The association of delayed graft function (DGF) and biopsy proven acute rejection (BPAR) of renal allografts is controversial. Borderline rejections comprise a major portion of biopsy results but the significance of such histologic changes is debated. The present study explores the impact of DGF on BPAR with a special emphasis on discriminating the effects of borderline rejection.Single center analysis of 417 deceased donor kidney recipients . Patients with primary non-function were excluded. DGF was defined as the need for dialysis within the first week after transplantation. Acute rejection was defined according to Banff criteria. Cox proportional hazards models were used to examine the relationship of DGF with BPAR within the first year.No graft loss was observed during the first year after transplantation. DGF significantly associated with BPAR in the first year, irrespective of whether borderline rejections were included  or excluded .DGF is significantly associated with rejection—with or without borderline changes—within the first year. Kidney transplantation represents the treatment of choice in patients with kidney failure. However, especially in the first weeks after transplantation, complications are not uncommon. Among these complications is delayed graft function (DGF), which is most commonly defined as the need for dialysis within the first week after transplantation . MultiplDGF has been shown to be a risk factor for chronic allograft dysfunction and allograft failure ,9. These‘Borderline rejection’ is an ambiguous category in the current Banff classification. It reflects the difficulty of distinguishing inflammatory lesions from changes induced by injuries other than rejection and defines changes insufficient for a diagnosis of acute rejection. It may reflect early T-cell mediated rejection, but it may also merely resemble the histological correlate of acute kidney injury. A study that examined molecular changes using microarrays revealed that 67% of indication biopsies classified as ‘borderline’ in light microscopy were reassigned as ‘non-rejection like’ after molecular phenotyping . To our The main objective of the present study was to explore the association of DGF and BPAR in the first year after transplantation, with special consideration of the impact of the histological diagnosis of borderline rejection.Patients (aged >18 years) who received a deceased donor kidney allograft at the University Hospital Erlangen between January 1, 2008 and February 28, 2015 comprised the study population of this observational cohort study. The cohort comprised recipients of extended criteria donors, dual kidney recipients, and recipients who had a prior kidney transplant. We excluded living donor kidney transplant recipients and recipients with primary non-function. Furthermore we excluded patients who were lost to follow up within the first year . All traPatient medical records were reviewed by trained abstractors to obtain information on age, gender, body mass index (BMI), cause of end-stage renal disease, recipients of ECD organs, recipient diabetes status and history of coronary artery disease, number of prescribed anti-hypertensives, dialysis vintage, number of previous kidney transplantations, donor age, donor gender, donor BMI, donor diabetes status, donor history of hypertension, donor terminal kidney function, immunosuppressive induction regimen, type of calcineurin-inhibitor, and human leukocyte antigen (HLA) mismatch. In addition information was abstracted on warm ischemia time (WIT), cold ischemia time (CIT), peak panel reactive antibody (PRA) level, delayed or immediate graft function, number of dialysis sessions after transplantation, histological results of kidney biopsies, rejection therapy, number of biopsies, and renal function 12 months after transplantation. All patients were followed until the completion of the first post-transplant year.All patients received a triple immunosuppressive regimen, consisting of prednisone, mycophenolate and either tacrolimus or cyclosporine. In our center, unsensitized patients > 55 years and patients with reported pathological glucose tolerance without any immunological risk factors are treated with cyclosporine. All other patients are treated with tacrolimus. Recipients in ECD-program or with identified panel reactive antibodies > 5%, donor specific antibodies as well as prior kidney transplantation(s) receive anti-thymocyte globulin (ATG). The standard induction therapy is basiliximab.Our center conducts protocol biopsies at 3 months after transplantation in patients with high PRA levels prior to transplantation, ECD organs or within the Eurotransplant acceptable mismatch program.The exposure of interest, DGF, was defined as the need for ≥ 1 dialysis session during the first week after kidney transplantation. The clinical outcome in the present study was time to first BPAR including or excluding borderline rejection, which was defined according to Banff criteria on a renal biopsy pathology report. All pathology reports were read at our department of nephropathology. Only the first rejection of an individual patient was considered in the models. To reduce the possibility of a diagnostic bias, only indication biopsies were taken into account; none of the protocol-biopsies at 3 months after transplantation were included in the analysis. Indications for biopsies were at the discretion of the treating physician and included rising creatinine levels, persistent DGF or inability to achieve a better renal function within the first couple of months after transplantation. In context to DGF: we usually biopsy within 7 to 10 days after transplantation, if the patient is still dialysis dependent. Exact timing may be also influenced by other factors such as organ quality, immunology, cessation of urine output, and cold ischemia time. Renal function at 12 months after transplantation was assessed by the estimated glomerular filtration rate (eGFR) using the MDRD formula .STATA 14  was used for all statistical analyses. A p-value <0.05 was considered statistically significant and all tests were two tailed. Descriptive data are presented as means (SD) for continuous variables or frequencies for count data. Two-sided Student’s t-test, with adjustment for unequal variances where appropriate, or the Wilcoxon rank-sum test were used to examine differences between groups. Kaplan Meier curves and the log rank test were used to examine the cumulative incidence of time to first rejection in both groups.Using a Cox proportional hazards model, the association of DGF with time to first BPAR, both including and excluding borderline rejection was tested. Despite full follow up a Cox proportional hazards model instead of a logistic regression model was chosen because of its ability to include the information of the exact timing of rejection –25. Log-Due to a high correlation coefficient among donor hypertension and donor age, donor diabetes and donor age as well as ECD status and donor age, only donor age was included in the models. Owing to the relatively recent cohort and only very minor changes in our centers’ transplant protocol during the observation period, we did not include the variable “transplant year” into our model, which is sometimes done to adjust for unmeasured era effects. To assess robustness of our analysis we also tested an alternative definition of DGF (≥2 (vs ≥1) dialysis sessions in the first postoperative week).A cut-off p-value of 0.2 was used for the univariate analysis. Linear regression was used to analyze determinants of renal function at the end of the observation period and its association with DGF. The linear regression model was adjusted for rejection, recipient age and sex, BMI, PRA, dialysis vintage, cause of end-stage renal disease, donor BMI, donor age, CIT, WIT, HLA-mismatch, HLA-DR mismatch, induction therapy, use of tacrolimus, prior transplant and terminal donor serum creatinine. We also tested for possible effect modification of DGF in combination with BPAR.During the study period, 602 patients received a kidney allograft at our center. We excluded 159 living donor recipients, 24 patients who suffered from primary non-function and 2 patients who moved away from our center before completion of a 12 month follow up. The cohort comprised 417 patients. Out of these, 15 were recipients of a dual kidney transplantation, 41 underwent either the second, third or fourth kidney transplantation and 110 received a kidney from an ECD.  Most comThe characteristics of the cohort stratified by DGF status are summarized in Relative frequencies of BPAR including borderline rejections in year 1 were 24.8% in the non-DGF and 37.1% in the DGF group. In a total of 121 biopsy-proven rejections, we registered 100 T-cell mediated rejections and 21 antibody-mediated rejections. Patients in the DGF group developed more frequent T-cell mediated rejections (23.1%) compared with the non-DGF group (12.4%) . Relative frequencies of BPAR excluding all ‘borderline rejections’ were 27.3% and 17.9% respectively .  Kaplan-MThe unadjusted hazard ratio for developing acute rejection in the DGF group was 1.68 . DGF remained an independent risk factor for BPAR after adjustment for multiple other variables in the stepwise cox regression models. Notably, hazard ratios did not change after expanding the model by covariates. In our full model (Model 5) recipient sex, dialysis vintage, CIT, WIT, cause of end-stage renal disease, recipient BMI, induction therapy, and terminal donor serum creatinine did not affect the association. Besides DGF, the hazard ratio for BPAR was significantly elevated for the categorical variable HLA-DR mismatch and prior transplant . PRA level and donor age missed the significance level . Protective factors for BPAR were older recipient age  and tacrolimus use . Multivariate cox models were calculated both with and without borderline rejections. . The HR was robust after expanding the model with the earlier mentioned covariates . HR for BPAR excluding borderline rejection was also significantly higher for HLA-DR mismatch . Use of tacrolimus  and older recipient age  were protective factors. Sensitivity analyses were conducted defining DGF as the need for at least 2 dialysis sessions. Of 143 patients undergoing post-transplant dialysis treatment, 111 (77.6%) required more than one session, of whom 41 (36.9%) experienced BPAR. After altering the definition for DGF, the hazard for BPAR was still significantly higher for DGF compared to non-DGF patients . However, for this definition of DGF, the association between DGF and BPAR did not reach significance after exclusion of borderline rejections . The overall number of biopsies in the first year was higher in the DGF group (non-DGF  >0.05). , S1 FigThere was a significant difference in renal function at the end of the observation period. Mean eGFR in the DGF group was at 44.8 (± 4.02) ml/min and 46.6 (±2.46) in the non-DGF group. A linear regression model with eGFR at one year as the outcome showed no association between DGF and the outcome. Our model identified BPAR (Coefficient (c):-5.01 ml/min, 95%CI: -8.18, -1.84) and donor age per decade  as significant factors for a reduction in eGFR at one year.  No effecIn the present study the hazard ratio for developing BPAR within the first year after transplantation was 71% higher in the DGF group. This association was independent of covariates related to DGF in our cohort as well as covariates that were reported in previous studies ,29. DespAn important difference of this study compared to previous studies is the thorough analysis of the contribution of borderline rejection. We believe that this is a critical distinction since biopsies labeled ‘borderline’ may reflect either early T-cell mediated rejection (which could advance to more severe inflammatory lesions), or the morphological correlate of AKI . HoweverOur results are supported by the implementation of using different definitions of DGF, as these are not uniform in the literature . The mosAfter a 12 months follow-up period, patients in the DGF group had a lower eGFR compared to those with immediate allograft function. This was a result from the higher incidence of BPAR in the DGF group. The difference was statistically significant, however the absolute difference of 1.8 ml/min is, from our point of view, not clinically meaningful. Two single center studies on DGF, where the outcome was graft survival, reported similar results ,37. A reOur study has several limitations. The most important caveat in any study of such kind is the possibility of a diagnostic bias from an unbalanced number of biopsies in the two groups. The overall number of biopsies in the first year was numerically higher in the DGF group. This difference was not statistically significant and was presumably caused by a greater number of repeat biopsies in the DGF group. In order to further reduce the risk of imbalance, we only considered results from indication biopsies for our analysis. The dataset lacked information on HLA- and donor-specific antibodies (DSA) at baseline and during follow up. We acknowledge that PRA is inferior to DSA regarding the risk for the development of an antibody mediated rejection (ABMR). However, the assessment whether or not patients with DGF have a predisposition to develop such antibodies was not our primary focus and incidence of T-cell mediated rejection outnumbered ABMR in our population. Nevertheless, due to the lack of HLA testing our data does not allow the conclusion of the association of DGF and ABMR. Additionally, information on immunosuppressant levels was not available. Although it is generally accepted that optimal calcineurin-inhibitor target concentrations reduce the risk for acute rejection, the effect is not always clearly seen in epidemiologic studies due to the interval between the beginning of a rejection episode and the ascertainment of the immunosuppressant level, as well as for suspected non-calcineurin driven mechanisms ,39. GeneOne of the strengths of this study is the high granularity of our cohort, which allowed us to include important covariates such as WIT, which we feel is underreported in the literature. In our non-DGF group no patient required dialysis treatment during the observation period and we had to exclude only 2 patients due to loss of follow up. Moreover, since all biopsies were analyzed at the same nephropathology lab, we have a high level of consistency of the histological diagnoses compared to registry data, which is of special relevance for our aim of identifying the contribution of borderline rejection.In summary our results confirm the importance of DGF as an independent risk factor for BPAR. The assumption is strengthened by omitting borderline rejections, which could have inflated the association due to an overestimation of rejection episodes in previous studies. Despite improvements in organ allocation and advances in immunosuppressive therapy, the incidence of DGF has increased since the 1990s and may still rise in the future due to the acceptance of more marginal organs ,40–43. AS1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S1 FigRelative frequency of biopsies in each group.(PDF)Click here for additional data file.


Introduction: Multiple system atrophy (MSA) has detrimental effects on swallowing function. The swallowing function of patients with MSA has not been systematically characterized and the underlying pathophysiological mechanisms of dysphagia remain poorly understood.Objectives: To investigate the characteristics of swallow function in MSA using high-resolution manofluorography (HRMF).Methods: We conducted a retrospective review of twenty-five MSA patients who underwent HRMF from 2016 to 2017. HRMF was utilized on patients with only oral diet  >3). Pharyngoesophageal and proximal esophageal pressure profiles were evaluated and compared to established normative data. The frequency and characteristics of upper esophageal sphincter (UES) and proximal esophageal abnormalities during rest and swallow were calculated.Results: The ages of patient cohort in our study ranged from 48–81 years (median 65 years) with male predominance (68%). We observed a distinct abnormal deglutitive proximal esophageal contraction (ADPEC) in 14 (56% of patients), which appears to reflect a discoordinated response of the striated muscle esophagus. Deficient UES relaxation duration, impaired UES relaxation, hypertensive resting UES pressure and hypotensive resting UES pressure were detected in 8 patients (32%), 3 patients (12%), 1 patient (4%), and 11 patients (44%) respectively.Conclusions: In patients with MSA, abnormal UES resting pressure is common. A discoordinated proximal esophageal pressure response was identified and may be a pathognomonic manometry finding for MSA. These findings may serve as indications of early stage swallowing dysfunction in patients with MSA. Multiple system atrophy (MSA) is a neurodegenerative disorder that causes systemic degeneration of the cerebellar, extrapyramidal and autonomic nervous systems in various combinations  and is gDeterioration of swallowing function is one of the manifestations of MSA that dramatically affects quality of life and prognosis of patients  and dyspTechnological advancements and utilizations of high-resolution manometry (HRM) have led to a better understanding of pharyngeal and esophageal disorders. HRM has been utilized to characterize swallowing dysfunction in patients with neuromuscular disease, such as Parkinson's disease but not in MSA. Moreover, high-resolution manofluorography (HRMF), an armamentarium combining high-resolution manometric and videofluoroscopic swallowing examinations, improves the accuracy of diagnosis of esophageal disorders and facilitates dysphagia management , 9. The This study was approved by the Human Ethics Committee of the University of Tokyo (No. 2487). Written informed consent was obtained from every patient and patients' anonymities were preserved.Twenty-five MSA patients whose diagnosis was made at the Department of Neurology in our institute between the years 2016 to 2017 were included. Patients' diagnoses were confirmed according to the Consensus Statement of diagnostic criteria and excluded from Gilman's criteria  in the upright position. The manometric catheter was lubricated with 4% viscous lidocaine and inserted transnasally. The videofluoroscopic swallow study (VFSS) was conducted in the lateral view simultaneously. The protocol consisted of a 5-min baseline recording, followed by 3 dry swallows and 3 wet swallows of 5 cc thickened contrast agent . A solid-state high-resolution manometer  was used for all data acquisition. The manometric catheter  has an outer diameter of 4 mm and 20 circumferential pressure sensors spaced 1 cm apart. The data acquisition frequency was 40 Hz for each sensor. The system is calibrated to record pressures between −50 and 300 mmHg. Video was recorded at a rate of 30 frames/s and analyzed by Star.exeve 8.1 . Pharyngeal and proximal esophageal measures were obtained on all patients.The following parameters were obtained from the manometric output: maximum swallowing pressures , integrals , UES relaxation duration, UES relaxation pressure (nadir) and UES resting pressure Figure .Abnormal HRMF metrics in the UES and proximal esophagus were identified using the following criteria: impaired UES relaxation pressure/duration (relaxation pressure >12 mmHg/<0.45 s), hypertensive resting UES pressure (>104 mmHg), and hypotensive resting UES pressure (<34 mmHg) , 14. ProU-tests implemented in GraphPad Prism . Demographic variables  were compared by Fisher's exact test between patients with or without ADPEC. P < 0.05 was considered statistically significant.Statistical comparisons between groups were performed by using Mann–Whitney Data from the charts of 25 patients with MSA were abstracted. The age of the cohort  or presence of vocal fold immobility . There was no significant difference in severity stages of MSA between groups with and without ADPEC . These findings did not correlate with the severity stage, types of MSA, or concurrent vocal fold immobility.MSA is a progressive neurodegenerative disease and can affect swallowing function variably with disease progression. The disordered oral stage of swallowing manifests in delayed bolus transport to the pharynx and worsens progressively due to bradykinesia and disrupted tongue coordination . DiminisMSA can also cause esophageal stage impairments such as dysmotility . It has Complex sequences of swallowing are controlled and regulated by the medullary swallowing center, which is also known as the central pattern generators (CPGs) . The finVocal fold immobility is another frequent complication of MSA . SwallowHRMF can improve understanding and advance our capabilities of evaluating the pharyngo-esophageal region. In this study, concurrent UES and proximal esophageal abnormalities, possibly due to neuromuscular dysfunction, were frequently noted even in mild MSA patients, and ADPEC identified on HRMF may be suggestive of MSA. Our findings suggest that HRMF may assist with the earlier detection of deglutitive abnormalities before the symptom of dysphagia develops. However, it is not fully clear whether the ADPEC is an early indication of pathophysiologic and neurodegenerative changes in MSA patients, an indicator of MSA severity, or possibly a compensatory proximal esophageal contraction in response to ongoing pharyngo-esophageal dysmotility. Longitudinal observations are required to elucidate the clinical significance of ADPEC in patients with MSA.MSA affects the autonomic nervous system and swallowing function progressively. Pulmonary complications, malnourishments, or even mortality is related to clinical deterioration. The data suggest that HRMF may be beneficial for the early detection of swallowing dysfunction in MSA patients. Further investigation is required to confirm the accuracy of HRMF in the early detection of MSA and assess the effect of early detection on wellness and quality of life.UES pressure anomalies and a discoordinated proximal esophageal pressure response are common manometric findings in persons with MSA. Further investigation is required to investigate the mechanisms underlying this pressure pattern and validate the application of HRMF as a diagnostic tool for MSA.RU developed the concept, designed and performed the experiments, and analyzed the data. TN, PB, and TY developed the concept, designed the experiments. TG, TS, NN-Z, and SS performed the experiments, and analyzed the data. All authors contributed to interpretation of the data and writing 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.


BackgroundTight blood pressure control is critical in neurosurgical patients. Systolic blood pressure (SBP) must be low enough to avoid injury and minimize intraparenchymal hemorrhage (IPH) but high enough to maintain cerebral perfusion. American Heart Association (AHA) guidelines recommend SBP <140 in intracerebral hemorrhage. This paper sought to elucidate the effect of early control of SBP on IPH expansion.Methods134 patients with spontaneous IPH between 2011 and 2015 were analyzed utilizing chart review. Initial versus follow-up bleed size, presentation and discharge condition, discharge disposition, and blood pressure control adequacy were analyzed using the generalized linear model.ResultsAltered mental status was the most common presenting complaint (78%). Presenting GCS failed to demonstrate a significant main effect. Age, initial IPH volume, presenting SBP, and one-hour SBP significantly affected IPH percent expansion . Several two-way interactions affected IPH percent change implying synergistic effects of the predictor variables.ConclusionPatients aged 60-70 years had the largest percent IPH expansion followed by patients aged 20-30 years. Initial IPH volume of 65.23-78.26 ml showed the largest expansion. Initial IPH volume of 52.18-65.22 ml demonstrated the least percentage of IPH expansion. One-hour control of SBP to binned groups of 111-121 mmHg or 121-132 mmHg portends relative minima in bleed expansion corresponding with AHA recommendations for IPH patients. This study suggests that this degree of early and aggressive control of SBP is achievable, safe, and may minimize IPH expansion. Future studies are needed to elucidate the role of co-morbidities and to confirm these findings in broader populations. Control of blood pressure is a primary concern in neurosurgical procedures and in the medical management of acute stroke. Arterial blood pressure must be kept low enough to avoid injury and minimize bleeding but high enough to maintain cerebral perfusion in the setting of increased intracranial pressure. Since cerebral perfusion pressure (CPP) is equal to the difference between mean arterial pressure (MAP) and intracerebral pressure (ICP), a balance must be maintained between MAP and ICP to ensure adequate CPP. In the case of increased ICP due to events like hemorrhage or mass effect, the elevated ICP leads to compression of cerebral vasculature. This increased cerebral vascular resistance decreases the capillary flow and can lead to cerebral hypoxia and neuronal cell injury, ultimately resulting in death. Normal autoregulation of cerebral blood flow may be disturbed in settings requiring neurosurgical intervention. Therefore, antihypertensive treatment may need to be tailored depending on the specific clinical situation. Patients experiencing stroke have elevated blood pressure in most cases, regardless of stroke mechanism , 2. In aHypertension may be directly involved in the secondary expansion of initial hematoma formation . HematomTherapeutic SBP and MAP goals have been investigated with mixed results that have yet to demonstrate an absolute target SBP value. Based upon the currently available evidence, the American Heart Association (AHA) recommends reducing SBP to <140 mmHg immediately with SBP <130 mmHg being a reasonable long-term goal to minimize hematoma expansion, increase in ICP, and risk of re-bleeding . These gSmall studies have shown favorable outcomes with lower SBP targets. In a study of 211 patients in whom SBP was reduced to <160 mmHg within one hour of presentation, HE >33% of volume occurred in 17.1% of patients with neurological deterioration in 8.1% of patients [In a comparison between nicardipine and nimodipine for hypertensive control between 120 and 140 mmHg within one hour in 87 patients, 21.9% and 18.2% of patients experienced HE >33% at 24 hours, respectively . While small studies have shown intensive SBP goals to be tolerable and safe, larger trials have described a somewhat limited effectiveness of intensive goals in long-term outcomes. The Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) and the follow-up study, INTERACT2, examined the effect of reducing SBP to <140 mmHg compared with the previously less intensive AHA guideline goal of <180 mmHg , 21. INTThe Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) study assigned patients into treatment groups with goal SBP of 110-139 mmHg, 140-169 mmHg, and 170-200 mmHg to analyze HE based on the degree of SBP reduction . GreaterEarly reduction of blood pressure leads to better outcomes in ICH patients, and the target SBP has not adequately been elucidated up to this point. This study examined 134 patients from 2011 through 2015 with ICH and analyzed the reduction in SBP, time to reduction of SBP, HE, and functional outcomes.One hundred and thirty-four patients seen between 2011 and 2015 at a major county-based hospital for hypertensive intraparenchymal brain hemorrhage were included in this study. Patients who presented for brain hemorrhage but who had underlying pathologic conditions precipitating the hemorrhage such as a mass lesion, vascular lesions, or trauma were excluded from the study. A chart review was performed for each patient who met the inclusion criteria in this study, and the patient's age, ethnicity, presenting complaint, initial IPH size, and blood pressure at one hour were recorded. Size was calculated using the ABC/2 formula for IPH. Then, the size of the IPH on subsequent imaging was recorded. Subsequent imaging was obtained using the standard practice of the neurosurgical center, where-in patients undergo repeat imaging six hours after the initial non-contrast head CT. Lastly, data was collected on the patient's presenting Glasgow Coma Scale Score (GCS) and the patient's GCS at the time of disposition as well as the status of disposition . The data was then analyzed using a generalized linear model with patient age; presenting GCS; initial IPH volume; initial SBP; SBP at one hour; and whether SBP was controlled to < 140, between 140 and 160, or not controlled within one hour. The outcome variable was bleed expansion expressed as a percentage increase or decrease. Wald Chi-Square statistics are reported below. Analysis was completed using SPSS 23.0 . This study was reviewed and approved for chart review by the institutional review board at Arrowhead Regional Medical Center. Due to the nature of the data collection which utilized a chart review, the institutional review board waived the requirement for formal informed consent.In total, 134 patients met the inclusion criteria for this study. The mean age of patients was 59.61 years, with a minimum age of 20 years and a maximum age of 91 years. There were 95 males and 92 females. The most common presenting complaint was altered mental status (78%) with severe headache as the second-most common complaint (18%). ICU length of stay ranged from 1 to 34 days with a mean of 6.37 days. Hospital length of stay ranged from 2 to 60 days with a mean of 11 days. Initial presenting GCS ranged from 3 to 15 with a mean of 13.08, while GCS at Day 3 ranged from 8 to 15 with a mean of 13.35. Initial IPH volume ranged from 0.01 ml to 130.43 ml with a mean of 19.6 ml. Follow-up volume ranged from 0.04 ml to 187.44 ml with a mean of 28.63 ml. Percent change ranged from -79% to +1,935% with average change 103.49%. Initial SBP ranged from 104 mmHg to 260 mmHg with mean 166.07 mmHg, and SBP at one hour ranged from 102 mmHg to 209 mmHg with mean 145.79 mmHg. See Table Generalized linear model analysis was performed on the data set with patient age; presenting GCS; initial IPH volume; initial SBP; SBP at one hour; and whether SBP was controlled to less than 140, between 140 and 160, or not controlled to less than 160 within one hour. The outcome variable was hematoma expansion expressed as a percentage increase or decrease. Initial presenting GCS demonstrated no significant main effect on percent change in IPH size, χ2 (6) = 4.958, p = 0.550 Figure . PresentFactorial analysis revealed several significant two-way interactions. The interaction of age by BP group (as described above) was significant, χ2 (2) = 231.962, p < 0.0005. The interaction of initial SBP with initial IPH volume was significant, χ2 (3) = 171.443, p < 0.0005. The interaction of SBP at one hour of presentation and initial IPH volume was significant, χ2 (2) = 288.190, p < 0.0005. Finally, the interaction of initial SBP and SBP at one hour of presentation was significant, χ2 (1) = 121.677, p < 0.0005.The data presented in this study exhibit several important findings. Patients in the 60-70 years age bracket tended to have the largest percent IPH expansion followed by the 20-30 years age group. This may be accounted for by the notion that patients age 20-30 years who present with IPH are likely to have inherent predisposition either epigenetically or by exogenous factors such as drug abuse to stroke. Moreover, patients in the 60-70 years group are known to be at high risk for stroke. Patients older than this group may, in fact, be likely to overcome intraparenchymal hemorrhage by inherent predispositions to vascular and parenchymal stability - and this may have conferred the survival advantage that has allowed them to reach advanced ages.Initial volume of IPH on presentation also predicts IPH expansion with a group of patients who presented with initial IPH volume of 65.23 to 78.26 ml. There is also a second maximum in patients who presented with initial IPH volume of 0.01 to 13.04 ml. The expansion of the IPH in the group presenting initially with the smallest IPH is perhaps unsurprising as any expansion, even layering of blood, would be, in relative quantity, a large percentage change. Of more interest and clinical import, is the finding that patients who present with an initial bleed size between 65.23 and 78.26 ml have predictably larger IPH expansion on follow-up imaging. These patients, therefore, may require closer monitoring and more stringent control of secondary factors such as coagulopathy, blood pressure, cholesterol, and cerebral perfusion pressure. Notably, patients whose initial IPH size was between 52.18 ml and 65.22 ml demonstrated a nadir in IPH expansion. This may perhaps represent the boundary of the brain parenchymal ability to compensate for hemorrhagic insult.Taken in isolation, it would be easy to conclude that there exists a trend that patients whose SBP was controlled to < 140 mmHg after IPH had larger IPH expansion than patients whose SBP was controlled to between 140 and 160 mmHg (whose expansion was comparable to patients in whom SBP was not successfully controlled). A more nuanced approach, however, demonstrates that while patients did, in fact, have larger bleed expansion in the 132-143 mmHg managed group, patients whose SBP control fell lower than this bin, namely the 111-121 mmHg and 122-132 mmHg groups had relative minima in IPH expansion. This coincides with the AHA recommendation of ultimate SBP control in the face of IPH; however, this data suggest that if this control can reasonably be achieved early in the course of the disease, it may lead to smaller IPH expansion and, by extension, improved clinical outcomes. The relative maximum of bleed expansion in the 101-111 mmHg group may be attributable to derangements in CBF autoregulation that correspond to the low-normal SBP state experienced by these patients.Future work in this arena may include patients with IPH from our other major centers to expand the sample size and to better approximate the population. Furthermore, future investigation may focus on patient-specific factors in future analyses such as comorbid conditions and confounding factors such as drug use and any potential coincident illnesses such as ventilator-associated pneumonia, cancers, etc. It is well studied that control of systolic blood pressure is critical in patients with intraparenchymal hemorrhage and tight control of blood pressure is a primary concern in the neurosurgical patient. A balance must be achieved wherein the systolic blood pressure is kept low enough to avoid injury and minimize bleeding while simultaneously being kept high enough to maintain perfusion, particularly in the setting of elevated intracranial pressure. Normal autoregulation of cerebral blood flow may be disturbed in pathologic states such as trauma, tumor, or hemorrhagic stroke, and therefore, exogenous control is often required in the neurosurgical patient. Current American Heart Association (AHA) guidelines recommend the maintenance of systolic blood pressure to less than 140 mmHg in the setting of intracerebral hemorrhage with a long-term goal of SBP < 130 mmHg , 18.As mentioned, careful balance is key. Increased intracranial pressure results in elevated interstitial hydrostatic pressure and compression of the cerebral vasculature. This results in decreased capillary flow hydrostatic gradient and increased cerebral vascular resistance. Further, this can lead to cerebral hypoxia and deficient metabolic reserve causing neuronal cell injury and death. Elevated mean arterial pressure (MAP) in the setting of hypertension leads to increased cerebral perfusion pressure (CPP) and can cause endothelial damage with the destruction of the blood-brain barrier and vasogenic edema leading to further intracranial hemorrhage.Intraparenchymal hemorrhage is less common than ischemic stroke but has higher morbidity and mortality rates per incident. Therefore, urgent reduction in blood pressure can minimize hematoma expansion leading to a better outcome. Hematoma expansion can result in direct mass effect, cerebral edema, and intraventricular hemorrhage that leads to hydrocephalus. This leads to increased intracranial pressure and decreased cerebral perfusion pressure. At this time, nicardipine is the consensus intravenous continuous infusion drug of choice for emergent control of refractory hypertension; however, nimodipine, labetalol, esmolol, and other drips have been used with varying degrees of efficacy, complications, and clinical outcomes. The patient populations with the largest hematoma expansion are those who were 60-70 years and 20-30 years old and those whose initial ICH volume was 65.23 to 78.26 ml. While our data suggest that the ideal target range for SBP in the setting of acute IPH may be 121 - 132 mmHg, further evaluation of this patient population is required to definitively elucidate a target blood pressure range for the immediate post-insult period in intraparenchymal hemorrhage.


The relation between monocyte to high-density lipoprotein cholesterol ratio (MHR) and coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains controversial. The present study aims to assess the prognostic value of MHR in patients with CAD who underwent PCI.A total of 673 CAD patients were retrospectively enrolled and divided into four groups according to MHR values. Multivariate Cox regression analysis was performed to study the effects of different variables to clinical outcomes reported as major adverse cardiac events (MACE) and all-cause mortality (ACM).P = 0.026) and MACE . Having a MHR in the third and fourth quartile were associated with a 2.83-fold and 3.26 -flod increased risk of MACE.In a multivariate Cox analysis, after adjustment of other confounders, MHR was found to be an independent predictor of ACM (HR: 3.655; 95% CI: 1.170–11.419, MHR is an independent predictor of ACM and MACE in CAD patients undergoing PCI. During the past three decades, percutaneous coronary intervention (PCI) has become one of the dominant methods for revascularization in patient with coronary artery disease (CAD). Previous study suggested that inflammation, oxidative stress, and endothelial dysfunction play important roles in the initiation and progression of atherosclerotic process . MountinCirculating monocytes as a source of various cytokines and molecules, interact with platelets and endothelial cells and leading to aggravation of inflammatory, pro-thrombotic pathways , 5. High.We performed a 10-year retrospective cohort study, from January 2008 to December 2016 in the First Affiliated Hospital of Xinjiang Medical University, according to the strict inclusion criteria. Patients with serious heart failure, rheumatic heart disease, valvular heart disease, congenital heart disease and pulmonary heart disease were exclude. We also excluded patients with end-stage renal disease and serious dysfunction of the liver, clinical evidence of cancer, active or chronic inflammatory or autoimmune diseases, active infection and patients who received blood transfusion recently. CAD was defined as the presence of at least one significant coronary artery stenosis of ≥50% luminal diameter on coronary angiography. In the initial,we enrolled 698 consecutive patients with a diagnosis of CAD who underwent PCI. During the follow-up period, 25 patients were lost (changing telephone number or moving to another place). 673 patients were enrolled finally. The study complied with the Declaration of Helsinki, and the protocol was approved by the Human Ethical Committee of the First Affiliated Hospital of Xinjiang Medical University. Because of the retrospective design of the study, the need to obtain informed consent from eligible patients was waived by the ethics committee. Major adverse cardiac events (MACE) and all-cause mortality (ACM) were reported as the clinical outcomes. Follow-up data were obtained by review of the medical records and/or telephone interview with the patient or family members.A flowchart outlining our study was shown in Fig. 1Hypertension was defined as a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of ≥90 mmHg in at least 2 measurements or use of any antihypertensive drug. Diabetes mellitus was defined as fasting plasma glucose level ≥ 7.1 mmol/L on multiple measurements or current use of anti-diabetic medications. Hypercholesterolemia was considered as total serum cholesterol of ≥200 mg/dL or the use of lipid-lowering medications. Family history of CAD was considered in case of history of CAD or sudden cardiac death in a first-degree relative before the age of 55 years for men and 65 years for women. Smoking and drinking status was defined as current tobacco and alcohol use. Cardiovascular mortality, re-hospitalization due to unstable or progressive angina, heart failure, stroke, re-infarction, re-stents implanted, and coronary artery bypass grafting were regarded as MACE. Scoring of severity of coronary artery disease was performed with a modification of the coronary atherosclerosis scoring system which was called the standard of Gensini Method.Peripheral venous blood samples of the patients were obtained on admission to the inpatient ward. Data regarding clinical and demographic characteristics including age, sex, history of hypertension and diabetes mellitus, smoking status, alcohol intake, family history of coronary artery disease and medications were collected from medical records. Left ventricular ejection fraction and laboratory data including urea and creatinine levels, total cholesterol(TC), LDL-C,HDL-C and triglycerides(TG) levels, complete blood cell count and white blood cell (WBC) subgroups count were noted. During hospitalization and follow-up period, β-blocker, angiotensin-converting enzyme inhibitor, and statin were administered to all patients unless contraindicated.2) test. Stepwise regression was used to deal with the collinear problem. Multivariate Cox proportional hazard model were used for determination of independent parameters for MACE and ACM. To construct the Cox model, univariate models for each of the all predictor variables were run, with those variables that were significant (P < 0.05) in univariate Cox models were then simultaneously entered into a multivariable Cox model. The Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The cumulative survival curve for MACE and ACM was constructed using the Kaplan-Meier method and compared using the log-rank test. P < 0.05 was considered significant. Receiver operating characteristic (ROC) curve was performed to discuss the diagnostic value of risk factors for the prediction of poor prognisis.All analyses were performed using SPSS 22.0 for Windows statistical software .The normality of the distribution of continuous variables was evaluated by the Kolmogorov-Smirnov test. Continuous variables were expressed as Mean ± standard deviation. Parametric patient characteristics were compared using one-way ANOVA, whereas non-parametric characteristics were compared using the Kruskal–Wallis test. Categorical variables were summarised as percentages and compared using the Chi-square  with the diagnosis of CAD after PCI were enrolled. The mean follow-up period was 39 ± 25 months. The clinical, echocardiographic, and laboratory data of the study population are given in Table 1P < 0.05).The study population were assigned into quartiles (Q) based on pre-ablation MHR . Baseline characteristics, laboratory parameters, and coronary angiographic findings of the patient groups according to the MHR quartile groups are presented in Table . According to univariate Cox proportional hazard regression analysis, age, MHR, left ventricular ejection fraction (LVEF), diabetes, HR (heart ratio), haemoglobin B (HB), direct bilirubin DBIL, LDL-C and Gensini score were significantly associated with ACM (P < 0.05)  Table . MultivaP = 0.035), heart ratio , DBIL , LDL-C Gensini sore  and MHR  were independent predictors of ACM after adjustment of other variables . In multivariate Cox proportional hazard regression analysis, MHR was also found as an independent predictor of MACE , along with diabetes mellitus , hypertension , hemoglobin  heart ratio , LDL-C, and Gensini score  were found as independent predictors of MACE. Having a MHR in the third and fourth quartile were associated with a 2.83-fold  and 3.26-flod  increased risk of MACE.As shown in Table p = 0.006) . Kaplan-Meier curves among quartiles for both ACM and MACE , which represent worse outcomes as MHR increases, were shown in Fig. 4.Receiver operating curve (ROC) analysis showed that MHR levels could predict ACM with a sensitivity of 78.6% and a specificity of 61.5%  Fig. . The areIn our study, we found that elevated MHR is a useful marker of poor prognosis in patients with CAD undergoing PCI. In multivariate analysis, the MHR emerged as an independent predictor of ACM and MACE.Recently, MHR is considered as a novel and surrogate marker of inflammatory status. Acikgoz et al.  reportedThe exact mechanisms underlying the association between MHR and clinical outcomes after PCI are unknown. As previous studies have shown, atherosclerosis activates the adhesion molecule of endothelium cells and binds to mononuclear cells. When monocytes are bound to the arterial endothelium, they enter the endothelial lining and enter the intima to form foam cells. Activated monocytes interact with damaged or activated endothelium, affect lesional macrophage accumulation and plaque macrophage content , which lNonetheless, there are some limitations of this study. Firstly, the present study is retrospectively designed and is a single-center experience study. Secondly, a relatively small sample size is another limitation. Third, additional inflammation and thrombosis markers such as CRP, fibrinogen, plasma coagulation factors, or erythrocyte sedimentation rate were not evaluated in the present study.MHR can be calculated from simple blood analysis and could make a adverse prognostic value in CAD patients undergoing PCI.


Decreased ambient temperature significantly increases office blood pressure, but few studies have evaluated the effect of ambient temperature on home blood pressure.We aimed to investigate the relationship between short-term ambient temperature exposure and home blood pressure.We recruited patients with chronic cardiovascular diseases from a telehealth care program at a university-affiliated hospital. Blood pressure was measured at home by patients or their caregivers. We obtained hourly meteorological data for Taipei  for the same time period from the Central Weather Bureau, Taiwan.From 2009 to 2013, we enrolled a total of 253 patients. Mean patient age was 70.28 (SD 13.79) years, and 66.0% (167/253) of patients were male. We collected a total of 110,715 home blood pressure measurements. Ambient temperature had a negative linear effect on all 3 home blood pressure parameters after adjusting for demographic and clinical factors and antihypertensive agents. A 1°C decrease was associated with a 0.5492-mm Hg increase in mean blood pressure, a 0.6841-mm Hg increase in systolic blood pressure, and a 0.2709-mm Hg increase in diastolic blood pressure. This temperature effect on home blood pressure was less prominent in patients with diabetes or hypertension. Antihypertensive agents modified this negative effect of temperature on home blood pressure to some extent, and angiotensin receptor blockers had the most favorable results.Short-term exposure to low ambient temperature significantly increased home blood pressure in patients with chronic cardiovascular diseases. Antihypertensive agents may modify this effect. Exposure to extreme temperatures, either high or low, is known to significantly increase mortality, and most temperature-attributable death is due to low, rather than high, ambient temperatures ,2. A preRecently, a Japanese study showed that home blood pressure (HBP) may be an even more important parameter than office blood pressure for predicting future coronary artery disease (CAD) and stroke events . Few stuWe aimed to investigate the relationship between short-term ambient temperature exposure and HBP in patients with chronic cardiovascular diseases using a Web-based platform.This was a single-center, retrospective study and was approved by the Institutional Review Board of National Taiwan University Hospital, Taipei, Taiwan. We obtained informed consent from all participants.We conducted this study from January 2009 to December 2013 at the Telehealth Center of National Taiwan University Hospital. Patients older than 20 years with chronic cardiovascular diseases who were receiving telehealth care at our telehealth center were enrolled in the study group. Chronic cardiovascular diseases included (1) CAD with or without percutaneous coronary intervention, (2) prior myocardial infarction (MI), (3) heart failure, (4) peripheral artery disease, (5) prior stroke, and (6) hypertension. Patients who did not reside in Taipei during the study period were excluded. The decision on whether to receive the telehealth program was made by patients, their caregivers, or both.According to the classification of 4 generations of telemedicine in heart failure proposed by Anker et al , the telWe obtained all demographic and clinical data, including the prescription of antihypertensive agents, from the electronic database of the hospital. Chronic disease diagnosis was based on the electronic database. Blood pressure and other biometric parameters were measured at home by patients or their caregivers, and data were instantaneously transmitted to the hospital server for storage and analysis. In general, patients and caregivers were advised to take measurements twice daily, with the first measurement being in the morning before eating or taking any medications and the second being in the evening. However, each patient chose their own time of day and time interval to measure their blood pressure based on their own habits. The specific model of sphygmomanometer used in this study was the AViTA BPM65ZB , which is an electronic digital upper arm blood pressure monitor. We obtained hourly meteorological data for Taipei  for the same time period as the study from the Central Weather Bureau, Taiwan.P ≤.05 to be statistically significant. The distributional properties of continuous variables are expressed as mean (standard deviation), and categorical variables are presented as frequency and percentage. In the univariate analysis, we examined the differences in the distributions of continuous variables and categorical variables between male and female participants using Wilcoxon rank sum tests and Fisher exact tests, respectively.We performed statistical analyses using R version 3.4.2 software (R Foundation). For the statistical tests, we considered a 2-sided We conducted the multivariate analysis by fitting multiple linear regression models to estimate the adjusted effects of age, sex, comorbidities, heart rate, antihypertensive drugs, seasons, meteorological factors (see below), and other predictors on 3 continuous outcomes: (1) mean blood pressure (MBP), (2) systolic blood pressure (SBP), and (3) diastolic blood pressure (DBP). Since antihypertensive drug use and meteorological factors varied over time, we defined and included the following 2 groups of time-dependent covariates in our linear regression analyses:Antihypertensive drugs: of the 6 frequently used categories of antihypertensive drugs , we evaluated the antihypertensive drug categories and the number of categories of antihypertensive drugs used on the day of blood pressure measurement.Meteorological factors: we considered hourly averaged temperature, relative humidity, and wind speed within the hour of blood pressure measurement; daily highest and lowest temperatures; highest and lowest temperatures in the 12 hours prior to blood pressure measurement; highest and lowest temperatures in the 24 hours prior to blood pressure measurement; difference between the highest and lowest daily temperature; difference between the highest and lowest temperature in the 12 hours prior to blood pressure measurement; and difference between the highest and lowest temperature in the 24 hours prior to blood pressure measurement.More statistical details can be found in From January 2009 to December 2013, a total of 253 patients who participated in the Telehealth Care Program of National Taiwan University Hospital who had complete demographic and clinical data were enrolled in the study. We collected a total of 110,715 blood pressure measurements in the database during the study period. The demographic and clinical data are summarized in P=.003), higher proportions of CAD without prior MI  and CAD with prior MI , and a lower proportion with cancer . The mean hourly averaged temperature was 23.43 (SD 5.69) °C, and the mean relative humidity was 72.28 (SD 9.95) %. The mean wind speed was 2.47 (SD 1.60) m/s. The mean temperature differences in the past 12 and 24 hours were 3.71 (SD 2.32) °C and 5.72 (2.60) °C, respectively .The most frequently used antihypertensive agent class was diuretics , followed by ARBs , CCBs , and BBs  SBP, (2) DBP, and (3) MBP. Since patients’ use of antihypertensive drugs and meteorological factors varied over time, we defined and computed both as time-dependent covariates in these 3 regression analyses. Hourly averaged temperature had a linear negative effect on all 3 HBP parameters, so lower temperature resulted in higher HBP. The temperature difference between the maximum and minimum in the 12 hours prior to blood pressure measurement had a positive effect on MBP and DBP , but the effect was not significant for SBP. Relative humidity and wind speed had nonlinear effects on HBP, as shown in the generalized additive model plots  for MBP.Antihypertensive agents significantly affected HBP measurements and may modify the effect of ambient temperature  on bloodInterestingly, in patients with DM or hypertension, the effect of ambient temperature on HBP was less pronounced. Both extremely high and low temperatures have been shown to increase mortality , but theHintsala et al reported that even short-term cold exposure increased central aortic blood pressure , and theIn this study, patients with a diagnosis of either diabetes mellitus or hypertension appeared to be more resistant to the effect of temperature on HBP. The true underlying mechanism remains unknown, but medications appear to play a role. Chen el al  reportedThe fact that ACEIs had no significant influence on HBP, in contrast to ARBs, was somewhat surprising. However, the number of patients taking ACEIs was very small, so the analysis in this study may not have had sufficient power to detect the true effect of ACEIs. On the other hand, the proportion of patients taking ARBs and diuretics was the largest of the various classes, and this may have increased the power of the analysis to find an effect.As the final multiple linear regression models shown in This study was a retrospective registry with a relatively small number of patients. The patients all had chronic cardiovascular diseases with excellent adherence as they participated in a telehealth care program; thus, the study results should be extrapolated to other patient populations with caution. The ambient temperature was outdoor temperature in this study, and thus may have underestimated the true effect of indoor temperature. Previous studies have shown that both indoor and outdoor temperatures are inversely related to blood pressure, and there is a stronger association with indoor temperature than with outdoor temperature ,26-29. TWe did not include medications other than antihypertensive agents, such as oral antidiabetic drugs and statins, in this analysis. As a result, whether these drugs also modify the effect of temperature on HBP is unknown. We also did not include other environmental factors such as air pollutants in this study. Moreover, although the patients and caregivers were advised to take measurements twice daily, patients and their caregivers chose their own time of day and time intervals to measure blood pressure. There may thus be heterogeneity across patients regarding measurement behavior and potential confounding effects.Since the repeated measurements of SBP and DBP on the same patient were probably correlated, we could have applied the generalized estimating equations method to obtain robust estimates of standard errors for the estimated regression coefficients of the multiple linear regression models of SBP and DBP. However, we did not do so because the cluster sizes were too big .Short-term exposure to low ambient temperature significantly increased HBP in patients with chronic cardiovascular diseases, and antihypertensive agents could have modified this effect.


This easily found and cheap dietary intervention could significantly decrease the risk of suffering cardiovascular events and, in doing so, would help to diminish the mortality rate associated to this pathology. Hence, BRJ supplementation should be promoted as a key component of a healthy lifestyle to control blood pressure in healthy and hypertensive individuals. However, several factors related to BRJ intake  should be studied more deeply.According to current therapeutic approaches, a nitrate-dietary supplementation with beetroot juice (BRJ) is postulated as a nutritional strategy that might help to control arterial blood pressure in healthy subjects, pre-hypertensive population, and even patients diagnosed and treated with drugs. In this sense, a systematic review of random clinical trials (RCTs) published from 2008 to 2018 from PubMed/MEDLINE, ScienceDirect, and manual searches was conducted to identify studies examining the relationship between BRJ and blood pressure. The specific inclusion criteria were: (1) RCTs; (2) trials that assessed only the BRJ intake with control group; and (3) trials that reported the effects of this intervention on blood pressure. The search identified 11 studies that met the inclusion criteria. This review was able to demonstrate that BRJ supplementation is a cost-effective strategy that might reduce blood pressure in different populations, probably through the nitrate/nitrite/nitric oxide (NO Hypertension or high blood pressure (HBP) is a common disease that has become a pandemic for several years. High blood pressure is the main risk factor attributed to many deaths in middle-income countries, and the second, before tobacco, in low and high-income countries. In addition, it is the second risk factor that causes disability-adjusted life years . The numIt is widely known that some factors related to diets, such as excessive sodium intake, high consumption of alcoholic drinks, low intake of fruits and vegetables, and a sedentary lifestyle, could increase the prevalence of HBP. It has also been stated that deficiency of some vitamins, such as folic acid, riboflavin, and vitamins C and D, can be considered risk factors to develop this non-communicable disease . Faced wTaking into consideration the fact that HBP appears to have a complex association with endothelial dysfunction, a phenotypical alteration of the vascular endothelium, which precedes the development of cardiovascular events, could result in future cardiovascular risk; therefore, it is essential to achieve action regarding the above factors . Nitric 3−) is present in BRJ (≈25%) as well as in some other vegetables like spinach, rocket, cress, lettuce, celery, and radish (>250 mg NO3−/100 g), which concentrates in saliva and comes into contact with symbiotic bacteria on the dorsal surface of the tongue that reduce inorganic NO3− to nitrite (NO2−) through bacterial nitrate reductases . This saliva rich in nitrogen compounds reaches the stomach where a small part of the NO2− is reduced to NO through a non-enzymatic reaction, which is favored by the acidic environment of this organ. However, most of the NO3− and NO2− are quickly absorbed by the stomach and duodenum to get into systemic circulation [3− is reabsorbed from the bloodstream and concentrated in the salivary glands to later be a substrate of the bacteria as mentioned above and produce NO2− that is swallowed again for its subsequent reduction [3− and 373 ± 211 nM after 2–3 h equivalent to ≈400% increase for NO2−), which favors the production of NO in the wall of blood vessels and erythrocytes by employing reduction mechanisms of an enzymatic nature , and non-enzymatic . Nonetheless, this reduction process is stimulated during conditions with low oxygen availability and an acidic pH, which allows the synthesis of NO to be localized at certain specific times [+ channels), and it is associated with a significant decrease in blood pressure to muscle relaxation in the endothelium [In brief, a significant proportion of nitrate  investigating the effect of BRJ on SBP and diastolic blood pressure (DBP) is conducted, since previous reviews mixed dietary nitrate sources.Even when the production of NO decreases with age, and this could be associated with increased risk of hypertension and cardiovascular disease in the elderly, recent meta-analyzes ,16 have https://www.crd.york.ac.uk/prospero; CRD42018112041).The present systematic review was conducted according to established guidelines, and it is reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines . It was beetroot juice” OR “red beet” OR “beta vulgaris” AND (blood pressure or hypertension). This search was enriched with terms NOT exercise NOT sport. The data search was performed during June 2018.The RCT searching was carried out through the databases PubMed/MEDLINE and Science Direct, and further papers were sought by hand-searching. The data search was performed by using free language terms related to BRJ and blood pressure. The search string for all databases was the following “3− salts as a dietary supplement; and (5) studies with no control group.Specific inclusion criteria were as follows: (1) studies written in English; (2) published from 2008 onwards, as this would cover the most recent years of research; (3) RCTs; (4) trials that only evaluated the consumption of BRJ by using a control group, regardless of the gender; and (5) trials that reported the effects of these interventions on blood pressure. On the other hand, exclusion criteria were: (1) studies that did not correspond to original research ; (2) studies where their object of study was the effects of BRJ on exercise or sports performance; (3) studies that did not assess the effects on blood pressure; (4) studies that used NOAfter the search of the published articles, the filters options of the databases were used to meet the inclusion criteria 1 to 3. The remaining references were filtered by screening the title, abstract, or full text publication. The study selection, risk of bias, and data extraction was performed independently by two of the authors (AFP and DAB). Risk of bias of all included RCTs was assessed using the Cochrane risk of bias tool : selecti3− content; (5) placebo; (6) effect on systolic BP; and (7) effect on diastolic BP. All randomized participants in the analysis were included, as it was the least biased way to analyze intervention effects. The following data were obtained and analyzed from the selected studies: (1) characterization of the study population; (2) study length; (3) BRJ dosage; (4) NO3− as dietary supplement. A total of 11 studies met the inclusion criteria. A flow chart of the literature search is shown in The literature selection after using the search terms and Boolean operators resulted in 110 references. A screening of articles after filtration by species, publication date, article type, and text availability resulted in 54 potentially eligible studies. However, after checking the full texts of these studies, 41 of them were excluded since they were focused on exercise/sports performance and two because they included inorganic NO3− concentration) , and the type of intervention performed in the supplementation protocol  . The met3− as an adjuvant therapy.To analyze the clinical relevance in reducing blood pressure as a result of BRJ consumption, it is important to note that a decrease between 5 and 12 mmHg of SBP and between 5 and 6 mmHg of DBP is associated with a 14–38% risk reduction in stroke, from 9 to 16% risk reduction of mortality from coronary heart disease, 21% risk reduction of mortality due to coronary disease, and 7% risk reduction in mortality from all causes . It is i3− coming from the diet, probably due to a lower rate of non-enzymatic conversion of NO3−/NO2− to NO, also to a reduction in the response of the endothelium and vascular smooth muscle cells to NO. Alike, it has been made evident that aging produces changes in the oral microbiota and the gastric acid production, which could negatively influence the efficiency of the conversion of NO2− into NO. Despite the aforementioned, Bahadoran et al. [3−. Most of the studies reviewed found positive effects after supplementation with BRJ in healthy adult subjects ,21,22,23n et al.  reported3− using BRJ. Kapil et al. [2− could limit the reduction of blood pressure values after dietary intervention. In the same way, Cole and Clifon [Regarding gender, most of the study subjects were men. Few studies have evaluated whether there is a difference in blood pressure values between women and men after dietary supplementation with NOl et al.  reportedd Clifon  observedStudies like that of Jajja et al.  and AshoCurrently, there is some degree of controversy regarding whether supplementation with BRJ benefits hypertensive patients receiving pharmacological treatment or healthy subjects with slightly elevated blood pressure values. In this study, we found seven studies showing a greater effect in healthy subjects and four studies that find positive effects in patients with hypertension.On the one hand some studies, such as Bondonno et al. , have no3− for the studies included in this systematic review was between 300 and 500 mg NO3− , which is higher than the acceptable daily intake of NO3− as defined by the WHO (3.7 mg/kg body weight per day) [3− and the hypotensive effect [3− or whether other components of the BRJ mediate this physiological response, such as betalains, oxalic acid, hydroxycinnamic acids, among others. In this sense, some studies have not shown significant changes on blood pressure after the administration of NO3−-depleted BRJ versus NO3−-rich BRJ [3−-depleted BRJ as a placebo on blood pressure values. This generates the need to evaluate the role of NO3−-depleted BRJ and its effect on blood pressure and other health markers, bearing in mind that future research could consider the effect of other compounds present in BRJ, such as betalains.During supplementation with BRJ, the amount of NOper day) . It has e effect . Howeverrich BRJ ,22,23. Frich BRJ  reported3− content of commercial BRJ have been found previously, where the variety Mona Lisa might be the optimal recommended source of beetroot raw material, due to the high NO3− concentration (4.6 g/L) [It is important to highlight that large variations (from 0.01 to 2.4 g/L) in the NO4.6 g/L) . It beco3−-independent effects.The BRJ volumes reported in the studies of this review had a reasonably wide range, ranging from 70 to 500 mL. In general, there was no significant difference between the volumes administered; however, the recent meta-analysis by Bahadoran et al.  suggesteFrom the experimental design of the 11 revised RCTs, there are acute and chronic supplementation protocols, where the blood pressure analysis was carried out between 24 h and six weeks after BRJ administration. There are better effects at the postprandial level during the first 3 h and up to 24 h after the consumption of BRJ. Additionally, when evaluating the effect of beet supplementation, it is concluded that interventions over two weeks generated better results ,24,26, c3−/NO2−/NO pathway, although more research is required to establish if other secondary metabolites of BRJ may mediate the effect . Individual factors influencing the effects of BRJ supplementation on blood pressure encompass baseline blood pressure, overweight/obese status, gender, and age. It is recommended that an administration period of minimum two weeks is used in order to have sustained results; however, more research is needed to evaluate the relevance and long-term effect of BRJ administration in hypertensive individuals. This reduction in blood pressure, especially SBP, not only would decrease morbidity and mortality, but it would also decrease public health expenditure.In conclusion, BRJ supplementation might be an easy, accessible, safe, and evidence-based strategy to reduce blood pressure. Its attractive cost-effectiveness ratio would benefit pre-hypertensive patients when pharmacological treatment should not be the first alternative. The potential reduction in blood pressure after BRJ administration might contribute to the diminishment in mortality rate for cerebrovascular diseases . This sy


The aim of this study was to investigate the pathogenic role of obesity on blinding eye diseases in a population of severely obese patients with no history of eye diseases, and to verify whether weight loss induced by bariatric surgery may have a protective effect.2 were consecutively recruited and received a complete ophthalmological evaluation and optical coherence tomography. Twenty-nine patients who underwent gastric bypass were evaluated also 3 months, and 1 year after surgery.This was a pilot, monocentric, prospective, and open label study conducted at the University Hospital of Pisa. Fifty-seven severely obese patients with a mean body mass index value of 44.1 ± 6 kg/mAt baseline, blood pressure value were directly and significantly related to intraocular pressure values . Blood pressure values were also significantly and inversely related to retinal nerve fiber layer thickness, particularly in the temporal sector . Moreover, minimum foveal thickness values were significantly and inversely associated with body mass index . A significant reduction of body mass index (p<0.05) and a significant (p<0.05) improvement of blood pressure was observed three months and one year after gastric bypass, which were significantly associated with an increase in retinal nerve fiber layer thickness and minimum foveal thickness values in both eyes (p<0.05).The results of this study suggest that obese patients may have a greater susceptibility to develop glaucomatous optic nerve head damage and age-related macular degeneration. Moreover, weight reduction and improvement of comorbidities obtained by bariatric surgery may be effective in preventing eye disease development by improving retinal nerve fiber layer and foveal thickness. Worldwide, the proportion of adults with a body-mass index (BMI) of 25 kg/min women .Obesity and obesity-related systemic diseases determine a greater risk for blinding eye diseases, such as cataract, glaucoma and age-related macular degeneration (AMD) . BariatrThis was an explorative, prospective, monocentric open-label study. The study was conducted according to the principles defined in the Declaration of Helsinki and amendments, and was approved by the local Ethical Committee . Between July 2015 and January 2016, 57 consecutive obese patients, aged 18 to 65 years , were selected among those attending the Obesity Center of the Endocrinology Unit, at the University Hospital of Pisa, Italy. All patients gave their written informed consent.2 orBMI≥35 Kg/m2 with co-morbidities. Patients with a diagnosis of type 2 diabetes or with pre-existing ocular diseases or visual alterations were excluded to avoid confounding factors related to pre-existing retinal pathology, independent from obesity per se. Patients with dementia, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis or other severe neurological diseases were also excluded since ophthalmologic parameters may be altered in these conditions. Patients with lens opacities that made impossible the posterior segment examination, or with a refractive error > +5 or <-8 diopters spherical equivalent were also excluded.The inclusion criteria were BMI≥40 Kg/mThe following parameters were recorded: age, body mass index (BMI), waist and hip circumference, heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP), reported as average of two measurements in the sitting position with an interval of 2 minutes with an appropriate cuff. Blood glucose, glycated hemoglobin, fasting insulin, creatinine, fasting leptin, vitamin D, vitamin B, folic acid , co-morbTwenty-nine patients underwent gastric bypass surgery (GBP) . After sIn each eye, right eye (RE) and left eye (LE), the following data were collected: Visual acuity ; intraocular pressure (IOP); central corneal thickness (CCT); foveal thickness (FT) average value; FT minimum value; FT maximum value; average retinal nerve fiber layer (RNFL) thickness value; RNFL thickness superior, temporal, inferior, and nasal sector; cataract present or absent.The anterior segment was examined by slit-lamp biomicroscopy, best corrected visual acuity was recorded as Snellen equivalent, opacity of the lens was classified using the Lens Opacities Classification System III (LOCS), and intraocular pressure was measured with Goldmann applanation tonometry. The posterior segment was examined after pupil dilation; central corneal thickness was measured with Tomey EM-3000 specular microscope. All images of the optic nerve head and of the fovea were acquired with the Spectralis Spectral Domain-Optical coherence tomography  by the same expert operator. The scan speed of the instrument is 40000 A-scan per second, and the scan circle diameter around the optic nerve is 12°. Typically, the scan diameter (mm) is 3.5–3.6 mm and relays on the axial eye length of the eye. The quality score of all scans is > 20 . The meaData were organised in a Microsoft Excel XP table to perform statistical analysis. The Kolmogorov-Smirnov test was used to assess normality of data. Pearson (r) and Spearman (rho) correlation coefficients were calculated to quantify associations between Gaussian and skewed variables, respectively. Changes at follow-up were calculated as the difference between follow-up and baseline measurements, and were analysed by paired Student’s t test when assessing differences in mean values. A p-value <0.05 was considered statistically significant. Data are presented as mean ± standard deviation (SD). Analyses were performed using SPSS Of the 57 patients enrolled, 46 were women and 11 were male. Their anthropometric measures are listed in Twenty patients were on treatment for hypertension. All ophthalmologic values registered at baseline are shown in In the univariate analysis blood pressure values were directly and significantly related to intraocular pressure values. In the right eye there was a direct association both for diastolic and systolic pressure , while in the left eye only the diastolic pressure was associated with intraocular pressure values. Systolic blood pressure values remained significantly associated with IOP in both eyes, even after correction for age and body mass index, explaining 8–9% of IOP variability. Furthermore, BP values were significantly and inversely related to RNFL thickness, particularly in the temporal sector of the left eye  and in the superior sector of the right eye  .BMI values were significantly and inversely related to minimum foveal thickness values in both eyes . Blood glucose, glycated hemoglobin, fasting insulin, creatinine, fasting leptin, vitamin D, vitamin B, folic acid and lipid profile did not correlate with eye parameters before surgery.Using the LOCS III system for classification, cataract was observed in 8 patients (14%); 1 patient was classified as NO 4 C2 P1 in the right eye 3 were classified as NO 3 C1 P1; other 3 patients as NO 2 C1 P1 and 1 as NO 1 C2 and P1.Three months after bariatric surgery, a significant reduction of BMI value (p< 0.05), associated with a statistically significant improvement of BP values (p< 0.05) was observed . The ophAfter one year, a marked weight reduction was observed. RNFL thickness increased further in the superior sector in both eyes (p<0.005), and in the left eye also in the inferior and temporal sector (p<0.05) . Among 1The absolute decrease of SBP was significantly and inversely associated with an increase in the RNFL thickness in the superior sector of the left eye , to confirm the inversely association found at baseline .Additionally, there was a significant increase of minimum FT value in both eyes  (Tab 3).Lens opacities, defined using the LOCS III classification system, did not show any change in all 29 patients three months and one year after GBP.From an ophthalmologic point of view, all patients enrolled in this study can be defined as naive since they did not have a history of ophthalmologic diseases particularly glaucoma, retinopathy or AMD. Blood pressure was as an independent determinant of IOP, and was inversely related to RNFL thickness. Despite the limitation of a single BP measurement at each time point of the study, it is tempting to hypothesize that severely obese patients may have an initial, subclinical damage of the RNFL, somehow related to increased blood pressure values. Indeed, Dogan et al.  observedAs expected, body weight loss after bariatric surgery was remarkable. Consequent to BMI reduction, blood pressure values, both systolic and diastolic, were significantly reduced and most patients could discontinue or reduce their anti-hypertensive medications. In parallel with BP reduction, RNFL thickness increased significantly in our population, supporting the hypothesis that blood pressure may affect the RNFL. In line with this view, studies in hypertensive patients suggest that anti-hypertensive medications may be protective against glaucoma . The relBurgansky-Eliash  and ÇekiYet, the actual interplay between BMI and POAG represents a debated question –32. RaciThe second relevant observation of our study is the inverse relationship between BMI and minimum foveal thickness values. This association may give explanation for the greater susceptibility of the obese population to develop AMD. In 2001 Schaumberg et al. studied a cohort of 21,121 men participating in the Physician’s Health Study. Men with normal BMI had lowest incidence of dry AMD. The AMD incidence was not related to age and smoking and did not show any correlation with diabetes or hypertension . FollowiLens opacities remained unchanged after surgery. The short follow-up of the study and the young age of our population do not allow a definite conclusion. Yet, our results are reassuring about the potential adverse effects of bariatric surgery and fast weight reduction on crystalline transparency in the short run.Limitations of our study are represented by the small sample size of the bariatric surgery group, the absence of additional control groups  and the lack of anterior eye structural endpoints such as CCM or Oculus Pentacam. Furthermore, our study-population was mainly composed by women since the F:M ratio in bariatric studies enrolling consecutive patients is typically in favour of women. We acknowledge that this is a limitation and larger numbers are required to verify the potential gender effect on the studied parameters.In conclusion, severely obese patients may be at risk of developing glaucoma and age-related macular degeneration. Body weight reduction and improvement of comorbidities achieved by bariatric surgery may be effective in preventing eye disease development by improving RNFL and foveal thickness. Optical coherence tomography, together with a complete eye examination, is a quick and non-invasive exam that may be useful in severely obese patients to detect and classify early change of the optic nerve head and the fovea, even in the absence of a history of eye diseases.S1 Filehttps://doi.org/10.5061/dryad.1g6vm34).Anthropometric parameters, biochemistry, blood pressure values and ophthalmic parameters tested before (baseline), three months and one year after surgery. ((XLSX)Click here for additional data file.


IntroductionBeta-blockers again are now considered as first-line therapy for various cardiovascular diseases. In this study, we compare the cardiovascular event between two beta-blocker, i.e. Nebivolol and Bisoprolol.Materials and Methodsst Jan 2016 to 30th July 2019 in tertiary care hospital, Nawabshah. One thousand and fifty-six (n=1056) hypertensive patients were enrolled after informed consent, which were randomized into two equal groups. Patients were followed up for one year.It is a two-arm open-label randomized prospective study that was conducted from 1ResultsComparison between Nebivolol and Bisoprolol showed that all-cause mortality (9.8% vs 11.48%), cardiovascular mortality (5.4% vs 7.0%), all-cause hospitalization (14.4% vs 16.3%), and cardiovascular hospitalization (9.8% vs 12.09%) was numerically lower in nebivolol but the difference was not statistically significant.ConclusionFurther large scale multicentric trials with a longer follow up period are needed to compare various beta-blockers for cardiovascular event. Agents that block the adrenergic β-receptors, beta-blockers, have been a cornerstone for the treatment and management of cardiovascular disease (CVD) for more than a decade. Increase survival rate and expectancy of patients with CVD due to the development of primary prevention and early-detection strategies along with the development of new and effective therapeutic agents has increased the prevalence of cardiovascular disease . In 2013This two-arm open-label randomized prospective study was conducted from 1st Jan 2016 to 30th July 2019 in tertiary care hospital, Nawabshah. One thousand and fifty-six (n=1056) hypertensive patients were enrolled after informed consent, which were randomized by a 1:1 ratio using an online software research randomizer. Group A was given standard hypertensive therapy  and Nebivolol. Group B was given standard hypertensive therapy and Bisoprolol.Patient’s characteristics such as age, gender, history of smoking, duration of hypertension, family history were noted in the self-structured questionnaire. Their standing blood pressure was also recorded. Patients were followed for a minimum of one year for the development of any cardiovascular event. Patients with less than one year of follow up were counted as lost to follow up.Statistical analysis was done using SPSS v. 22.0 . Continuous variables including age, blood pressure (BP), and duration of hypertension were analyzed via descriptive statistics and were presented as mean and standard deviation (SD) while categorical variables, including gender, smoking history, and cardiovascular outcomes were presented by percentages and frequencies.One thousand and fifty-eight 1058) participants were enrolled and randomized into two equal groups; one with Nebivolol and one with Bisoprolol. The characteristics were comparable between the two groups except for BMI. Lost to follow up were 29 and 33 participants for Nebivolol and Bisoprolol, respectively , which concluded there is no difference in blood pressure control between nebivolol and Bisoprolol . CARNEBIIndividual trials of both Nebivolol and Bisoprolol have shown that they reduce cardiovascular events. Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS) showed that nebivolol significantly reduces all-cause mortality or cardiovascular hospitalization compared to placebo (95% CI): 0.86 (0.74-0.99); p = 0.039 . The carBetter cardiovascular protection by Nebivolol can be explained because of its unique mechanism of action and super selectivity. Nebivolol has 321-fold higher affinity for human cardiac beta1-receptors versus beta-2-receptors making it more selective for beta1-receptors than any other agent in its class . NebivolTo the best of its knowledge, it is the first study that has compared the cardiac outcome of patients on Nebivolol and Bisoprolol in Pakistan. However, the study has its own limitation. First, there was a statistical difference in body mass index (BMI) between the two groups. Secondly, the follow-up period was only one year. Hence, long-term results were not noted. There were other confounding factors such as cholesterol level and lifestyle, which was not taken to account.In this study, overall mortality, over-all hospitalization, CV mortality, and CV hospitalization even though was numerically better in Nebivolol than Bisoprolol but there was no significant difference between the two. With the advancement of beta-blockers, they are now again becoming an important option in the management of patients with hypertension and other cardiac diseases. It is important to understand the properties and advantages of various beta-blockers so that maximum advantage can be provided to the patients. Further, large-scale multicentric trials are needed to compare various beta-blockers.