A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1–4 as most to least likely to respond based on the algorithmic assessment of individual patient’s genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis ( Hypertension (HTN) is a major preventable contributor to cardiovascular disease (CVD) and accounts for approximately 360,000 of the 2.4 million 14%) annual deaths in the United States 4% annual. With th+ intake [Hypertension has a strong heritable component, estimated at approximately 50%, with current studies suggesting the responsiveness to HTN therapy may be heritable as well ,14,15,16+ intake ,17. Addi+ intake ,19,20. C+ intake ,15.In an effort to control HTN, given the potential for ineffective monotherapy, the current standard of care is to “layer” BP drugs . If guideline-directed blood pressure goals continue to be elusive , the process is reinitiated with a different combination of drugs, different classes of drugs, different drug options within a given class of drugs, different dosages or all of the above. This trial-and-error standard of care is clearly not optimal and presents consequences, such as increased side effects, costs to the patient, increased health care service utilization, and reduced quality of life ,22. Furt1-adrenergic receptor (ADRB1), β2-adrenergic receptor (ADRB2), cytochrome P450 2D6 (CYP2D6), lysine deficient protein kinase (WNK), sodium-chloride symporter (SLC12A3), alpha subunit of the epithelial sodium channel (SCNN1A), alpha-adducin (ADD1), renin, angiotensin, angiotensin-converting enzyme (ACE), and angiotensin receptor variants as playing key functional roles in response to HTN therapy [+ and Cl− excretion, decreased adverse events  and decreased mortality risk [Research examining genetic determinants to HTN therapy response have identified βorter SLCA3, alpha therapy ,24,25,26orter SLCA3, alpha therapy ,34,35,36 therapy ,12,16,24ity risk ,39,40,41Collectively, these previous studies demonstrate that genetic variations in proteins responsible for BP modulation may be responsible, in part, for the variability of HTN therapy effectiveness. To date, most research on BP therapies efficacy has been monogenic and have not adequately taken into account the multi-organ and multi-system integrative nature of HTN. Furthermore, while emerging data has employed the use of a simple algorithm, taking into account the total number of functional genotypes within an organ system, to predict BP response to therapy, pilot work by our group has demonstrated that this approach alone does not accurately predict BP response. Indeed, some genotypes demonstrated functionality with respect to BP response to HTN therapy whereas some genotypes demonstrated functionality with respect to BP control using a <140/<90 mmHg cutoff. These differences suggest that a more complex and logical algorithm is needed to more accurately predict BP response to HTN therapy . This laclinicaltrials.gov identifier: NCT02524873). Patients provided DNA for genetic analysis, and a detailed medical chart review was performed between 30 November 2015 and 30 November 2018 with a focus on the present study in the 12-months prior to DNA collection. All patients provided written informed consent prior to enrollment and data collection (University of Minnesota IRB# 00000756). Patients included non-smokers with a family history of HTN and a history of BP control (<140/<90 for two consecutive office measures). The primary outcome variables included an office BP (averaged from one year of patient visits) and level of BP control using traditional guidelines for patients with and without diabetes (<140/<90) and Systolic Blood Pressure Intervention Trial (SPRINT) guidelines (<120/<80). Primary chart measurements included systolic blood pressure (SBP) and diastolic blood pressure (DBP), and mean arterial pressure (MAP) was calculated. Additional measures included current medications, a detailed hypertension medication history, side effects from previous medications, and medication adherence. Three-years of medical chart data were examined at six-month intervals for BP and medication history to quantify the number of medications needed to obtain BP control and BP control history. Current and past pharmacotherapies were also assessed via chart review. Additional variables included a change in BP measurements from diagnosis to the most recent one-year chart review period.This study was designed and performed in a primarily retrospective manner and included patients within Fairview Health Services , ACE inhibitors (ACEI), angiotensin receptor blocker (ARB), beta-blockers, and Ca2+ channel blockers. Subjects were excluded from participation if one or more of the following conditions were met: a diagnosis of secondary HTN or a complication of pregnancy, currently prescribed and taking any additional class of medication(s) for HTN not included in the inclusion criteria list, and SBP > 140 or DBP > 90 documented within the immediate six months prior to the study visit.All patients enrolled in the study were HTN patients who had their BP under control for at least six months and who had an HTN diagnosis for at least one year. In addition to BP history, demographic information collected included age, sex, height, weight, race, and ethnicity. Inclusion criteria for the study included: 20–85 years of age, patient on the same class/classes of blood pressure medication for a minimum of six months , a body mass index (BMI) between 19 and 45 kg/mADRB1 (rs1801252 and rs1801253), (2) ADRB2 (rs1042713 and rs1042714), SCNN1A (rs2228576), alpha-adducin , SLC12A3 (rs1529927), (3) angiotensin , renin , WNK1 , angiotensin-converting enzyme , angiotensin receptor , and cytochrome P450 2D6 . With the exception of the ACE insertion/deletion (indel) genotype, all genotype polymorphisms were quantified using a two-step process beginning with a multiplex PCR, directly followed by a single base extension (SBE) reaction. The products of the SBE reaction were pooled and subsequently flown on a genomic mass spectrometer  to generate individual genotypes. The ACE indel status was assessed using a standard fluorescently labeled PCR primer set and protocol, followed by fragment analysis via a 3730 DNA analyzer . Pre-characterized Coriell cell line DNAs consisting of all possible genotype combinations were run in parallel for each single nucleotide polymorphism (SNP) as controls. All genotype data in aggregate was also used to compute population allele frequencies which were then confirmed against known existing frequencies in publically available databases .Two buccal swabs were collected for each patient. Cells were first collected via a buccal brush by swabbing the inside of their right cheek repeatedly (for fifteen seconds using moderate pressure) (A-swab). The patient then deposited the swab in 750 µL of lysis buffer consisting of 50 mM Tris pH 8.0, 50 mM EDTA, 25 mM Sucrose, 100 mM NaCl, and 1% SDS to lyse the cells and stabilize DNA during transit prior to extraction. This process was repeated with the left cheek (B-swab) to ensure adequate cell collection necessary to achieve a minimum yield of 500 ng total gDNA for downstream genotyping. Subsequent lysate from buccal swabs was used in DNA isolation via Qiagen DNeasy isolation kits according to the manufacturer’s recommended specifications . Patient isolated DNA was then assayed for 17 functional alleles in 11 genes with known functionality in the heart, kidney, and vasculature: (1) ADRB1, ADRB2, CYP2D6, WNK, SLC12A3, SCNN1A, alpha-adducin, renin, angiotensin, ACE, and the angiotensin receptor). These genotypes were weighted according to previous effect size in the literature  as well as the number and quality of peer-reviewed papers supporting each functional variant. Specifically, the genotypes that had the largest effect  were CYP2D6, both sites of ADRB1, position 27 ADRB2, one site of WNK (rs227869), the alpha-adducin genotype, and two genotypes for angiotensin (rs5051 and rs699) , SLC12A3, SCNN1A, renin, ACE, angiotensin (rs7079), and the angiotensin-II receptor. In addition to weighing based on the ΔBP from the previous literature, genotypes were also weighted based on the strength of the peer-reviewed literature. Genotypes with more peer-reviewed papers were given a higher scoring priority with the assumption that there is more agreement in the functionality, as also summarized in This study builds on our previous work in that we use weighted scoring for each genotype to develop a weighted multi-gene algorithm to determine if a patient would respond to one drug over another. Functional genotypes affecting BP response to pharmacotherapy as identified by current literature were included in the mathematical prediction, including 17 SNPs in 11 genes (d rs699) . FollowiAll data were coded for statistical analysis  and were analyzed with SPSS version 21. Normality of the data was assessed using Levene’s test prior to statistical analysis to assess equality of variance to ensure appropriate statistical methodology. Descriptive statistics were computed  and reported as mean ± standard deviation (SD). Post-hoc correction for univariate analysis of the variance was conducted using Bonferroni analysis. Ordinary least squares regression via univariate modeling was used to estimate the magnitude of linearity between drug classes that yielded the best blood pressure control and those which were mathematically predicted based on the sum of genotypes for the subject. All statistical analyses were considered significant at an alpha level of 0.05.Three hundred and eighty-four subjects met the inclusion criteria, were genotyped, and had complete chart data for review. The distribution of patients currently on the target drug class of each polymorphism is presented in p < 0.05 for SBP and DBP). Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation   and SPRINT guidelines . Howeverand MAP) .In order to better assess the effect of the algorithm on drug response, we calculated the change in BP and HTN control rates in a sub-group of patients on monotherapy . In thisBecause many patients are on more than one pharmacotherapy, we also assessed the response to treatment for patients who matched the drug recommendation one or drug recommendation two from the algorithm. From this analysis, we found that there was no significant difference in the drop in blood pressure between patients matching recommendation one or recommendation two, but that patients who did match were slightly more likely to have their BP under control with the newer SPRINT guidelines  .In this study, we assessed the BP values and hypertension status between HTN patients who matched the top drug recommendation using a multi-gene scientifically-weighted algorithm and those who did not match. Our data suggest that few patients’ (24%) prescribed therapy matched their recommended therapy using the weighted algorithm. However, patients who matched the primary recommendation had a significantly greater drop in BP , from the time of diagnosis to current clinical data, when compared to patients who did not match. Further, the difference between diagnoses to the current one-year average BP was lower in the group that matched the top recommendation. Additionally, for patients on monotherapy, those matching the primary algorithmic drug recommendation were ~50% more likely to have their BP under control using the newer SPRINT guidelines. Interestingly, subjects who matched the first drug recommendation were heavier and tended to exercise less, suggesting the possibility that the findings are rather conservative. Collectively, these data suggest that a multi-gene scientifically-weighted algorithm is more effective in determining BP response and guiding HTN therapy than monogenic therapy alone.1-adrenergic receptor (ADRB1), β2-adrenergic receptor (ADRB2), cytochrome P450 2D6 (CYP2D6), lysine deficient protein kinase (WNK), sodium-chloride symporter (SLC12A3), alpha subunit of the epithelial sodium channel (SCNN1A), alpha-adducin (ADD1), renin, angiotensin, angiotensin-converting enzyme (ACE), and angiotensin receptor variants as playing functional roles in response to HTN therapy [Hypertension is a highly multi-factorial disease modulated by multiple susceptibility genes, suggesting a large genetic determinant to HTN therapy response. Research examining genetic determinants to HTN therapy response have identified βorter SLCA3, alpha therapy ,24,25,26rs7079), the C variant of Angiotensin (rs699), the C variant of the angiotensin-II receptor (rs5186), and the C-5312T variant of REN (rs12750834) have shown improved response to ACEI and Ang II receptor antagonism and decreased risk of stroke and coronary heart disease with therapy [A primary pathway responsible for the modulation of fluid balance and BP maintenance is the renin-angiotensin-aldosterone system (RAAS). Within the RAAS, renin and angiotensin-converting enzyme (ACE) are integral in the formation of angiotensin II (Ang II), the primary product of RAAS and a potent vasoconstrictor . Angiotef REN rs150834 hav therapy ,29,30,69ADRB1, ADRB2). The beta-adrenergic receptors are found primarily in the heart and juxtaglomerular cells of the kidney where they mediate important cardiovascular responses and RAAS activity [+ transport and plays a functional role in fluid volume and BP regulation [+ retention [ADRB1 and ADRB2. Specifically, the Ser49 and Arg389 of ADRB1 (rs1801252 and rs1801253 respectively) and the Arg16 and Glu27 of ADRB2 (rs1042713 and rs1042714 respectively) have demonstrated improved responsiveness to and decreased adverse event risk and mortality with beta-blockade [Additional regulators of RAAS products, integral in BP homeostasis, are the beta-adrenergic receptors  stimulation [+ reabsorption and H2O diffusion across the apical membrane of renal nephrons [SCNN1A is the primary regulator of Na+ flux through ENaC and genetic variations of SCNN1A are associated with BP modulation [+ transport across the luminal plasma membrane, Na-K-ATPase regulates Na+ transport across the basolateral plasma membrane. This suggests that the complex interplay between the Na-K-ATPase and ENaC is an important pathway in fluid volume regulation [−ATPase and subsequently increases renal tubular Na+ reabsorption [ADD1) influencing HTN development risk and diuretic therapy responsiveness [rs4961) has been shown to be more responsive to a diuretic and to halve the risk of myocardial infarction and stroke with BP control [Additional mechanisms of action of aldosterone and Ang II is the modulation of Namulation . The epinephrons ,85. The dulation ,87. Whilgulation . The prisorption ,89,90. Tsiveness . Specifi control ,40.+ reabsorption in the kidneys, including members of the SLC12 family of ion transporters and have vital roles in regulating electrolyte transport and BP [SCL12A is a kidney-specific isoform expressed in the distal convoluted tubule, and the C variant of SLC12A3 (rs1529927) has been demonstrated to be more responsive to diuretic therapy [WNK1 (the kidney-specific isoform) plays a regulatory role in electrolyte transport across renal membranes and epithelia, suggesting a functional role in BP maintenance [WNK1 have been associated with an ~5–6 mmHg variability in BP response to hydrochlorothiazide  [+ and Cl− excretion associated with these variants [Other pathways in fluid volume and BP regulation include ion co-transporters that modulate Nat and BP . These t therapy ,91. Furt therapy . The resntenance ,92,93. F2277869) ,36. Thisvariants .CYP2D6 [CYP2D6 only accounts for 2–8% of all hepatic CYPs, it is responsible for the metabolism of approximately 25% of clinically used drugs [CYP2D6 have been identified as either fully functional (CYP2D6*1) or non-functional (CYP2D6*4). These genetic variations of CYP2D6 have been associated with responsive beta-blocker therapy through differential metabolism. The research has demonstrated CYP2D6*4 carriers to have an up to 5-fold increase in plasma drug levels after beta-blocker therapy [To further understand the influence of pharmacotherapy on BP response, it is necessary to consider pharmacokinetics. The liver is the principal site of drug metabolism, primarily by a class of proteins called Cytochrome P450 (CYP). To date, 12 human CYPs have been identified, including CYP2D6 . While Ced drugs ,95. Two Cumulatively, these data suggest that HTN is a complex, multi-factorial disease comprised of multiple organ systems and pathways. While there is a push towards a “personalized medicine” approach to BP pharmacotherapy, the current clinical treatment strategy is based on a set algorithm which bases its recommendations on drug class and does not differentiate between drug classes . As a reThe influence of the aforementioned genetic variants on BP response to therapy clearly demonstrates the impetus for a multi-gene approach to pharmacotherapy. This study has been built on previous monogenic studies with the inclusion of multiple genotypes in multiple organ systems, and on previous multi-gene studies with the implementation of a weighted, multi-gene algorithm for determining BP response to therapy. The current study demonstrated a significantly greater drop in BP in patients who matched the primary recommendation when compared to patients who did not. Further, the difference between diagnoses to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an algorithm that is weighted based on the strength of previous peer-review studies, is multi-gene in nature and predictive of the BP response to pharmacotherapy compared to the current standard of care, however, prospective trials are needed.The purpose of this study was to assess seventeen common genetic variants in the liver (drug metabolizing enzyme), cardiac, vascular, and renal systems to determine the effectiveness of a weighted multi-gene algorithm on predicting BP response to therapy. We demonstrated an association between a scientifically-weighted multi-gene algorithm and the BP response to pharmacotherapy. From a patient-centric outcomes perspective, this magnitude of the difference is associated with a significant reduction in heart attack and stroke risk. These findings can be applied to improving therapeutic guidance for clinicians based on known functional alterations of the protein through these genetic changes. Based on these findings, clinicians can guide therapy with knowledge specific to their patient, rather than “trial-and-error” based on population data, which will improve therapy efficacy and reduce healthcare costs, adverse events, and time to control BP. Given the retrospective nature of this trial, future randomized trials, which are controlled for the standard of care, are needed.


Reducing intrathoracic pressure in the setting of compromised cerebral perfusion due to acute brain injury has been associated with reduced intracranial pressure and enhanced cerebral perfusion pressure and blood flow in animals. Noninvasive active intrathoracic pressure regulation lowers intrathoracic pressure, increases preload, reduces the volume of venous blood and cerebral spinal fluid in the skull, and enhances cerebral blood flow. We examined the feasibility of active intrathoracic pressure regulation therapy in patients with brain injury. We hypothesized that active intrathoracic pressure regulation therapy would be associated with lowered intracranial pressure and increased cerebral perfusion pressure in these patients.At three institutions, active intrathoracic pressure regulation therapy  was utilized for 2 consecutive hours in five mechanically ventilated patients with brain injury. A 30-minute interval was used to collect baseline data and determine persistence of effects after device use. End-tidal carbon dioxide was controlled by respiratory rate changes during device use. The intracranial pressure, mean arterial pressure, and cerebral perfusion pressure were recorded at 5-minute intervals throughout all three periods of the protocol. Results for each interval are reported as mean and standard deviation.p = 0.005). This effect on intracranial pressure (15 ± 6) was still present in four of the five patients 30 minutes after therapy was discontinued (p = 0.89). As a result, cerebral perfusion pressure was 16% higher during (81 ± 10) compared to before active intrathoracic pressure regulation (70 ± 14) (p = 0.04) and this effect remained present 30 minutes after therapy was discontinued. No adverse events were reported.Intracranial pressure was decreased in all five patients by an average of 21% during (15 ± 4 mmHg) compared to before active intrathoracic pressure regulation (19 ± 4) (These data support the notion that active intrathoracic pressure regulation, in this limited evaluation, can successfully augment cerebral perfusion by lowering intracranial pressure and increasing mean arterial pressure in patients with mild brain injury. The measured effects were immediate on administration of the therapy and persisted to some degree after the therapy was terminated. Brain injury alone is very common and affects three out of every 1000 Americans each year accounting for as many as 60,000 deaths and an estimated 70,000 to 90,000 patients with permanent neurological disabilities . The ecoSeveral mechanisms can cause brain injury: TBI, subarachnoid hemorrhage (SAH), stroke, and intracerebral hemorrhage (ICH) are the most prevalent. Following brain injury, the contents of the intracranial compartment can be compressed due to increased intravascular volume (hyperemia) and tissue edema. Small increases in intracranial volume and the subsequent elevation in intracranial pressure (ICP) that impedes cerebral blood flow (CBF) can be accommodated by the movement of blood and cerebral spinal fluid (CSF) out of the cranium. However, as compensatory mechanisms become overloaded, cerebral circulation becomes compromised. A reduction in cerebral perfusion leads to ischemia, and, therefore, is a significant factor in secondary BI. Cerebral ischemia results in neuronal injury and cerebral edema. Cerebral circulation is generally assessed by measuring the cerebral perfusion pressure (CerPP), defined as the difference between the mean arterial blood pressure (MAP) and the ICP. It has been suggested that CerPP be maintained above 60–70 mmHg to minimize BI and optimize patient survival following brain injury , 6.According to the Brain Trauma Foundation Guidelines, “Hypotension, occurring at any time from injury through the acute intensive care course, has been found to be a primary predictor of outcome from severe head injury for the health care delivery systems within which prognostic variables have been best studied. Hypotension is repeatedly found to be one of the five most powerful predictors of outcome and is generally the only one of these five that is amenable to therapeutic modification. A single recording of a hypotensive episode is generally associated with a doubling of mortality and a marked increase in morbidity from a given head injury” .Reducing intrathoracic pressure (ITP) in the setting of acute brain injury has been previously associated with reduced ICP and enhanced CerPP and CBF in animal models –10. NoniThe purpose of this study was to evaluate the physiological response to application of aIPR in mechanically ventilated patients with compromised cerebral circulation. Adverse events were also evaluated as a measure of device safety. The hypothesis of this interventional study was that the physiological effects of aIPR therapy would improve cerebral circulation in patients with brain injury or intracranial pathology without causing any negative impact on other physiologic parameters.2) ≥ 90% with positive end-expiratory pressure (PEEP) requirement of no more than 7 cmH2O immediately prior to initiation of study aIPR treatment; be hemodynamically stable  or about to undergo neurosurgery with planned placement of an invasive ICP monitor.To be included in the study, patients must: be ≥18 years of age; be intubated and able to be mechanically ventilated on a volume-controlled ventilation mode; be undergoing treatment for a head injury or other intracranial pathology; have a functioning ICP monitor at time of study; present with compromised cerebral perfusion per the attending physician for at least 30 minutes at any point within the past 24 hours prior to enrollment; have an arterial line in place or an alternative pressure measuring device (cuff) with continuous arterial pressure monitoring; have an oxygen saturation ; had respiratory disease, for example, chronic obstructive pulmonary disease (COPD), interstitial lung disease, or other parenchymal or pulmonary vascular disease; had marked hypertension, which was defined as systolic blood pressure (SBP) > 180 mmHg; had heart failure; had a positive serum or urine pregnancy test or breast feeding for women.2) delivered at 40% or < 90% with FiO2 at 100%; ICP increased by > 20% from baseline, resulting in an ICP > 20 that did not resolve within 5 minutes , in the absence of a concomitant increase in CerPP.aIPR treatment was discontinued if: the SBP was > 220 mmHg; the blood oxygen level dropped to < 85% with fraction of inspired oxygen . It was desired that the aIPR be the only treatment during the study. However, at the attending physician’s discretion, patients who were receiving mannitol therapy and patients with pentobarbital coma were included as long as all patient selection criteria were met.Patients were deeply sedated or under general anesthesia during aIPR treatment to prevent spontaneously triggered breathing or spontaneous breathing (not-triggered). Elimination of spontaneously triggered breathing was verified on the ventilator display before start of study and prior to collection of the study hemodynamic data. Neuromuscular blockade was used, as appropriate, at the physician’s discretion.2O. The device utilized in this evaluation generates a negative airway pressure of − 12 cmH2O during the expiratory phase of ventilation between positive pressure breaths [Patients received aIPR treatment with the CirQlator™ , Mercy Hospital , and University of Colorado Hospital .2, and end-tidal carbon dioxide (ETCO2). Three arterial blood gas (ABG) measurements, one draw 2–6 minutes prior to the end of each period , were drawn to measure pH, partial pressure of carbon dioxide in arterial blood (PaCO2), partial pressure of oxygen in arterial blood (PaO2), bicarbonate (HCO3−), base excess (BE), and arterial oxygen saturation (SaO2). Adverse events were also recorded. Anticipated adverse events that were particularly monitored were device failure, sustained (> 30 seconds) relative increase in ICP by > 10 mmHg in the absence of a concurrent or greater rise in CerPP, elevation of absolute ICP to > 30 mmHg (assume ICP at baseline was less than 20 mmHg), sustained (> 30 seconds) decrease in MAP by > 20 mmHg, and reduction in SpO2 to < 90% for > 30 seconds.Patient demographics, relevant clinical history, and type of neurosurgery or neuro-intervention including prior medication, sedation, and neuromuscular blockade, were recorded and summarized in Table The primary study endpoints included measured ICP and MAP with CerPP calculated at the end of each period. Secondary endpoints included times to maximum decrease of ICP and increase of CerPP during each aIPR treatment interval, change in CerPP 30 minutes after removal of the aIPR, and any other changes to hemodynamic or ABG values during aIPR treatment compared to baseline and following removal of aIPR.The timeline of the study is described in Fig. T) was adjusted to 6–8 ml/kg plus ~ 50 ml to account for the dead space of the device in circuit, RR was adjusted to maintain normocarbia (ETCO2 of 35 ± 1 mmHg), and PEEP was set to 0 cmH2O.During the first period, “Before aIPR use” (30 minutes), the aIPR device was set in the patient’s airway circuit but not activated (vacuum source was not engaged), tidal volume , the aIPR device was activated and the vacuum source was adjusted to ensure an airway pressure of − 12 cmHDuring the third and last period, “After aIPR use” (30 minutes), the aIPR device was inactivated but was not removed from the airway circuit. RR was adjusted to maintain normocarbia.2, ETCO2, and ABG values. Statistical analyses were performed with two-tailed paired t-tests with SPSS 21.0 . A p-value of < 0.05 was used to determine that any differences between measurements were not the result of chance alone. The p-values used to compare hemodynamic values are nominal and unadjusted. Values are expressed as means ± standard deviation (SD).The primary study endpoint was CerPP calculated at the end of each period. Other measurements collected and analyzed included BP, MAP, ICP, CerPP, RR, SpOFive participants, with a mean age of 43 ± 15 years, were included in the study, two participants were female. The mechanisms of BI for participants enrolled were TBI (two participants), SAH (one participant), ICH (one participant), and undisclosed brain injury (one participant). Prior to aIPR therapy, three participants received treatment with mannitol. None of the participants had received pentobarbital. ICP monitoring was conducted by intracranial bolt in two patients, external ventricular drain in one patient, ventriculostomy in one patient, and a Camino in one patient. Two patients were receiving neuromuscular blockade.p = 0.005) during aIPR (15 ± 4 mmHg) compared to before aIPR (19 ± 4 mmHg) . The effect was that CerPP was increased in all five patients, resulting in a 16% higher average value during aIPR (81 ± 10 mmHg) compared to before aIPR (70 ± 13 mmHg) (p = 0.04). This effect on CerPP was still present 30 minutes after the aIPR device was turned off (76 ± 14 mmHg) (p = 0.40 compared to aIPR). Even though aIPR was observed to cause an immediate effect once the device was activated, it took 35 minutes for that effect to be statistically different for ICP and 40 minutes for CerPP. The use of aIPR did not provide a statistical change in MAP. The average maximun effect on ICP was reached 62 ± 34 minutes after device activation and 49 ± 30 minutes after activation for CerPP. The effect on ICP and CerPP was maintained throughout the therapeutic interval. Figure aIPR decreased ICP in all patients, resulting in an average ICP that was 21% lower  ratio > 250. Comparative studies focused on histopathology of lung sections in traditionally ventilated pigs compared to pigs subjected to aIPR for 24 hours showed no differences in the level of atelectasis and edema, or lung compliance (unpublished data). These studies also determined that shunting does occur during the highest level of aIPR (− 12 cmH2O), but was limited to approximately 15% compared to traditional positive pressure mechanical ventilation with 5 cmH2O PEEP.In the different studies that have been performed with aIPR, no significant gas exchange abnormalities have been observed, although all studies have been performed on animals and/or patients with uncompromised lungs: PaOThis human translational study has several limitations. The cost of the commercial device has not been established yet and may be a future limitation. We recognize that low enrollment in this study may have been due to the exclusion criteria that limited the recruitment of a significant number of patients with brain injury. In particular, due to the nature of this therapy and its desired effect on ITP there was a necessity to exclude potential participants who presented with cardiac or pulmonary injury impacting ITP and/or cardiac function and participants with respiratory disease, as many patients with brain injury also present with some kind of respiratory injury or can develop lung injury after being placed on a ventilator. In addition, treatment was limited to only 2 hours and duration of compromised cerebral flow is typically substantially longer in head injury. Finally, the exact role of this approach whether it be utilized as a first-line defense, in combination with osmotic agents to reduce ICP, or whether it be utilized as a salvage therapy, has not been determined yet and further study will be necessary.These data support the notion that aIPR, in this limited evaluation of patients with brain injury, can successfully augment CerPP by lowering ICP and increasing MAP in brain injured patients. The measured effects were immediate on administration of the therapy and persisted to some degree after the therapy was terminated.


Previous studies have shown that a variety of biomarkers are closely related to the occurrence and development of early-stage diabetic nephropathy (DN) in patients. The aim of this study was to evaluate the role of multiple sera and urinary biomarkers in the diagnosis of early-stage DN in patients with type 2 diabetes.n = 144), microalbuminuria (n = 94), or macroalbuminuria (n = 49) groups based on their urine albumin to creatinine ratios (UACR), along with 42 healthy controls. We assessed 13 biomarkers, including transferrin (Tf), immunoglobulin G (IgG), podocalyxin, neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-beta-glucosaminidase, α-1-microglobulin, 8-hydroxy-deoxyguanosine, tumor necrosis factor-alpha (TNF-α), and interleukin-18 in urine samples, along with cystatin C, total bilirubin, and uric acid in sera samples, to evaluate their diagnostic roles. From the measurements, the blood neutrophil to lymphocyte ratio was also calculated.We enrolled 287 patients with type 2 diabetes, who were classified into normoalbuminuria  and found that urinary IgG (0.894), NGAL (0.875), Tf (0.861), TNF-α (0.763), and the combination of urinary Tf + IgG + TNF-α + NGAL (0.922) showed good diagnostic value for early-stage DN.Urinary Tf, IgG, NGAL, TNF-α, and the combination of all four biomarkers demonstrated excellent diagnostic value for early-stage DN in patients with type 2 diabetes. Diabetic nephropathy (DN), also known as diabetic kidney disease, is a common and severe microvascular complication of type 2 diabetes that can result in end-stage kidney disease. With the increasing incidence of type 2 diabetes worldwide, DN has become a global health concern . The effCurrently, microalbuminuria is the most widely investigated biomarker for the diagnosis of DN. However, its diagnostic value in early-stage DN is limited as renal injury commonly precedes proteinuria. In a previous study, It has been well-established that glomerular damage, tubular injury, inflammatory responses, and oxidative stress contribute to the development of diabetic kidney disease . In thisn = 144), microalbuminuric (n = 94), and macroalbuminuric (n = 49) based on their urine albumin to creatinine ratios (UACR) of <30, 30–300, and >300 mg/g, respectively.In this cross-sectional study, 287 patients with type 2 diabetes (according to the 1999 WHO criteria) who were hospitalized in the Department of Endocrinology, Second Affiliated Hospital of Anhui Medical University between January 2018 and March 2018, were selected. In the same period, 42 healthy medical volunteers from the Health Management Center of our hospital were selected as the healthy controls. The collection of specimens was completed by the nursing staff, and the samples were submitted to the clinical laboratory of our hospital for analysis. The 287 enrolled patients with type 2 diabetes who were classified as normoalbuminuric .X (where X is a number) in the raw data which were values that were below the detection threshold of our method used to measure biomarker concentrations, the threshold value were used as the estimate in the analysis.Demographic and clinical parameters, including gender, age, duration of diabetes, blood pressure, height, body weight, body mass index, and fundus lesions, were collected. Fasting blood samples were drawn, and hemoglobin A1c (HbA1c) was measured using the HA-8160 HbA1c analyzer . Fasting blood glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL), total bilirubin (TBIL), serum creatinine, cystatin C (CysC), uric acid (UA), neutrophil count, and lymphocyte count were measured using UniCel Dxc 800 biochemical analyzer . The neutrophil to lymphocyte ratio (NLR) and estimated glomerular filtration rate (eGFR) were calculated. The eGFR was calculated using the CKD-Epi formula . The firt-test. Categorical variables were compared using the Wilcoxon rank-sum test or chi-squared test. The multivariate linear regression analysis was used to analyze the correlation between the different biomarkers and UACR. Correlation with UACR was defined if the t-test for the partial regression coefficients were statistically significant in the regression models. Receiver operating characteristic curve (ROC) analysis were used to assess the diagnostic values of each biomarker and the combination of biomarkers, and also to test whether the null hypothesis that biomarker were not indicative of early-stage DN was true. The area under the curve (AUC), sensitivity, and specificity of parameters were calculated based on the ROC. The ROC curve was the plot of all possible pairs of sensitivity and specificity values obtained by scrutinizing all possible values of the cut off. The optimal cut off point with relevant sensitivity and specificity was found where the Youden’s index was maximum . Continuous variables with normal distribution were expressed as mean ± standard deviation, and non-normally distributed data were expressed as median . Differences among the groups were analyzed by the one-way analysis of variance, and comparisons between two groups were analyzed by the Student’s  maximum . P < 0.0P < 0.05 for UA, P < 0.001 for other parameters). The NGAL, TNF-α, and NLR levels in the macroalbuminuria group were higher than those of the healthy control and normoalbuminuria groups (P < 0.001). The NLR levels in the macroalbuminuria group were higher than those in the microalbuminuria group (P < 0.05). TBIL in the macroalbuminuria group was lower than the normoalbuminuria and microalbuminuria groups (P < 0.001). The Tf, IgG, PCX, NGAL, NAG, α1MG, 8-OHdG, TNF-α, IL-18, and NLR levels of patients in the microalbuminuria group were higher than the healthy controls and normoalbuminuria groups . The Tf, PCX, NGAL, NAG, α1MG, TBIL, and IL-18 levels in patients with normoalbuminuria were higher than the healthy controls (P < 0.001 or P < 0.05).The parameters of each group are shown in P < 0.001) (P < 0.001)  . The dia< 0.001)  and the < 0.001) .P < 0.001)  .Diabetic nephropathy is a chronic and progressive kidney disease characterized by microalbuminuria and decreased glomerular filtration rates, which can eventually lead to end-stage renal disease and death. However, its early diagnosis and intervention could allow for the prompt treatment of DN, which would delay the pathological progression of the disease. In this study, we evaluated several potential biomarkers for their diagnostic potential for detecting early-stage DN. The primary finding of this study was that urinary Tf, IgG, NGAL, and TNF-α levels, both individually and in combination, are valuable biomarkers for assessing early-stage DN in patients with type 2 diabetes.While some highly sensitive and specific biomarkers were previously identified for the diagnosis of DN , this stGlomerular damage leads to increased urinary excretion of plasma proteins, such as Tf, IgG, and PCX . Tf is aRenal tubular injury is a critical characteristic of DN . UrinaryOxidative stress is one of the mechanisms for DN . 8-OHdG Diabetic nephropathy is a low-grade inflammatory disease , yet thiUsing the ROC analysis, four biomarkers  showed diagnostic value in terms of high AUC, in type 2 diabetic patients with DN. Urinary IgG showed a high specificity of 92.3%, yet the sensitivity was relatively low. Similarly, urinary NGAL was highly sensitive but suffered from its low specificity. Further analyses revealed the combination of these four biomarkers had better diagnostic value, in terms of AUC values, than those of the biomarkers individually. The AUC was as high as 0.922 for the combined biomarkers, indicating a superior value in the detection of early-stage DN.In conclusion, this study found that urinary Tf, IgG, NGAL, and TNF-α levels may be used as biomarkers for the diagnosis of early-stage DN in patients with type 2 diabetes. However, the combination of these four biomarkers showed higher sensitivity and specificity in comparison to the biomarkers when used individually. The four biomarkers assessed in this study are involved in glomerular damage, tubular injury, and inflammation, respectively, which represents different aspects of the pathogenesis of DN. The combined use of these novel biomarkers may improve the detection of early-stage DN. However, further studies using larger sample sizes should be performed to establish the diagnostic value of other biomarkers for detection of early-stage DN.10.7717/peerj.7079/supp-1Supplemental Information 1Raw data showed gender, age, blood pressure,BMI,FBG,TC,TG,LDL, TBIL,Scr,CysC,eGFR,UA,NC,LC,NLR,HbA1c,Tf,NAG,IgG,α1MG,Ucr,PCX,NGAL,8-OHdG,TNF-α,IL-18and UACR index of all the participants in the Healthy controls.Click here for additional data file.10.7717/peerj.7079/supp-2Supplemental Information 2Raw data showed gender, age, duration of diabetes, fundus lesions,blood pressure,BMI,FBG,TC,TG,LDL,TBIL,Scr,CysC,eGFR,UA,NC,LC,NLR,HbA1c, Tf,NAG,IgG,α1MG,Ucr,PCX,NGAL,8-OHdG,TNF-α,IL-18and UACR index of all the participants in the normoalbuminuria group.Click here for additional data file.10.7717/peerj.7079/supp-3Supplemental Information 3Raw data showed gender, age, duration of diabetes, fundus lesions,blood pressure,BMI,FBG,TC,TG,LDL,TBIL,Scr,CysC,eGFR,UA,NC,LC,NLR,HbA1c, Tf,NAG,IgG,α1MG,Ucr,PCX,NGAL,8-OHdG,TNF-α,IL-18and UACR index of all the participants in the microalbuminuria group.Click here for additional data file.10.7717/peerj.7079/supp-4Supplemental Information 4Raw data showed gender, age, duration of diabetes, fundus lesions,blood pressure,BMI,FBG,TC,TG,LDL,TBIL,Scr,CysC,eGFR,UA,NC,LC,NLR,HbA1c, Tf,NAG,IgG,α1MG,Ucr,PCX,NGAL,8-OHdG,TNF-α,IL-18and UACR index of all the participants in the macroalbuminuria group.Click here for additional data file.


Previous studies have demonstrated that high-dose allopurinol is able to regress left ventricular (LV) mass in cohorts with established cardiovascular disease. The aim of this study was to assess whether treatment with high-dose allopurinol would regress LV mass in a cohort with essential hypertension, LV hypertrophy and well-controlled blood pressure but without established cardiovascular disease.We conducted a mechanistic proof-of-concept randomized, placebo-controlled, double-blind trial of allopurinol (600 mg/day) versus placebo on LV mass regression. Duration of treatment was 12 months. LV mass regression was assessed by Cardiac Magnetic Resonance. Secondary outcomes were changes in endothelial function (flow-mediated dilatation), arterial stiffness (pulse wave velocity) and biomarkers of oxidative stress.P = 0.012). Oxidative stress markers (thiobarbituric acid reactive substances) were significantly higher in the allopurinol group versus placebo . Other markers of vascular function were not significantly different between the two groups.Seventy-two patients were randomized into the trial. Mean baseline urate was 362.2 ± 96.7 μmol/l. Despite good blood pressure control, LV mass regression was significantly reduced in the allopurinol cohort compared with placebo (LV mass −0.37 ± 6.08 versus −3.75 ± 3.89 g; Treatment with high-dose allopurinol in normouricemic controlled hypertensive patients and LV hypertrophy is detrimental. It results in reduced LV mass regression and increased oxidative stress over a 12-month period. This may be because of an adverse impact on redox balance. Cohort selection for future cardiovascular trials with allopurinol is crucial. Essential hypertension is an established risk factor for cardiovascular disease. Furthermore, left ventricular hypertrophy (LVH), which is highly prevalent in treated hypertensive patients  is an inThus, the main aim of this study was to assess whether high-dose allopurinol could regress left ventricular mass (LVM) in a cohort with essential hypertension and LVH but well-treated blood pressure. The secondary aim was to assess the effect of allopurinol on LV volumes, markers of circulating oxidative stress, endothelial function and arterial stiffness in this patient group.The study was a single-centre, randomized, double-blind, placebo-controlled mechanistic proof of concept trial with 12 months’ follow-up between 2014 and 2017. The study treatment was allopurinol 600 mg/day, given as 300 mg twice per day or twice daily placebo. The primary objective of the study was to assess LV mass regression after 12 months using cardiac magnetic resonance (CMR). It was approved by the Tayside Research Ethics Committee and was carried out in accordance with the declaration of Helsinki. EudraCT: 2014-002083-33. ClinicalTrials.gov: NCT02237339.2 for men and more than 95 g/m2 for women  were acquired from the atrio-ventricular ring to the apex using the vertical and horizontal long axis of the left ventricle as a guide. The short-axis imaging parameters were repetition time (TR) of 2.5 ms, echo time (TE) of 1.1 ms, flip angle (FA) of 60°, and slice thickness 6 and 4 mm gap.Cardiac MRI was performed on a 3T MAGENTOM Trio-PrismaAnalysis was performed offline by trained observers (C.R.G. and S.J.G.) blinded to the study allocation using Argus software . Using the short-axis stack ‘region-of-interest’ contours were placed around the left ventricular endocardial and epicardial borders at end diastole and at end systole to calculate left ventricle ejection fraction (LVEF), left ventricular mass (LVM), end-diastolic (LVEDV), end-systolic (LVESV) and stroke volumes (LVSV). The base and apex were labeled and frames with at least 50% full thickness myocardium were included in the LVM. Papillary muscles were also included in the LVM if the muscle was contiguous with the myocardial wall. Each scan was analyzed twice to ensure consistency, a third measurement was conducted if the LVM varied by more than 5%.Endothelial function was assessed by measuring flow-mediated dilation (FMD) of the brachial artery using a Sequoia 512  and an 8-MHz linear array ultrasound probe. Measurements were conducted at baseline and 12 months according to the International Brachial Artery Reactivity Task Force guidelines  by a sinPulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months by a single investigator (C.R.G.) blinded to study allocation. Measurements were recorded with a SphygmoCor  machine using a high fidelity micromanometer.Blood was collected at the baseline and final visit and analysed for uric acid , N-terminal pro B natriuretic peptide , high sensitivity C-reactive protein , N-terminal pro b-type natriuretic peptide , thiobarbituric acid reactive substances  and sST2 .t test or Mann–Whitney U test, categorical variables were analysed by the chi-squared test. Comparison between arms of the trial was assessed by the regression coefficient for the treatment arm with the final visit LVM as the dependent variable and baseline LVM, baseline BP and sex as covariates in a general linear regression model. All statistical analysis was undertaken using SPSS software version 22 . A P value less than 0.05 was considered statistically significant.Using data from previous LVH regression studies conducted at our unit ,6 powereThe primary end-point was to assess whether allopurinol regressed left ventricular mass (LVM) in hypertensive patients with controlled blood pressure. Secondary end-points assessed a change in other LV MRI parameters , parameters of endothelial function and vascular stiffness , biomarkers , left atrial MRI parameters  and BP.In total, 72 participants were recruited  or BP changes all yielded consistent results with the primary analysis.There was no statistically significant difference seen in FMD, PWV and PWA between the two treatment arms Table .Baseline blood pressure, number of antihypertensives  and prescribed major classes of antihypertensives was similar between both groups at baseline and remained so throughout the trial. Both cohorts had consistently controlled blood pressure at baseline  and at the end of the trial period . Overall, there were three serious adverse events that required hospital admission; however, all were unrelated to the study medication. Of the three participants who withdrew because of side effects in the allopurinol arm, two developed nausea and one had a rash.The main finding from this study is that over a 12-month period, allopurinol treatment adversely impacts on the LV mass regression expected with good blood pressure control in patients with hypertension and LVH. Indeed, the expected LVM regression with time because of good blood pressure control was actually reduced in the allopurinol cohort compared with the placebo cohort. We also found that, unlike cohorts with preexisting cardiovascular disease, CKD or diabetes, endothelial function and vascular stiffness did not improve with high-dose allopurinol in this cohort.Allopurinol has been shown to regress LVM in different cohorts along the cardiovascular spectrum –6 with sThe results of this present study is consistent with the findings of the Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial where those with uric acid levels of less than 565 μmol/l (9.5 mg/dl) showed a trend towards worsening compared with those with uric acid levels greater than 565 μmol/l . The datIt is widely accepted that LVH regression occurs with time in patients whose blood pressure is well controlled and this has been confirmed in meta-analysis and systematic reviews of the available trial data ,16 and iMyocardial hypertrophy is known to be triggered by reactive oxygen species (ROS) and oxidative stress ,8,18,19.The lack of LVM regression in this present cohort, unlike other cohorts we have previously studied, suggests that reducing uric acid in normouricemic patients but without established vascular disease, and therefore low-background oxidative stress or inflammation could tip the anti-oxidant pro-oxidant balance negatively and cause detriment.This might be an explanation for our findings as uric acid is the most abundant naturally occurring aqueous antioxidant in humans and contributes as much as two-thirds of all free radical scavenging capacity in plasma ,21. UricWe stress that the results of this study is a preliminary indication of a possible mechanism. Further in-depth research is required to evaluate if indeed a redox imbalance directly results in a reduction in LV mass regression. This study suggests that reducing uric acid had a detrimental impact on redox balance and of ROS levels and myocardial structure, consistent with findings of previous trials, such as FREED , CARES  and OPT-This is a single-centre study. Screening for LVH was done by echocardiogram by a qualified echocardiographer. Due to the cost of CMR, it was not used as a screening tool. However, LV mass regression was determined by cardiac MRI, the current gold standard modality for this purpose. Reassuringly, the baseline CMR-determined LV mass was comparable with previously published studies on LV Mass regression on other cohorts –6.As the results of this study contrast with the beneficial effect of allopurinol in LVH regression seen in patients with IHD, type 2 diabetes and CKD, we acknowledge that there is always a possibility that the results of this study may have occurred by chance. However, the lack of LVM regression is consistent with results in all other CMR, vascular stiffness and endothelial function measures we studied. Furthermore, the worsening of oxidative stress burden seen with the TBAR levels, although a secondary outcome, and therefore not powered, lends support to the findings.In conclusion, this study, in conjunction with previously published data, including the OPT-CHF trial , CARES  and FREEAuthor contributions: A.D.S. and J.G. conceived the idea for the study. A.D.S., J.G., S.J.G., T.M.M., C.C.L. and J.G.H. designed the study. C.R.G., R.S. and S.J.G. performed research. S.J.G., P.T.D. and C.R.G. analyzed the data. All authors contributed to the writing of the manuscript.Sources of funding: This study was funded by a grant from the British Heart Foundation (PG/13/67/30444). This trial was supported by the Tayside Clinical Trials Unit.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02237339;ISRCTN number: ISRCTN40476871.https://www.clinicaltrialsregister.eu/. Unique identifier: 2014-002083-33.EUDRACT: A.D.S. and the University of Dundee have applied for a patent on the use of xanthine oxidase inhibitors to treat angina pectoris. All other authors have no conflicts of interest.


BackgroundNormal tension glaucoma (NTG) is a clinical entity that poses a diagnostic and therapeutic challenge. The study elaborates ocular and systemic risk factors of NTG in the South Indian population. It determines the correlation between risk factors and severity of glaucomatous damage.MethodsThis descriptive study was done on 81 eyes of 41 patients. A brief history of hypertension, heart disease, migraine, and family history of glaucoma were noted. The parameters measured include blood pressure, lipid profile, visual acuity, refraction, intraocular pressure (IOP) by applanation tonometry, diurnal variation, slit lamp biomicroscopy, central corneal thickness (CCT), and perimetry (Humphrey 24-2).ResultsThe mean age was 51.75 years. There was female predilection (63.41%). Thirteen patients (32.5%) had hypertension, five (12.5%) had migraine, and seven had hyperlipidemia (17.5%). Perfusion pressure demonstrated a negative correlation value of -0.319  with visual field defects (p<0.05) and -0.266  with glaucomatous cupping (p=0.093). The IOP varied from 10 mmHg to 19 mmHg with a mean of 15.34. The average CCT was 522.06±36.09 microns. Neuroretinal rim thinning was seen in 12 eyes (14.8%), polar notching in six eyes (7.4%), and peripapillary atrophy in 20 eyes (24.6%). Two eyes (2.4%) had splinter hemorrhage at disc margin. A lower value of CCT was associated with lower IOP, a weak positive correlation . Optic disc cupping is strongly associated with severity of field defects, r value 0.743, (p<0.00).ConclusionNormal tension glaucoma is common in females. Hypertension and lower diastolic perfusion pressure are important risk factors. Lower CCT is associated with lower IOP (applanation tonometry). Optic disc cupping and diastolic perfusion pressure strongly correlate with severity of visual field defects. Glaucoma is the second common cause of blindness worldwide. One-third of patients with primary open angle glaucoma (POAG) are reclassified as normal tension glaucoma (NTG) . NTG is A cross-sectional study was done on 41 outpatients (81 eyes) attending the glaucoma clinic for two years at a tertiary care hospital. Ethical clearance was obtained from the institutional ethics committee. Informed consent was obtained from all patients.The inclusion criteria were a mean intraocular pressure (IOP) ≤ 21 mmHg (Goldmann applanation tonometry) on diurnal testing, open angles on gonioscopy, typical optic disc changes, and characteristic visual field defects. The exclusion criteria were patients with secondary cause for optic neuropathy , corneal opacity, previous intraocular surgery, contact lens wearers, corneal edema, corneal astigmatism >2D and those with other optic nerve abnormalities or intracranial disease.Preliminary demographic data of patients were noted. A brief history of hypertension, heart disease, haemodynamic crisis , family history of glaucoma, and migraine were noted. Blood pressure was measured and fasting lipid profile was done. The ocular examination included visual acuity (Snellen’s chart), refraction, tonometry (applanation), slit lamp examination, fundus examination , optic disc fundus photography, and CCT by ultrasonic pachymetry.Optic disc cupping, neuroretinal rim thinning, disc hemorrhage, peripapillary atrophy, focal notching, nerve fiber layer defects, and laminar dot sign were examined. Patients were subjected to diurnal variation test. Field evaluation was done using Humphrey field analyzer (24-2). A second visual field report of every patient was taken for analysis accounting for consistency of findings and the patient’s learning curve. Visual field defects were analyzed using Anderson’s criteria and graded accordingly.Eighty-one eyes of 41 patients were studied. The mean age in the study group was 51.75 [standard deviation (SD -10.91)] years. Twenty-six (63.41%) patients were females and 15 (36.59%) patients were male.Systemic risk factorsThirteen patients (32.5%) were hypertensive. Other risk factors were distributed as shown below Figure .Twenty patients (48.78%) had systolic blood pressure ≤110 mmHg, and 21 (51.21%) patients >110 mmHg  patients had ocular perfusion pressure (derived by subtracting intraocular pressure from diastolic blood pressure) below 50 mmHg. Perfusion pressure had a negative correlation (rho) value of -0.319 (p<0.05). The correlation is statistically significant and suggests worsening of visual field with decreasing perfusion pressure. Cup to disc ratio also had negative correlation with perfusion pressure, with rho value of -0.266 (p=0.093) The intraocular pressure (Goldmann applanation tonometry) varied from 10 mmHg to 19 mmHg with a mean IOP of 15.34 mmHg (±2.65 mmHg). Forty eyes (49.38%) had IOP >15 mmHg and 41 eyes (50.61%) <15 mmHg.Central corneal thickness (CCT)About 50% eyes had CCT between 500 to 550 microns. Twenty-three eyes (28.39%) and 19 eyes 23.45%) had corneal thickness between 451 to 500 microns and 551 to 610 microns, respectively  had a cup to disc ratio between 0.6 and 0.7. Seventeen eyes (20.9%) had a cup to disc ratio ≤ 0.5 and 14 eyes (17.2%) had a cup to disc ratio ≥ 0.8 . Six eyes (7.4%) had notching, and 20 eyes 24.6%) had peripapillary atrophy. Two eyes (2.4%) in this study had splinter hemorrhage at the disc margin  had normal fields. Minimal and early field defects were seen in 10 (12.3%) and six eyes 7.4%), respectively. Moderate defects were seen in 27 eyes (33.3%), and severe field defect in 17 eyes (20.9%). Three eyes (3.7%) had field defects close to fixation. Localized defects were seen in four eyes (4.9%) with focal notching of neuroretinal rim. Arcuate defects were seen in six (7.4%) eyes of which three (3.7%) had superior arcuate and three (3.7%) had inferior arcuate defects. Double arcuate scotoma was seen in two (2.4%) patients. Twenty-eight eyes (34.5%) had field defects predominantly in the superior hemifield  and cup: disc ratioCCT and cup to disc ratio have a positive correlation with Pearson’s coefficient  of 0.130. The correlation has no statistical significance as the p value is 0.248   and intraocular pressure (IOP)The measured IOP and CCT demonstrated a positive correlation. The Pearson’s correlation coefficient  is 0.121. The level of significance (two tailed) is 0.282. With increasing CCT, there may be a false high measurement of intraocular pressure by Goldmann applanation tonometry Figure .Correlation of central corneal thickness and visual field defectCCT and visual field loss have a weak positive correlation by bivariate analysis with an ‘r’ value of 0.133 (Spearman’s rho coefficient) Figure .Correlation of cup: disc ratio and visual field defectCup to disc ratio has a strong positive correlation with visual field defect. The correlation coefficient “r value” is 0.743 (‘p’ <0.00). Hence the correlation is statistically significant Figure .Correlation between IOP, cup to disc ratio, CCT, and visual field defectsThe effect of IOP, cup to disc ratio, and CCT in predicting the severity of visual field loss is analyzed using linear regression analysis. The beta coefficient and level of significance are tabulated Figures -13.The most significant parameter affecting visual field defects is the severity of optic disc cupping. The β coefficient value is 0.703 with ‘p’ value of 0.000, suggesting that the visual field defect deteriorates with increasing cupping Table .Diagnosis of normal tension glaucoma (NTG) depends on ophthalmoscopic signs and field defects in the absence of other explanations for disc abnormality and visual field loss. This clinical entity poses a challenge for ophthalmologists and forces us to think about pressure dependent and pressure independent causal factors. The theories that explain the pathogenesis of NTG are mechanical and vascular theories, explained by structurally weak lamina cribrosa and vasospasm compromising optic nerve head perfusion. Vascular factors explain optic nerve head damage caused by migraine, Raynaud’s phenomenon, and smoking .The collaborative normal tension glaucoma study group (CNTGS) has shown that intraocular pressure is a part of the pathogenic process of NTG . Raised Age distributionThe mean age in the study group was 51.75 ± 10.91 years, which corresponds to the study done by Nana Meng et al. with a mean age of 51.9 ± 9.56 .Sex ratioIn this study, 63.41% of subjects were females, the ratio being 1.8:1 . Similar female preponderance was reported by Fang EN et al. (60%) and Goldberg et al.  ,11.Family historyIn this study, positive family history was noted in one patient (2.5%). Zeiter JH et al. showed positive family history in 5-40% and Nana Meng et al. in 10% ,12. GoldSystemic risk factorsFang EN et al. found vascular risk factors to be significantly higher in patients with NTG and POAG . MoreoveIn this study, diastolic perfusion pressure had an inverse correlation with visual field defect, which was statistically significant. Dada T et al. studied 113 eyes of NTG patients and proved that a larger circadian mean ocular perfusion pressure (MOPP) fluctuation was significantly associated with decreased mean deviation, increased pattern standard deviation, increased AGIS (Advanced Glaucoma Intervention Study) score and reduced neuroretinal rim area [In the Baltimore Eye Survey, a diastolic perfusion pressure < 30 mmHg carried a six-fold higher risk. A diastolic perfusion pressure < 53 mmHg conferred a 2.2 times greater risk in the Barbados Eye Studies ,14. In tThe Early Manifest Glaucoma Trial showed cardiovascular risk factors to significantly affect long-term disease progression. Baseline predictive factors were lower ocular systolic perfusion pressure (≤160 mmHg), cardiovascular disease in patients with a higher baseline IOP, and lower systolic blood pressure (≤125 mmHg) in patients with lower baseline IOP .Pillunat LE et al. hypothesized that generalized vascular disease may lead to NTG. He showed that there is lack of autoregulation in optic nerve head circulation only in NTG whereas Anderson suggested defective autoregulation in POAG and NTG .In this study, seven patients 17.5%) had hyperlipidemia. Chumbley LC et al. reported hyperlipidemia in 41.5% NTG and 18% of POAG .5% had h.Hypotension aggravates visual field loss but hypertension may be protective till the onset of hypertensive vascular disease, which becomes a risk factor in its own right . In thisTreatment of hypertension, rather than the disease itself, is a risk factor for progression of glaucoma. Nocturnal dip in blood pressure augmented by nocturnal antihypertensives, is the major vascular risk factor defined . In thisDisc hemorrhage is a vasospastic sign and is found to have a higher prevalence in NTG. This suggests that local circulatory changes within the optic nerve head are involved in the pathogenesis of NTG .Optic disc cuppingKamal D et al. performed an analysis on a group with NTG, POAG, and ocular hypertension to determine any significant disc morphology and found advanced neuroretinal rim loss and peripapillary atrophy in NTG. In this study, 12 (14.8%) patients had neuroretinal rim thinning. Acquired optic disc pit was more frequent in NTG . Levene Caprioli J et al. showed that the degree of field defect is related to the peripapillary atrophy  . Twenty Disc hemorrhage was observed in two patients 2.4%) in this study. Studies have reported disc hemorrhage to be more common in NTG. Drance et al. reported disc hemorrhage in 24.4% of NTG .4% in th. Kamal DIntraocular pressure (IOP)Intraocular pressure is a risk factor linked with the development and progression of glaucoma. This modifiable risk factor, if reduced to lower levels, provides us with a therapeutic option.Cartwright MJ et al. analyzed 14 cases of NTG with asymmetrical IOP and found that the eye with higher IOP suffered more severe glaucomatous cupping and visual field loss . Though Kamal D et al. showed that an average reduction from 18 to 10 mmHg correlated with a significant slowing of progressive visual field loss .The Normal Tension Glaucoma Study investigated the effect of 30% reduction of intraocular pressure on the rate of visual field progression. Zeiter JH et al. showed that a 25% lowering of IOP is essential to prove effective in slowing the rate of field loss .Central corneal thickness (CCT)The mean CCT (CCT) in this study is 522.06 ± 39.06 microns. This is lower than the average CCT of 534 (±30 microns) in glaucoma patients reported by Thomas R et al. He reported an average CCT in NTG in the South Indian population as 517 microns, which was slightly lower than the study group .Ventura ACS et al. found the mean CCT to be thinner (518 ± 0.5) in NTG than in ocular hypertensives (563 ± 29), POAG (515 ± 35), and normals 524 ± 25) . In a st . In a sThe positive correlation between CCT and intraocular pressure has been well demonstrated in this study. The influence of scleral rigidity and CCT on intraocular pressure was first discussed by Goldmann and Schmidt. Copt R et al. postulated that Goldmann applanation tonometry yields accurate measurements only around 520 microns. The average error evoked by thicker or thinner cornea was 0.7 mmHg per 10 micron deviation from a “normal” value of 520 . The intThe Early Manifest Glaucoma Trial demonstrated that glaucoma progression was lessened by 10% for every mmHg decrease in IOP. So adjustments in intraocular pressure for decrease in CCT may alter a patient’s risk for visual field progression. POAG patients with thinner CCT may need closer follow-up and more aggressive treatment .Visual field defectsLevene RZ et al. noted a higher frequency of dense defects extending to within five degrees of fixation in NTG (92%) than POAG (20%) . In thisIn this study group, superior hemifield defects were seen in 28 eyes (34.5%). Chumbley LC et al. reported a higher percent of subjects (84%) with superior hemifield defects .Kim JW et al. showed visual field progression in 53% at three years and 62% at five years, proving a linear mode of field progression in NTG . NoureddNormal tension glaucoma is more common in females. Systemic risk factors are closely associated with the severity and progression. A lower central corneal thickness is associated with lower intraocular pressure measurement on Goldmann applanation tonometry. Optic disc cupping and diastolic perfusion pressure correlate with the severity of visual field defects. Assessment of risk factors and determination of correlation of risk factors with glaucoma progression may provide us with a newer therapeutic strategy. NTG is a clinical entity where substantial research is indicated to define patient characteristics and to correlate risk factors with severity of glaucomatous damage.


Multivariate linear regression revealed that donor age, donor gender, and recipient eGFRdischarge  better predict eGFR1year than AoAC combined with recipient eGFRdischarge . During 1-year follow-up, four (10.81%) patients experienced cardiovascular events, which were predicted by PWV ratio , but not related to AoAC score . In conclusion, KTR without previous vascular events have quite low cardiovascular/CVE rate within 1-year follow-up. VC evaluated as AoAC on pretransplant chest X-ray together with recipient eGFRdischarge could be related to kidney function in one-year follow-up.Vascular calcification (VC) is linked to post-transplant cardiovascular events and hypercalcemia which may influence kidney graft function in the long term. We aimed to evaluate whether pretransplant aortic arch calcification (AoAC) can predict post-transplant cardiovascular or cerebrovascular events (CVEs), and to assess its association with post-transplant plasma calcium levels and renal function in one-year follow-up. Our single-center observational prospective study enrolled 37 kidney transplant recipients (KTR) without previous history of vascular events. Two radiologists evaluated pretransplant AoAC on chest X-ray as suggested by Ogawa et al. in 2009. Cohen’s kappa coefficient was 0.71. The mismatching results were repeatedly reviewed and resulted in consensus. Carotid-femoral (cfPWV) and carotid-radial pulse wave velocity (crPWV) was measured using applanation tonometry before and one year after transplantation. Patient clinical, biochemical data, and cardiovascular/CVE rate were monitored within 1 year. We found out that eGFR Kidney transplantation (KT) is the most effective treatment method for patients with end-stage renal disease (ESRD) that increases life expectancy , but theInterrelationship between aortic calcification and aortic stiffness ,14, a haThe pathogenesis of VC could involve either the intima layer, linking to inflammation and atherosclerosis, or the media layer, causing vascular stiffness . VasculaMany present prospective observational studies focus on evaluation of coronary artery calcification , but theSingle-center observational prospective study of 60 deceased KT recipients was performed in Vilnius University Hospital Santaros Klinikos between November 2015 and December 2016. Only 37 of them  were eligible for the further investigation. Each participant should have been older than 18 years, without previous history of CVEs (ischemic stroke), cardiovascular events and diseases  and without clinically evident peripheral artery disease . All 37 KT recipients who met the inclusion criteria were studied before KT, at the day of discharge from hospital and after a median 12 months follow-up. One patient died within first month of observation. All procedures performed in this study were performed with all the subjects’ written informed consent and were in accordance with the ethical standards of the Lithuanian Bioethics Committee and with the 1964 Helsinki declaration and its later amendments.Our study did not influence the choice of initial or maintenance immunosuppressive treatment. Induction therapy was considered when necessary according to immunological risk  and included methylprednisolone, basiliximab, or antithymocyte globulin. All patients received standard maintenance triple therapy which consisted of calcineurin inhibitor (cyclosporin A or tacrolimus), mycophenolate mofetil and methylprednisolone and had stable kidney graft function 6 months after kidney transplant.2 (kg/m2). Blood tests were drawn at the time of admission to the hospital for KT, at the time of discharging from hospital after successful KT and after one-year follow-up. They included white blood cell count, hemoglobin, platelet count, creatinine, urea, calcium, ionized calcium, phosphorus, parathormone, albumin, total cholesterol, uric acid, and C-reactive protein (CRP). The estimated glomerular filtration rate (eGFR) was calculated based on the modification of diet in renal disease (MDRD) equation: eGFRdischarge – based on creatinine level at the time of discharging from hospital and eGFR1year – based on creatinine 1-year after KT. Data about cardiovascular events within follow-up were also calculated. Cardiovascular events were defined as primary end-point. Bearing in mind, that eGFR is a predictor of long-term kidney graft function, we decided to determine the factors which could forecast the eGFR1year.Demographic and clinical data about age, gender, cause of kidney failure, hypertension, time on dialysis, type of dialysis, donor and recipient cytomegalovirus (CMV) serostatus and prescribed antihypertensive and maintenance immunosuppressive regimen were collected from medical records and interviews with patients. We measured body height and weight and calculated body mass index (BMI) by using formula weight/height® N Sphygmomanometer, Jungingen, Germany ) on the arm without arterio-venous fistula and average value was recorded. Central BP, mean BP, heart rate, pulse pressure, carotid-femoral pulse wave (cfPWV) velocity and carotid-radial pulse wave velocity (crPWV) were determined using applanation tonometry  as previously reported [Before KT, systolic and diastolic blood pressure (BP) were measured by trained medical doctor for three times, with 2 min interval, in supine position after 15 min resting with manual BP monitor  3.3.2 version.Continuous data were expressed as mean ± SD and discrete data as median. Categorical variables were presented as numbers with percentages in parenthesis. For normally distributed continuous data, an Baseline characteristics of the whole study population as well as according to evidence of AoAC are listed in p = .001), had significantly higher body height , higher end systolic BP , brachial diastolic and central diastolic BP , higher brachial mean and central mean BP , higher crPWV , lower PWV ratio . There was no significant difference in time on dialysis before KT between groups.The mean age of 37 participants was 46.94 ± 11.95 years, two (11.8%) patients had diabetes, 32 (86.49) were with hypertension, 12 (32.43%) with higher than 6.2 mmol/L total cholesterol, seven (18.92%) on peritoneal dialysis and the rest on hemodialysis. Patients without evident calcification were significantly younger , central systolic BP , central diastolic BP (100.21 vs. 89.98 p = .007), cfPWV  was observed. There was no significant difference in brachial or central diastolic BP  nor in crPWV  (results not listed in a table).Comparing BP and vascular parameters before and 1-year after KT, significant decrease in brachial systolic BP  and negatively with transplant rejection episodes and donor age . There was no significant correlation with pretransplant PWV ratio or AoAC score. In multivariate linear regression after application of stepwise model selection, two models independently correlated with eGFR1year: Model 1 with donor age, donor gender and recipient eGFRdischarge and Model 2 with evident AoAC and recipient eGFRdischarge  patients had worsening KT function. In the univariate linear regression, eGFRischarge . When cop = .007) and PWV ratio  predict cardiovascular events. AoAC score had no predictive value . Similarly, the other traditional cardiovascular risk factors showed no significant impact on CVE prevalence in study population. We did not perform multivariate Cox-regression analysis due to small sample size and quite low event rate.In our study, we also collected data about cardiovascular or CVEs in posttransplant period. During one-year follow-up, four (10.81%) participants experienced CVE: two myocardial infarctions, one pulmonary artery embolism, and one stroke. Therefore, the rate of CVE was 7.6 cases per 1000 person-days. Univariate Cox-regression  revealedIt is the first study analyzing pretransplant AoAC not only in the context of cardiovascular/CVEs, but also as predictor of kidney graft function.The prevalence of VC in kidney transplanted patients is reported to be ranging 24 and 80% . In our Comparing to the general population, cardiovascular disease plays more pivotal role in KT recipients, due to annual cardiovascular events risk of 3.5–5% . DespiteVascular calcification is pathophysiologically related to inflammation, atherosclerosis, and vascular stiffness, which are usually observed in patients with ESRD . We analDeLoach et al. have reported association of CRP with aortic calcification in kidney transplant recipients (KTRs), however, it has not proved by all studies ,46. Our discharge independently correlates with recipient eGFR1year, but has worse descriptive value than recipient eGFRdischarge combined with donor age and gender. Unfortunately, we did not measure urine calcium level and had no information about urine volume changes in our patients. Further research is needed to define the predictive role of AoAC progression to eGFR change and prognosis.Abnormal bone and mineral metabolism tends to persist in most KTRs, even though a successful KT improves regulatory hormones levels and excretion of accumulated waste products and electrolytes . The preThe limitations of this current research include small size of study population, which together with low number of cardiovascular events are related to weak statistical power in predicting the impact of AoAC and arterial stiffness on cardiovascular outcomes. This may be explained by enrollment of participants without previous history of cardiovascular/CVEs. On the other hand, it may represent better understanding of KT role in VC and its related outcomes. Future studies with larger sample sizes would be necessary to determine the interrelationship between AoAC, measured by more accessible in clinical practice and cost-effective X-ray, kidney function and cardiovascular events after KT with longer observation period.In conclusion, AoAC is prevalent among kidney transplanted patients, but there is lack of evidence that pretransplant AoAC could predict early cardiovascular outcomes and decline of graft function in patients without previous history of cardiovascular/CVEs. Arterial stiffness and inflammation markers might be considered to have predictive value, but more data are needed for further risk stratification in renal transplant recipients.


To study the effects of different positive end expiratory pressure (PEEP) on blood pressure and heart function in elderly patients with hypertension.n = 18) and a hypertension group (n = 22) patients with essential hypertension. Changes in blood pressure, central venous pressure (CVP), central venous oxygen saturation (ScvO2), heart rate, and airway pressure were determined in response to different selected PEEP levels of 0, 2, 4, 6, 8, 10 and 12 cm H2O under SIMV(PC) + PSV mode throughout the study.Forty elderly patients above 65 years of age treated with mechanical ventilation were divided into two groups: a control group of non-hypertensive subjects (2O in the hypertension group, a decrease in blood pressure and ScvO2, and an increase of heart rate were observed. These results indicated that cardiac output significantly decreased.In both groups, the increase in PEEP led to an increase in CVP and airway pressure. When PEEP was above 4 cm HHigh levels of PEEP can significantly influence changes in blood pressure and heart function in elderly patients with hypertension.ChiCTR-ROC-17012873. The date of registration is 10-2-2017.This trial was retrospectively registered, The Chinese trial registration number is  The number of elderly patients with essential hypertension is increasing annually at a rapid rate worldwide , 2. Rece2) and consumption (VO2). The most often used bedside parameter to assess the relationship between oxygen supply and consumption is central venous oxygen saturation (ScvO2) [2 decreases under low oxygen supply conditions as in occurs during low cardiac output, decreased hemoglobin, decreased arterial oxygen saturation, or in cases of increased oxygen demand that occurs with shivering, fever, agitation, and hypermetabolic state [2 is associated with cardiac output.Multiple methods exist for the measurement of cardiac output. However, accurate measurement of cardiac output, such as that obtained using a SwanGanz catheter and cardiac color ultrasound requires advanced instrumentation. Another important factor for hemodynamic stability is the balance between oxygen delivery (DO (ScvO2) , 7. ScvOic state , 9. TherElderly hypertensive patients have poor cardiorespiratory function and often require ventilator assisted breathing . As far This study aimed to explore the effects of different PEEP levels on blood pressure and heart function in elderly patients with hypertension, and to minimize the adverse effects of PEEP on hemodynamics.2, heart rate (HR), and airway pressure were determined in response to different selected PEEP levels of 0, 2, 4, 6, 8, 10 and 12 cm H2O. Each PEEP level exposure lasted 2 h. The researchers were blinded to patient treatment conditions. If a significant decrease in blood pressure and an obvious decrease of peripheral oxygen saturation (SpO2) were noted, the study was terminated to ensure patient safety. No patients withdrew from the study.For all selected patients, the SIMV (PC) + PSV ventilator mode  was utilized to assist breathing. The tidal volume was controlled (10 ml/kg) to maintain pulmonary oxygenation and promote carbon dioxide exhalation, as well as the inhalation time (1.2 s), and respiratory frequency (18 times/min). Oxygen concentration maintenance at 40% made the peripheral oxygen saturation more than 95%. All patients underwent radial artery puncture and subclavian venous catheter. Phlegm was removed from the airway, and subjects were placed at a comfortable 30° half supine position with infusion speed regulated at 40–50 drops/min. Midazolam 0.05 mg/kg/h was used to limit spontaneous breathing. Tidal volume was maintained relatively constant, and changes in blood pressure, central venous pressure (CVP), ScvOn = 18) and a hypertension group of patients (n = 22) with essential hypertension , mean airway pressure (Pmean), tidal volume (VT) and minute ventilation volume (MV).To ensure that the subclavian vein catheter  was located in the superior vena cava, the position of the catheter was confirmed by bedside X-ray or CT. The subclavian vein catheter was connected to a multi-parameter cardioelectric monitor  to measure CVP. Extraction of 1.5 ml central venous catheter blood was used by blood gas analysis  for ScvOHypertension was defined as systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg under sufficient sedation during mechanical ventilation without man-machine confrontation and/or the self-reported use of antihypertensive medication in the previous 2 weeks .t test, analysis of variance (ANOVA), Mann–Whitney test, or Kruskal–Wallis test was utilized depending on their distribution and number of variables. Correlation was analyzed by Pearson correlation analysis. Confounding factors were controlled by multiple linear regression analysis. Statistical significance was considered at P < 0.05.We determined the sample size for the study using statistical analysis software, NCSS PASS. All data were presented as mean ± SD or median (interquartile range) as indicated by data distribution tested by the Shapiro-Wilk test. To compare data between groups, a P < 0.05). There were no statistically significant differences in age, triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterin (LDL-C), fasting plasma glucose (FPG), hemoglobin (HB), or body temperature (T) between the two groups (P > 0.05). When PEEP was 0 cm H2O, there was also no statistically significant difference in CVP between the groups (P > 0.05).Descriptive characteristics are summarized in Table P > 0.05). In the hypertension group, when PEEP was below 4 cm H2O, blood pressure was also unaffected by PEEP (P > 0.05). However, when PEEP was above 4 cm H2O, this increase in PEEP led to an decrease in blood pressure (P < 0.05) , DBP , and MABP . Using multiple linear regression analysis to control confounding factors, the results showed that with the increase of controlling factors, the negative correlation between PEEP and blood pressure still existed . With an increase in controlling factors, a positive correlation between PEEP and CVP was still observed (Table 2 were unaffected by PEEP (P > 0.05). In the hypertension group, when PEEP was less than 4 cm H2O, HR and ScvO2 were also unaffected (P > 0.05). However, when PEEP was above 4 cm H2O, an increase of HR and a decrease of ScvO2 were observed  and negatively correlated with ScvO2 . Using multiple linear regression analysis to control confounding factors, the correlation between PEEP and HR, ScvO2 still existed  and Pmean . Using multiple linear regression analysis to control confounding factors, a correlation between PEEP and airway pressure was still observed  . Elevati2 can be used to evaluate the condition of left cardiac ejection, which is simple and reliable and can be used in clinical application [2, with higher ScvO2 corresponding with increased cardiac output [2 to reflect left cardiac ejection.In our study, we found that the increase in PEEP led to an increase in CVP but a decrease in cardiac output. Studies assessing fluid status have shown that CVP monitoring is as effective, and safer, than more invasive means such as pulmonary artery occlusion pressure . It is clication . A studyc output . As such2O could have maximal impact on improving oxygenation, and minimize its impact on hemodynamics. However, due to the limited patient source, the appropriate PEEP value setting should be confirmed by the large sample multicenter clinical study.For elderly hypertensive patients, this study showed that PEEP of approximately 4 cm H2 shows obvious advantages, which can be used to predict cardiac preload under mechanical ventilation. For elderly patients with hypertension, low levels of PEEP have less effect on blood pressure and cardiac output, while higher levels of PEEP can significantly affect blood pressure and cardiac output. Therefore, the effects of PEEP on the hemodynamics of elderly patients with hypertension should be taken into consideration.Traditional static index CVP cannot accurately reflect changes in cardiac preload with positive pressure ventilation, though ScvO


Objective: To assess the relationship between free testosterone level and components of MS in women with PCOS. Materials and methods: This is a cross-sectional study which was conducted on 215 women with PCOS. PCOS was diagnosed based on the Rotterdam criteria. Patients were divided into two subgroups of patients with and without MS based on ATP III criteria. In each subgroup, the association between individual components of MS with free testosterone was measured. Data were analyzed using SPSS software.Results: The prevalence of MS was 28.8% (n = 62). The mean level of free testosterone in patients with blood pressure ≥ 130/85 was significantly higher than those with blood pressure < 130/85 mm/hg. (p = 0.029) Also, in patients with diastolic blood pressure ≥ 85, the level of free testosterone was significantly higher than patients with diastolic blood pressure < 85. (p = 0.026). Results showed significant positive correlation between the level of free testosterone and cholesterol (p = 0.024). But no significant correlation was noted between levels of free testosterone and other variables.Conclusion: Regarding the relationship between blood pressure and high levels of free testosterone, it seems that regular blood pressure screening has a higher priority of concern comparing other complications for preventing cardiovascular adverse effects in women with PCOS and hyperandrogenism. Polycystic ovarysyndrome (PCOS) manifests as anovulation, oligomenorrhea and hyperandrogenism with the prevalence of 5-10% in women of childbearing age  , 2. Clinical hyperandrogenism  or laboratory hyperandrogenism , and 3.Morphological features of PCOS in ovarian ultrasound  .After the necessary explanations, informed consents were obtained. Age, weight and height were measured and recorded for all patients. BMI was calculated by dividing weight by squared height. Waist circumference was measured by a tape meter from the top surface of iliac crest and just below the umbilicus. Hip circumference was measured in the horizontal plane and it was measured at the widest part. Systolic and diastolic blood pressure were measured in the sitting position after 10 minutes rest.Patients with PCOS were divided into two subgroups of patients with and without MS based on ATP III criteria. Criterion of having the MS  was the Waist circumference ≥88 cm, triglycerides ≥ 150 mg/dl, HDL < 50 mg / dl, diastolic blood pressure ≥ 85 mm Hg and systolic blood pressure ≥ 130 mm Hg, and fasting glucose ≥100 or taking diabetes medication.Women with hypothyroidism (TSH > 5), hyperprolactinemia ( serum prolactin ≥ 100ng/ml), congenital adrenal hyperplasia, androgen producing tumor, Cushing's syndrome, diabetes mellitus, and kidney disease were diagnosed by physical examination and assessment of TSH, PRL, 17α-OHP, TG, Cholesterol, HDL, LDL and FBS were excluded.Finally, in each of these subgroups, the association between individual components of MS with free testosterone was measured.Statistical analyses: Data were analyzed using SPSS software version 21. Using independent t-test, mean testosterone levels between the patients with and without MS were analyzed. The difference between mean levels of testosterone among different components of the MS including waist circumference, blood pressure, fasting blood sugar, triglyceride levels and HDL levels were analyzed using independent t-test. Using the Pearson correlation coefficient, correlation between testosterone levels and anthropometric and laboratory parameters were evaluated. P.value < 0.05 indicated statistical significance and 95% confidence interval was noted.In this study, 215 patients with PCOS were assessed. The prevalence of MS was 28.8 percent (n = 62). The mean age of participants was25.63 ± 5.17. Most of the participants lived in urban area, were housewives and had academic education. There was no significant difference between groups regarding all variables except the family history of diabetes (p = 0.043) . In reviewing the components of MS in all participants (215 patients), results showed that 72.6 % (156) had waist circumference ≥ 88 cm, 9.3%  had blooThe mean testosterone level in patients with and without MS was not significant, however comparing with its components; mean free testosterone was significantly related with diastolic blood pressure and hypertension. Whereas in patients with diastolic blood pressure ≥ 85, the level of testosterone was significantly higher than patients with diastolic blood pressure < 85 (p = 0.026). Also, the mean level of testosterone in patients with blood pressure ≥ 130/85 was significantly higher than those with blood pressure < 130/85 mmhg. (p = 0.029). There was no significant difference between other components of MS and free testosterone level .Results showed significant positive correlation between the level of free testosterone and cholesterol (p = 0.024). But no significant correlation was noted between levels of free testosterone and other variables .One of the most common disorders in women with PCOS is MS, which increases the risk of cardiovascular disease and diabetes. PCOS women consistently had higher risk of developing MS compared to others. The prevalence of MS of Thai women was 18% and Apridonize et al mentioned 43%as the prevalence of MS in women with PCOS which was about twice higher than the 24% in NHANES population , 18.Also, Mandrella et al and Rahmanpour et al mentioned 37.5% and 33.3% as the prevalence of MS, respectively , 20. It Also, PCOS significantly indicated as a significant health problem due to the higher prevalence of MS in women with PCOS, the overlap between metabolic and anthropometric disorders, and the association between MS and subsequent long-term increased risk of type 2 diabetes and cardiovascular disease.The results of this study showed that comparing demographic variables between PCOS women with and without MS, 50.8% of patients with MS had a family history of diabetes. Also, 19.4% of women with PCOS had fasting sugar ≥ 100 which was higher than women without MS. However, no significant difference was noted between free testosterone and blood sugar which would be as a result of the exclusion criteria and the mentioned 19.4% belonged to Glucose intolerance. Studies showed that women with diabetes had higher level of free testosterone comparing women without diabetes. Therefore, reduction in the sex hormone binding globulin (SHBG) and high levels of free testosterone are accepted for the occurrence of diabetes type 2 and highlights the relationship between androgens and insulin sensitivity.Reports revealed that free testosterone even in non-diabetic patients had a significant relation with hyperinsulinemia and hyperglycemia which are the components of MS and supported the androgen roles in the regulation of glucose homeostasis. There are several mechanisms that may link androgens and insulin resistance. Abdominal obesity by conversion of and rostenedione to testosterone by 17 beta-hydroxy steroid oxidoreductasecan itself cause hyperandrogenism, decrease in sex hormones binding globulin and increase the amount of free testosterone .Previous Studies confirmed the relationship between MS and insulin resistance and hyperandrogenism. They mentioned high levels of androgens as a marker to identify MS . In a stAlthough in this study, no statistically significant difference was noted between the mean testosterone levels in patients with and without MS, in a review article by Muraleedharan et al inconsistent results were noted . They reForrestar et al also demonstrated that MS in women with PCOS was not affected by hyperandrogenism. Because according to the diagnostic criteria for NIH which compared four high testosterone, moderate testosterone, high testosterone in obese and normal testosterone in thin participants, t-test noted no significant difference in glucose, lipid profile, LH and FSH, prolactin, and blood pressure .Moulana et al observed that MS was associated with the occurrence of insulin resistance, dyslipidemia, hypercholesterolemia and diabetes type 2. Also, obesity and MS in men and women were associated with an increased risk of cardiovascular disease and hypertension. In men, obesity and MS associated with reduced level of testosterone and in obese women with MS, the increased level of testosterone and the activity of inflammatory cytokines were observed . OreillyAlso Munzker et al mentioned higher levels of total and free testosterone and DHT in patients with PCOS compared with the control group. They also observed that the TT / DHT in patients with PCOS were significantly higher in women with obesity, MS, glucose intolerance, and insulin resistance. In this study, TT / DHT has been noted as a good marker to assess severe metabolic outcomes in patients with PCOS .Yet there is uncertainty about the normal androgens limit, the selected androgens, and techniques used to analyze it . The mos In the relationship between testosterone with components of MS, results showed that the mean free testosterone levels was significantly related with diastolic blood pressure, high blood pressure and cholesterol levels in people with MS. In patients with diastolic blood pressure ≥ 85 and also with blood pressure ≥ 130/85, significantly higher testosterone levels were noted and with increasing levels of testosterone, cholesterol levels increased. However, inconsistent result was noted by Huisman et al . They noEvidence from animal and clinical studies showed that testosterone had beneficial effects on vascular reactions, inflammation, lipid concentration, and hemostatic factors and can affect cardiovascular health. According to the prevalence of MS in women with PCOS and its association with atherosclerotic diseases, it is predicted that it might induce 7 times increased risk of cardiovascular diseases in this group of women .In the present study, there was a significant correlation between free testosterone level and cholesterol, so that by increasing testosterone levels, increased cholesterol levels were noted and vice versa. Velasco et al also mentioned high prevalence of hypercholesterolemia (26%) . Since, Regarding the relationship between blood pressure and high levels of free testosterone, it seems that regular blood pressure screening has a higher priority of concern comparing other complications for preventing cardiovascular adverse effects in women with PCOS and hyperandrogenism.In our study by increasing in testosterone level, cholesterol and blood pressure were increased in women with PCOS and MS. It can be confirmed that high levels of androgens are sensitive indices to predict MS in women with PCOS.