field are mandatory.Secondly, the long investigation period of our study and slight changes in anesthesiologic management may have affected therapeutical decisions and restricted data evaluation. Thus, there may be undetected factors such as the ability to maintain high blood pressure and the effectiveness of vaso-active inotropic agents in individual recipients. However, perioperative hemodynamic management and volume administration did not change relevantly during the study period.Third, a mismatch between recipients and donor arterial blood pressure levels prior to terminal events (often unknown) may also affect intraparenchymal hemodynamics in a way undetectable by standard clinical perfusion measurements. Our study showed no significant correlation between donor hypotension episodes and incidence of DGF and reduced long-term outcome; however, these confounding effects could not be completely ruled out.Appropriate blood pressure levels and optimum blood flow in the peri- and postoperative phases are crucial to early graft function and long-term graft outcome. A MAP > 91 mmHg is a strong independent parameter for an increased pancreas long-term survival, as well as enhanced graft function and outcome. Further prospective and controlled studies with larger patient populations are necessary to evaluate long-term prognosis in SPKT recipients to verify our results and lead to a better understanding of the use of dynamic analyses of flow parameters for optimal fluid management in these specific patients who often have impaired cardiovascular physiology and reduced hemodynamic autoregulation due to end-stage kidney disease and diabetes mellitus.


This prospective, observational study involved adult hypertensive patients with newly diagnosed type 2 diabetes mellitus at two university hospitals in Vietnam. The median time of follow-up was 4 years (August 2016–August 2020). The primary outcome was time to all-cause mortality.  246 patients were included with a mean age of 64.5 ± 10.4. 58.5% were females. 64.2% were categorized as high risk. At baseline, ischemic heart disease, dyslipidemia, and chronic kidney disease (CKD) were present in 54.9%, 67.1%, and 41.1% of patients. Renin–angiotensin–aldosterone inhibitor, metformin, and statin were prescribed in 89.8%, 66.3%, and 67.1%. Among three risk factors, LDL-c control was the hardest to achieve, increasing from 5.7% to 8.5%. In contrast, blood pressure control decreased from 56.1% in 2016 to 30.2% in 2020, when the second wave of COVID-19 hit our nation. While contemporary targets resulted in persistently low simultaneous control at 1.2%, significant improvement was observed with conventional criteria , increasing from 14.6% to 33.7%. During follow-up, the mortality rate was 24.4 events per 1000 patient-years, exclusively in patients with early newly diagnosed diabetes. Improving control overtime, not at baseline, was associated with less mortality. Conversely, age >75 years (HR = 2.6) and CKD (HR = 4.9) were associated with increased mortality.  These findings demonstrated real-world difficulties in managing hypertension and newly diagnosed diabetes, especially with stringent criteria from novel guidelines. High-risk profile, high mortality, and poor simultaneous control warrant more aggressive cardiorenal protection, focusing more on aging CKD patients with early newly diagnosed diabetes. Hypertension is the leading preventable cause of premature mortality worldwide, affecting 31.1% of the world population . PersistAmong coexistent conditions, diabetes emerges as significant comorbidity, with expanding epidemiology and accelerating cardiovascular mortality. Recent evidence has revealed the copredictive nature of hypertension and diabetes, further increasing the risk of cardiovascular events . In patiRegardless of the order of diagnosis, risk factor control remains the cornerstone of treatment for coprevalent hypertension and diabetes. Simultaneous control together with lifestyle modification significantly reduced and delayed time to first cardiovascular event , 9. Yet,In Southeast Asia, coprevalence of diabetes and hypertension has been rising, ranging from 20.6% in India to 78.4% in Thailand . In VietHypertensive patients with new-onset type 2 diabetes (diagnosed at least 2 years after hypertension onset)Age ≥18 yearsRegular follow-up in the previous 6 monthsInclusion criteria: Acute coronary syndrome, stroke, or hospitalization within 3 monthsUntraceable pharmacological/herbal treatment from out-of-recruitment sitesSecondary hypertensionPregnancy or lactation2Renal replacement therapy or eGFR<15 ml/min/1.73 mHepatic failureConcurrent participation in any interventional trialExclusion criteria:We designed a prospective, observational study, which was conducted at outpatient departments in the University Medical Center and Nhan Dan Gia Dinh hospital. The study was approved by the Ethics Committee of Biomedical Research at the University of Medicine and Pharmacy at Ho Chi Minh city and appropriate bodies at recruitment sites. All patients gave informed consent prior to participation. The study adhered to principles laid down in the Helsinki Declaration.Details on study procedure and patient selection are depicted in Office blood pressure ≥140/90 mmHg on at least 2 visits, 1 to 4 weeks apartOffice blood pressure ≥180/110 mmHg and high cardiovascular risk24-hour blood pressure monitoring (Holter BP) ≥130/80 mmHg, daytime (awake) Holter BP ≥135/85 mmHg, nighttime (asleep) Holter BP ≥120/70 mmHgPreviously diagnosed with hypertension and currently receiving antihypertensive treatmentHypertension (HTN) was defined as either of the following:2). Categorization of BMI was based on Asian Pacific criteria: underweight (<18.5), normal (18.5–<23), overweight (23–<25), and obese (>25). Nonsmokers were those who never smoke. Comorbidities were identified from the electronic medical record or newly diagnosed. Established ischemic heart disease included a documented positive noninvasive test, angiogram, or prior revascularization. Chronic kidney disease (CKD) was defined using the definition of the 2012 KDIGO guideline [Diabetes (DM) was diagnosed using the 2016 ADA guideline for diabetes or currently on antiglycemic therapy . We onlyuideline . Atrial (1)120–<130/70–<80 mmHg for patients without chronic kidney disease and aged between 18 and 65130–<140/70–<80 mmHg for patients with chronic kidney disease or ≥65 years oldTherapeutic range of blood pressure:(2)HbA1c <7.0%(3)LDL-c<55 mg/dL for very high-risk patients and <70 mg/dl for high-risk individuals –13. RiskNovel criteria for risk factor control were consistent with the most updated 2018–2019 European guidelines, including the following , 12:(1)TAt enrolment, each patient underwent physical examination and blood tests to determine baseline values on blood pressure, HbA1c, and LDL-c levels. For blood pressure, at least 2 measurements were performed at each visit, with an interval of 1 to 2 minutes. An additional measurement would be required if the first two differed by more than 10 mmHg. The average value of the last two readings was recorded. Both arms must be measured in the first visit, the one with higher reading was chosen for subsequent follow-up. Prior to each measurement, patients were required to relax for at least 5 minutes and to empty their bladder. No smoking, exercise, or caffeine consumption was allowed in the 30 minutes preceding blood pressure recordings. Standard cuffs were placed at the level of the heart, in a seated position with back and arms supported. Larger or thinner cuffs would be employed for larger or thinner arms. Talking or leg-crossing during measurement was prohibited.We then collected data on blood pressure, HbA1c, and LDL-c at least once per year, or more frequently in case of medication titration/initiation or change in patients' condition. For patients who were lost to follow-up or died during the study, the last documented dataset of blood pressure, HbA1c, and LDL-c would serve as “end-of-follow-up” values. For patients who completed the study, data on the final follow-up were collected in July–August, 2020.t-test or Wilcoxon rank-sum test for continuous variables and Chi-square or Fisher exact test for dichotomous or categorical variables. The Kaplan–Meier survival plot and log-rank test were used to describe the univariate analysis of the time-dependent event. Multivariable Cox proportional hazard regression was employed to investigate factors associated with the primary outcome. All tests were 2-tailed. A p value <0.05 was considered statistically significant. We used R for analysis.Continuous variables with normal distribution were presented as mean ± standard deviation; otherwise, the median (interquartile range) would be reported. Categorical variables were presented as proportion. We used the 246 eligible hypertensive patients with newly diagnosed diabetes were recruited. Baseline characteristics on demographics, comorbidity, investigations, and medications are described in n = 3), at final follow-up (n = 3), and both (n = 0), we divided patients into 2 main categories: those who achieved at least 2 risk factors' control at final follow-up (n = 39) and those who did not (n = 207). p = 0.049).Patients were further categorized into groups according to change of risk control overtime, including “control to control,” “uncontrol to control,” “control to uncontrol,” and “uncontrol to uncontrol.” No mortality was recorded in the “uncontrol/control to control” group, as opposed to the highest mortality in the “uncontrol to uncontrol” group . SpecifiWe performed univariate Cox progression on age, gender, BMI, smoking status, baseline risk, CAD, CKD, dyslipidemia, stroke, HF, AF, multimorbidity (≥ 2 comorbid conditions), uptake of RAAS inhibitor, statin, metformin, and ≥ 2 risk factors controlled at baseline. Statistical significance was achieved in age >75 years , baseline CKD , ≥2 comorbid conditions , and metformin  . In multOur study was the first multicenter, longitudinal research in Vietnam that tracked the changes of simultaneous risk factor control overtime using 2018–2019 guidelines of the European Society of Cardiology. Focusing on hypertensive patients with newly diagnosed diabetes, we described a predominantly female population (58.5%), who reported a high rate of CKD (41.1%), CAD (54.9%), and dyslipidemia (67.1%), together with high baseline uptake of RAAS inhibitor (89.8%), metformin (66.3%), and statin (67.1%).Despite the high-to-very-high risk profile, the majority of patients only managed to control one to two risk factors . The lowDifferent criteria lead to varying trends of simultaneous control. Conventional targets  resulted in an increasing pattern, from 14.6% to 33.7% whereas no change was observed with the state-of-the-art, risk-based recommendation. In regard to individual factor control overtime, blood pressure experienced a significant decrease in 2020, which may be associated with the second wave of COVID-19 in our nation. In July 2020, the first COVID-19 related mortality due to myocardial infarction was announced, followed by series of cardiovascular-related death, causing a significant surge in outpatient visits and increasing blood pressure readings. While the anxiety over COVID-19 could affect multiple risk factors, blood pressure was more prone to daily fluctuations.In terms of mortality, our study demonstrated similar incidence (24.4 per 1000 patient-years) to contemporary trials in Western Asia (28.2 events per 1000 patient-years) and Europe (21.8 per 1000 patient-years) , 7. InstIn multivariable regression analysis, old age and CKD were associated with increased mortality. Escalating CKD incidence among diabetic patients, as well as increasing CKD-induced mortality merit careful attention , 27, 28.p < 0.001). While the number of comorbid conditions alone was insufficient to fully expound adverse consequences in aging individuals with high cardiovascular risk [Aging was associated with increasing lifetime cumulative risk factors and decreasing functional capacity. In a meta-analysis of 19 elderly cohorts, frailty appeared as a strong predictor for medium- (RR = 9.49) and long-term mortality (RR = 7.94) . Nonethelar risk , it did In our study, mortality occurred exclusively in patients with early newly diagnosed diabetes, supporting the hypothesis on mortality discrepancy among hypertensive patients with different timings of diabetes diagnosis. In early new-onset diabetes, insulin resistance acted as the common pathway, leading to the diagnosis of hypertension and diabetes within a short interval , 40. TheOur findings imply three important clinical implications about the management of newly diagnosed diabetes in hypertensive patients. Firstly, a few patients achieved simultaneous control despite the high-risk profile. This finding was of particular concern as uncontrolled diabetes and hypertension were associated with increasing risks for severe COVID-19 complications –43. SecoOur research should be interpreted in light of certain limitations. The study was designed as an observational, prospective study, with no randomization. We did not explore the effect of lifestyle modification or dosing of RAAS inhibitors. For risk factor control, we only compared baseline and final values and disregarded interval measurements, thereby overlooking possible fluctuations between follow-ups. Study recruitment sites could serve as a selection bias, as tertiary settings were often associated with more severe diseases and aggressive control. Self-reported variables were subject to recall bias, such as the history of smoking, family history, and duration of diseases. Finally, the study was initiated in 2016, when sodium-glucose cotransporter-2 inhibitor and glucagon-like peptide-1 receptor antagonist were not widely available in Vietnam. Therefore, the synergistic effect of modern cardiorenal protective therapy on high-risk diabetes could not be evaluated , 45. MorOur study depicted a high-risk population, who experienced high mortality incidence despite a high intake of RAASi and statin. Simultaneous control of blood pressure, HbA1c, and LDL-c was comparable to most contemporary studies, yet still far from expectation. Poor control rate, especially in regard to LDL-c, was further aggravated by rigorous targets from the state-of-the-art guidelines. Improving control over the course of treatment was associated with less mortality. Aggressive simultaneous control and integrative cardiorenal management should be enhanced, especially in aging CKD patients with early newly diagnosed diabetes.