The ORS-treated group trended toward having a lower DBP than control, but there was no significant difference. Blood urea nitrogen (BUN) and serum creatinine (Cr) were not different between the ORS-treated and control groups . The percentage of renal tissue affected by tubulointerstitial fibrosis was significantly lower in the ORS-treated group (1.68 ± 0.60) compared to controls . These findings suggest that treatment with ORS reduces SBP and ameliorates renal damage in SHR.Oryeongsan (ORS), a traditional medicine used to regulate body fluids, has a long history of use as a diuretic in Korea, China, and Japan. ORS is commonly thought to lower blood pressure, but high-quality data on its effects are sparse. The purpose of this study was to determine the antihypertensive and renal protective effects of ORS in rats with hypertension. Spontaneously hypertensive rats (SHR) were divided into two groups with similar mean baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP). Then, 10 mL/kg of vehicle (distilled water) or 200 mg/kg of ORS extract were administered orally once a day for 3 weeks. SBP and DBP were measured at weeks 1, 2, and 3. At the end of the experiment, blood was collected, and kidneys were removed for histology. By the 2nd and 3rd week after initiation of treatment, the ORS-treated group had significantly lower SBP than control-treated rats (191.3 ± 6.5 vs. 206.3 ± 9.8 mmHg,  Hypertension is a leading risk factor of death from cardiovascular and chronic kidney disease. Indeed, lowering blood pressure is the most effective way to prevent stroke and slow the progression of hypertensive renal disease . DespiteThe medicinal herbs required to formulate ORS were purchased from Kwangmyungdang Medicinal Herbs Co. in Korea and authenticated by the Department of Prescription, College of Korean Medicine, Woosuk University. The formula of ORS was based on the Chinese Pharmacopoeia , and theThis study was conducted in compliance with Good Laboratory Practice (GLP) regulations and was approved by the KPC Labs Institutional Animal Care and Use Committee (protocol P172005). Male spontaneously hypertensive rats  were purchased from Charles River Laboratories Japan, Inc. . The rats were individually housed in standard laboratory cages at standard temperature (21–24°C), humidity (45–60%), and lighting conditions (12 h light/dark) with free access to rodent chow and water.When they were 10 weeks old, the rats were distributed into two groups according to systolic blood pressure (SBP) and diastolic blood pressure (DBP), creating a similar average baseline blood pressure in both groups . Each trAt the end of 3 weeks, the rats were anesthetized with isoflurane, and 10 mL blood was collected from the abdominal aorta . The right kidneys were removed, and one slice of the middle transverse section from each kidney was fixed in 10% buffered formalin solution and then embedded in paraffin. The remaining portion of each kidney was stored at −70°C until protein extraction.Blood pressure was measured on the 7th, 14th, and 21st day after the start of treatment. Measurements of SBP and DBP were repeated three times for each animal, and the mean value was recorded. The animals were allowed to rest for at least 15 minutes at 30°C before blood pressure was measured. Blood pressure was measured by a tail-cuff using a BP-2000 series II instrument .Blood samples were centrifuged for 10 minutes at 6,000 rpm at 4°C. Blood urea nitrogen (BUN) and creatinine (Cr) were measured using DRI-CHEM-4000i .μm thick sections and then stained with periodic acid-Schiff and trichrome according to common methods. Glomerular injury was measured by determining the sclerosis index [Paraffin-embedded kidneys were sectioned into 4-is index . Every gt-tests using SPSS 26.0 . Comparisons resulting in p values <0.05 were considered significant.Data collected during the study were expressed as mean ± SD. Statistical analysis was performed with independent p = 0.022 at 2nd week; 195.8 ± 7.8 vs. 217.0 ± 8.1 mmHg, respectively, p = 0.003 at 3rd week). During the 2nd and 3rd week, the ORS-treated group showed a trend toward lower DBP than the control group, but there was no significant difference  was similar . One week after treatment, the ORS-treated group showed a nonsignificant trend toward a lower SBP (194.1 ± 18.3 mmHg) relative to control (209.0 ± 7.8 mmHg). On the 2nd and 3rd week after treatment, the ORS-treated group had significantly lower SBP than control   .p = 0.127) meaning that, in this animal model, hypertension did not cause significant injury. However, the percentage of tissue area with evidence of tubulointerstitial fibrosis was significantly smaller in the ORS-treated group (1.68 ± 0.60) than in the control group  (Figures The glomerular sclerosis index was generally very low in both groups (0.00 ± 0.0 in ORS-treated group vs. 0.01 ± 0.01 in control,  Figures .n-butanol, the major components of A. orientale and P. cocos, were found to increase urine volume and electrolyte excretion [P. umbellatus extract increased urine volume and electrolyte excretion by inhibiting the mRNA expression of aquaporin 2 and vasopressin 2 receptors, which are involved in resorption of water in the kidney [A. macrocephala also exhibited a diuretic effect by inhibiting the mRNA expression of aquaporin 2 [C. cassia, is related to blood pressure regulation, and it exhibited a vasodilatory effect by inhibiting the influx and release of Ca+ through an endothelial independent pathway [ORS is composed of five medicinal herbs, each of which is known to have a diuretic or antihypertensive effect. In each animal experiment, ethyl acetate and xcretion , 16. In e kidney . A. macraporin 2 . Cinnama pathway . Studies pathway . In the  pathway . SHRs ar pathway . In the  pathway . The dos pathway . In one  pathway . On the  pathway . Thus, t pathway , 26. Hyp pathway . The eva pathway . Althoug pathway . The ren pathway .Together, our findings suggest that ORS is effective in reducing SBP and ameliorating renal damage in SHR. Furthermore, these studies provide new evidence supporting the renal protective effects of ORS in SHR. One main limitation of this study was that we could not determine whether ORS acted via a diuretic effect. Future research should clarify the mechanisms by which ORS lowers blood pressure and should directly compare its effects against other diuretic agents.


An observational clinical study to evaluate the effect of phenylephrine infusion on maternal temperatures during scheduled cesarean delivery under spinal anaesthesia was conducted in 40 ASA physical status II parturients. Following placement of spinal anesthesia, phenylephrine infusion was initiated at 40 μg/min and titrated to maintain mean arterial pressure within 20 percent of baseline. Maternal oral temperature, heart rate, and blood pressure were measured at baseline, spinal placement, every 10 minutes thereafter for 60 minutes. Phenylephrine dose received was documented every ten minutes. The range in maternal temperature change was 0.06–0.29°C. The lowest recorded temperature was 36.3°C. Decreased maternal temperature was associated with duration of anesthesia and cumulative phenylephrine dose in a univariate model . The multivariable model showed an association between a greater decrease in maternal temperature with larger doses of phenylephrine being administered. Heat is stored in the body in two compartments: core and peripheral. Normal core temperature averages 37°C with peripheral temperatures measuring 2°C cooler. Thermoregulatory mechanisms with an interthreshold range of 0.2–0.4°C maintain temperature in awake patients . During In the perioperative setting, hypothermia has been identified as an independent risk factor for adverse outcomes. It has been linked to elevated transfusion requirements due to coagulopathy, impaired wound healing, higher infection rates, prolonged postoperative recovery, adverse cardiac events with increased oxygen consumption, increased postoperative nausea and vomiting, shivering, and worse patient comfort scores ,5,6. Des1-adrenergic receptor agonist, did demonstrate a reduction in intraoperative hypothermia in elective orthopedic cases under spinal anesthesia [In the United States, Cesarean delivery is the most common indication for laparotomy with a rate greater than 31.3% –12. For esthesia . To our Our hypothesis was that a continuous infusion of phenylephrine would decrease the degree of intraoperative hypothermia during Cesarean delivery under subarachnoid anesthesia. The primary outcome of this study was the change in maternal temperature and secondary endpoints included the incidence of shivering, nausea and emesis, blood loss, and surgical site infection.Ethical approval for this study was provided by the Institutional Review Board for Human Research and Office of Research Integrity of the Medical University of South Carolina, Charleston, SC (Vice-Chairman Steven Swift) on 3 January 2012.Following IRB approval, forty parturients underwent written informed consent and were enrolled in this observational, prospective study with patient enrollment from April 2012 to June 2013. Inclusion criteria included non-laboring parturients 18 to 40 years old scheduled for Cesarean delivery with spinal anesthesia. Exclusion criteria included ASA physical status score of III or greater, thyroid disease, Raynaud’s syndrome, autonomic neuropathy, hypertensive disease of pregnancy, preeclampsia, BMI greater than 35, and non-English speaking.One liter of lactated Ringers solution was co-loaded, over 15 minutes, via free drip using 10 gtt/mL IV tubing with open roller clamp, through a fluid warmer set at 40°C during spinal anesthesia placement  in an operating room maintained between 25–26°C. Following subarachnoid injection, a phenylephrine infusion was initiated at 40 μg per minute and titrated to maintain mean arterial pressure (MAP) within 20% of baseline throughout the case. Patients were positioned supine with left uterine displacement. Loss of discrimination to cold temperature was used to determine level of anesthetic block and additional warm blankets housed in a warmer set at 50°C were provided based on patients’ comfort. Data on maternal oral temperature was noted by sublingual measurement using a Welch-Allyn SureTempPlus 692 digital temperature probe. Heart rate and blood pressure were collected at baseline and every ten minutes following spinal placement for sixty minutes. Phenylephrine dose received was documented every ten minutes. The incidence of maternal hypotension, bradycardia, patient’s endorsement of nausea, witnessed episodes of vomiting, shivering, blood loss , and wound infection were also recorded to analyze as secondary outcomes. Hypotension and bradycardia were defined as a decrease of 20% from baseline. Nausea and vomiting was documented either as absent or present. Shivering was documented using the Bedside Shivering Assessment Scale (BSAS) from 1 to 4: (1) None: no shivering noted on palpation of the masseter, neck or chest wall; (2) Mild: shivering localized to the neck and/or thorax only; (3) Moderate: shivering involves gross movement of the upper extremities (in addition to neck and thorax); (4) Severe: shivering involves gross movements of the trunk and upper and lower extremities . Chart rA sample size of 40 patients was calculated to detect a correlation of 0.43 with 80% power (α=0.05). Additionally, our multivariate model that included 4 covariates from 40 patients is consistent with Harrell’s rule of thumb that at least 10 observations per predictor are needed to prevent over-fitting for multivariable modeling ,16 of a Change in maternal temperature, maternal heart rate, and maternal mean arterial pressure were analyzed using linear mixed regression models accounting for repeated measures on each subject. First order auto-regressive, heterogeneous auto-regressive, compound symmetry and unstructured covariance structures were considered and the best structure selected by comparing Akaike information criterion (AIC) and Bayesian information criterion (BIC) for each model. Secondary outcomes included estimated total blood loss, occurrence of shivering during the procedure, and occurrence of nausea or vomiting during the procedure. The association between cumulative phenylephrine dose before PACU and blood loss was examined using Pearson’s correlation. The Mann-Whitney U test was used to determine association between cumulative phenylephrine dose before PACU and nausea/vomiting or shivering. All analyses were conducted in SAS v. 9.3 Data were collected on 40 patients between April 2012 and June 2013.Collected data on maternal temperature, change in temperature, heart rate, mean arterial pressure, and phenylephrine dose administered are presented in Univariate associations for change in maternal temperature were examined . MaternaChange in maternal temperature was also examined in a multivariable model . A greatThe predicted decrease in maternal temperature over time associated with an increasing dose of phenylephrine is shown in P=0.486 and 0.388 respectively). Receiving a higher cumulative phenylephrine dose was found to be associated with increased blood loss (P=0.018). A 100 μg increase in cumulative phenylephrine dose before PACU was associated with a 10 mL increase in estimated blood loss.Secondary endpoints are presented in This investigation suggests that concomitant administration of phenylephrine during Cesarean delivery under spinal anesthesia is associated with a decreased magnitude of perioperative maternal hypothermia. Although maternal temperature did decrease, it was limited to a temperature change of no more than 0.29°C with none of the patients reaching temperatures less than 36.3°C.1 receptor activation. Our study is the first to investigate the effect of phenylephrine on maternal temperature during Cesarean delivery under spinal anesthesia and the results suggest that phenylephrine used during Cesarean delivery for maintenance of MAP may have an added beneficial effect on decreasing the magnitude of redistribution hypothermia.Redistribution as a cause of hypothermia occurs primarily during the first hour of surgery . The shoThe multivariable model associated the greatest decrease in maternal temperature to larger doses of phenylephrine being administered earlier in the delivery process . HoweverP=0.644). In addition to coagulopathy, other studies have linked hypothermia to complications such as increased surgical site infections with delayed wound healing [Increasing emphasis has been placed on avoiding intraoperative hypothermia due to the significant morbidity associated with its presence. Winkler et al.  reported healing . There wOther secondary endpoints evaluated during this study included nausea, vomiting, and shivering. The incidence of nausea for subjects was 10%. Previous studies have reported rates of nausea as high as 80% and attributed this to hypotension, visceral pain and stimulation, vagal hyperactivity, use of uterotonic agents, and IV opioid administration . With reThere are limitations to consider. First, there was not a control group due to the necessity to treat hypotension following spinal anesthesia. Other considerations include the lack of standardization of total IV fluids administered, IV flow rate, and absence of defined core body temperature monitoring. Additionally, we are not able to prove cause and effect with an observational study.In conclusion, limited studies have addressed the issue of perioperative hypothermia during Cesarean delivery. Common interventions employed to prevent hypothermia during Cesarean delivery have included pre-warming the patient prior to surgery, intraoperative warmed intravenous fluids and forced air-warming; unfortunately, these interventions have not proven consistently effective . This st


To correlate optical coherence tomography (OCT) measurements with clinical parameters in idiopathic intracranial hypertension (IIH).  A cross-sectional study was conducted with 22 patients with IIH and 11 controls. All participants underwent comprehensive ophthalmological examination followed by spectral-domain OCT (SD-OCT) and standard automated perimetry using the 30–2 program of the Humphrey visual field analyzer. Correlations between ganglion cell complex (GCC) thickness and retinal nerve fiber layer (RNFL) thickness, as measured by SD-OCT, and clinical parameters were assessed using generalized estimating equations. p=0.001 and p=0.038, respectively). The GCC was significantly thinner in the IIH group, with a mean of 90.535 ± 9.766 μm compared to 98.119 ± 6.988 μm for the controls (p=0.023). There was a significant association between GCC thickness and optic disc pallor (p=0.016) and between edema and visual acuity (p=0.037). No significant difference was found in RNFL thickness between patients and controls.  The mean age of the participants was 35.0 ± 10.83 years. The groups were similar regarding age, but were significantly different regarding sex and visual acuity ( The GCC was thinner in the patients with IIH compared to the controls, and there was an association between GCC and optic disc pallor. This might suggest a role for OCT parameters when the structural changes that occur in IIH are investigated, possibly guiding clinical decision making. Idiopathic intracranial hypertension (IIH) is a clinical condition of uncertain etiology characterized by high intracranial pressure (ICP) in the absence of expansive or vascular lesions, enlargement of the cerebral ventricles, or focal neurological signs except for sixth nerve palsy , 2. IIH Papilledema refers to optic disc swelling caused by intracranial hypertension. In general, it is bilateral, but may be asymmetrical. Papilledema probably results from increased perineural pressure with subsequent axonal swelling in the optic nerve head . A correSince use of the Frisén classification in IIH for rating the severity of papilledema involves some limitations , furtherDepending on the specific parameter to be evaluated and the characteristics of the study population, sensitivity for detecting damage according to the best performing RNFL parameters has been reported to range from approximately 60% to 98%, with specificity ranging from 80% to 95%. In fact, although sectoral RNFL parameters may increase the likelihood of detecting localized RNFL damage, the reproducibility of these parameters is often poor, as mean measurements refer to only relatively small areas. On the other hand, mean global RNFL thickness has generally been shown to be the most reproducible parameter, which is not surprising considering that its calculation involves mean measurements over a relatively large area. The gain in reproducibility, however, may come at the potential cost of missing some localized RNFL defects, particularly in cross-sectional evaluations. Nonetheless, even for the detection of localized RNFL defects, global RNFL thickness measurements still appear to perform at least as well as sectoral parameters, suggesting that the improved reproducibility may overcome the limitation of using mean measurements taken over a large area. In recent years, attention has increasingly been directed towards the macular region for the evaluation of glaucomatous damage. As a large proportion of total macular thickness is composed of RNFL and ganglion cell bodies, this region is an attractive area to identify structural damage caused by the disease. The macular retinal ganglion cell layer contains more than 50% of the ganglion cells of the entire retina (18). However, to the best of our knowledge, no study has yet been conducted in which macular and peripapillary ganglion cells are investigated in patients with IIH and then correlated with clinical findings.Therefore, the purpose of the present study was to evaluate the correlation between OCT assessments of RNFL thickness and ganglion cell complex (GCC) thickness and the clinical findings in patients diagnosed with IIH.This cross-sectional study was conducted in compliance with the requirements laid out in the Declaration of Helsinki. The internal review board of the Federal University of São Paulo approved the study protocol under reference UNIFESP/EPM-CEP 2418003. All the participants signed an informed consent form prior to their inclusion in the study. The complete Excel database generated in this study is provided in the supplementary data file to support the present findings.A total of 22 patients with IIH and 11 controls were included in the study. A review of their medical history was conducted, and all the participants underwent a comprehensive ophthalmologic examination that included a visual acuity test, slit-lamp biomicroscopy, intraocular pressure measurement (Goldmann tonometer), gonioscopy with Possner goniolens, and dilated fundoscopic examination with a 78-diopter lens. In addition, the participants were submitted to standard automated perimetry (SAP) using the 30–2 program of the Humphrey visual field analyzer  and underwent OCT according to the methodology described below.Participants in the IIH group had to be between 18 and 60 years of age with signs and symptoms of generalized intracranial hypertension or papilledema, documented elevated intracranial pressure with an opening pressure ≥25 cmH2O ; normal cerebrospinal fluid (CSF) composition; no evidence of hydrocephalus, tumor mass, or vascular injury at magnetic resonance imaging (MRI) or computed tomography (CT), and normal neurological examination except for sixth cranial nerve palsy.The participants of the control group were selected from the general community. Controls had to be between 18 and 60 years of age, with a corrected visual acuity ≥20/40, no ocular or systemic disease that could affect the visual field or alter the optic nerve, RNFL, or GCC; absence of opaque media; a current intraocular pressure <21 mmHg, and no previous history of elevated intraocular pressure, intraocular infection, eye surgery, or trauma. In addition, controls should have a normal optic disc.The exclusion criteria for both groups were age <18 years or >60 years, any concomitant physical or psychiatric diseases, other eye diseases, and refusal to sign the informed consent form. Individuals with coexisting retinal disease or nonglaucomatous optic disc neuropathy and those for whom the spherical equivalent was 5.0 diopters or greater were also excluded from the study.The exams conducted with standard automated perimetry were performed in a dark room with 1-lux ambient lighting level. While one eye was tested, the other was occluded.The perimeter used was the Humphrey Field Analyzer II  with the Swedish Interactive Threshold Algorithm-Standard (SITA-Standard). The assessment was performed in the central 30° of the patient's visual field, with a Goldmann size III white light stimulus. Only participants with reliable tests were included in the study. The test reliability applied the following criteria: loss of fixation ≤20%, and false positives and false negatives ≤15%. Visual fields with the following artifacts were excluded: evidence of border and eyelid artifacts, effects of inattention or fatigue, or damage to the visual field caused by a disease other than IIH.μm), the ganglion cell layer (μm), and the internal plexiform layer (μm) were evaluated. The peripapillary RNFL was evaluated using the fast RNFL thickness protocol. The fast RNFL scans consisted of three peripapillary scans (256 A-scans each) with a diameter of 3.4 mm, calculated by estimating the distance between the ILM and Bruch's membrane in a cylinder of 6 mm in diameter using the segmentation algorithm contained in the device software. The 3D optic nerve head (ONH) scan was performed using a custom protocol with 145 slices (B-scans), focusing the ONH with a scanning angle of 15° × 15° and a resolution of 384 A-scans per B-scan. The best peripapillary scan, based on a best quality signal for each eye, was selected for further analysis. When high-quality images, defined as a signal strength index of 30 or more, were not obtained, the individuals were excluded from the analysis. The OCT was performed within 1 week of CSF puncture in the patients with IIH.The RNFL of the macular, peripapillary, and papillary regions was evaluated by spectral-domain OCT . The RTVue-100 software program, version 4.0, was used for data analysis. The GCC measurements consisted of one horizontal line scan of 7 mm in length (467 A-scans) and 15 vertical line scans of 7 mm in length (each consisting of 400 A-scans) taken at 0.5 mm intervals. The scan center was shifted 0.75 mm towards the temporal periphery and encompassed a rectangular area measuring 7 × 7 mm. This scan configuration provided 14,810 A-scans in 0.58 s. The GCC thickness was defined as the distance between the inner limiting membrane (ILM) and the outer border of the inner plexiform layer (IPL). The nerve fiber layer (t-test was used to perform multiple comparisons between the groups (IIH and controls), or in the case of nonparametrically distributed variables, the Wilcoxon rank-sum test was used. Fisher's exact test was used for the categorical variables.Descriptive statistics included the calculation of means and standard deviations (SD) and medians and interquartile ranges for variables with normal and nonnormal distribution, respectively. The Skewness-Kurtosis test was used to determine whether or not distribution was normal. The When eligible, both eyes of each participant were included in this analysis. To correct for the bias introduced by the expected correlation between the two eyes of each participant, a generalized estimating equation (GEE) was used to adjust for intereye correlations . Next, aα level (type I error) was set at 0.05.Statistical analyses were performed using the commercially available Stata software program . The p=0.809). Differences were found between the two groups with respect to sex (p=0.001) and visual acuity (p=0.038). A total of 22 patients with IIH (43 eyes) and 11 controls (22 eyes) were included in the present study. There was no statistically significant difference between the two groups with respect to age, with the mean age of the participants in the IIH group being 34.90 ± 12.06 years compared to a mean of 35.45 ± 8.61 years for those in the control group . The optic disc head was normal in 30 eyes (69.77%), while optic disc swelling was found in 25 eyes (58.14%), pallor on fundoscopy was found in 6 eyes (13.95%), and central nervous system venous thrombosis was found in 7 patients (31.82%). In the entire sample, 8 patients (36.26%) were in use of acetazolamide 250 mg (2 tablets in the morning and 1 tablet at night). None of the patients in this study were candidates for bariatric surgery, CSF diversion procedures, or optic nerve sheath fenestration.μm and 116.012 ± 110.1010 μm, respectively; p=0.453). However, the GCC was thinner in the IIH group compared to the control group . In addition, a significant correlation was observed between swelling and visual acuity (p=0.037). Following adjustment for age and intraocular pressure, the association between thinner GCC measurements and pallor and the association between edema and visual acuity persisted .An association was identified between ocular findings and different clinical and demographic parameters for the entire IIH group. A significant correlation was found between GCC thickness and pallor  volume as a potential marker of the effectiveness of treatment and disease progression in IIH. In that cross-sectional pilot study in which 19 patients with IIH were compared with 19 controls, a significant correlation was found, with the volume of the ONH calculated using SD-OCT serving as a parameter for diagnosis of and progression in IIH. In fact, ONH volume ultimately proved more sensitive than the measurement of intracranial pressure .Previous studies evaluated the role of GCC or RNFL thickness in cases of IIH with papilledema , 10, 15.The principal objectives of this study were to investigate the thickness of the macular GCC, as evaluated by OCT, and to correlate the results with optic nerve pallor and visual prognosis in patients with IIH compared to a control group. The results should help assure adequate control for all patients with IIH, avoiding visual sequelae or irreversible loss of vision.Some limitations of the present study must be taken into consideration. (1) This was a cross-sectional study, and the sample size was small; however, it is the first study to identify a correlation between GCC and optic disc pallor. (2) The clinical examinations were subjective; however, one single ophthalmologist performed all the examinations to avoid any possible bias. (3) The usefulness of OCT in predicting poorer visual acuity in patients with IIH has its limitations. Although papilledema is a characteristic sign of intracranial hypertension, it has been reported to be absent in 6% of IIH patients . TherefoIn conclusion, there are significant correlations between the thickness of the GCC and optic disc pallor and between the presence of papilledema and poor visual acuity in patients with IIH. These results could possibly be extrapolated to other diseases that present with papilledema and may be useful in the future to ensure better control and treatment, hence preventing progression of the disease and loss of vision.


IntroductionHemodialysis is a vital management option for end-stage renal disease (ESRD) patients. With adequate hemodialysis, patients can have a good quality of life but complications do occur during the session, which can be minor to life-threatening. The objective of this study was to assess the frequency of acute complications during this procedure.Material and methodsAn observational, cross-sectional study was conducted at Jinnah Postgraduate Medical Centre, Karachi, Pakistan. Patient data were collected about access, comorbid conditions, frequency and duration of hemodialysis, and intradialytic complications. Those with acute kidney injury were excluded.ResultsThere was a total of 94 patients, with a mean age of 45.51±13.29 years, of which 62 (66%) were males and 32 (34%) were females. Diabetes mellitus was the most common cause of ESRD . Patients on twice and thrice-weekly sessions were 51 (54.3%) and 43 (45.7%), respectively. The most common complication was hypotension (28.7%), followed by hypertension (17%), and nausea/vomiting (11.7%). The arteriovenous fistula was the most common access used . Most patients were found to be on hemodialysis for more than five years .ConclusionBlood pressure changes are critical while performing hemodialysis, just like we found hypotension as the most common intradialytic complication in our results, followed by hypertension. Others were fever, muscle cramps, and nausea/vomiting. a prospective follow-up study shall be done to have comparative and long-term results related to the acute and chronic complications of dialysis. Globally, the prevalence of kidney diseases has increased in the last two decades, currently standing at 11-13% . The entThey are likely to have comorbid disorders like ischemic heart disease, peripheral vascular disease, cerebrovascular disease, and chronic obstructive pulmonary disease, all of which are associated with increased morbidity and mortality. Though hemodialysis is a life-saving treatment for ESRD patients, it is one of the relatively safe procedures having a mortality of 1/75,000 treatments. However, it is associated with various complications, some of which are acute, occurring during or immediately after the session, while others are chronic complications .Although the etiology of these complications is multifactorial and poorly understood, some are machine and procedure-related factors like the type of dialyzer, dialysis solution (acetate or bicarbonate), conductivity, blood flow, volume, and rate of ultrafiltration, an anticoagulant used, and contamination of Reverse Osmosis water. We call them technical complications. These are rare nowadays because of the advancement in technologies and equipment of hemodialysis. Other causes are patient-related factors like the primary disease, comorbid conditions, medications, intradialytic weight gain, frequency, length of the session, and duration of hemodialysis .Among the acute complications reported worldwide, the most common is hypotension 25-55%). The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative defines hypotension as a decrease in systolic blood pressure (SBP) >20 mm Hg or a decrease in mean arterial pressure by 10 mm Hg -55%. The,7. ThereThe prevalence of ESRD in Pakistan is 14.6% . MoreoveThis is a cross-sectional study conducted at the Department of Nephrology, Jinnah Postgraduate Medical Center, Karachi, Pakistan from March to August 2020, after approval from the ethical review board of the institution (N0.F.2-81-IRB/2020-GEN/49836/JPMC). Informed consent was taken from the patients for enrollment in the study.All the patients above the age of 18 years on hemodialysis for more than three months were included. Pregnant patients, those with acute kidney injury, dementia or disorientation, or those on hemodialysis for less than three months were excluded. A total of 94 patients were registered in the specified time duration.Patient data was filled on a self-designed questionnaire regarding age, gender, cause of ESRD, frequency, and duration of hemodialysis. Blood samples were taken for hemoglobin, serum calcium, phosphate, uric acid, albumin, iron, creatinine, urea, vitamin D, and intact parathyroid hormone (iPTH) as per schedule and recommendations. Adequacy of hemodialysis was calculated as urea reduction ratio (URR) and single pool (Sp) Kt/V . Each patient’s number and type of complications were noted.Data were analyzed by IBM Statistical Package for the Social Sciences (SPSS) Statistics for Windows, version 21.0 . Mean with standard deviations were calculated for age, blood sample values, URR, Sp Kt/V, and duration of hemodialysis, while frequency and percentages were calculated for all the categorical ones. Stratification was done according to gender, dialysis access, duration, and sessions per week. Post-stratification, the chi-square test was applied, with a p-value of <0.05 as statistically significant.We enrolled 94 patients of ESRD that were on hemodialysis, with a mean age of 45.51±13.29 years, of which 62 (66%) were males and 32 (34%) were females.Most were on three times per week hemodialysis schedule (45.7%). Over six months, a total of 5544 sessions were performed, where 3096 were in the thrice-weekly schedule and 2448 were in the twice-weekly schedule. The majority were found to be on hemodialysis for more than five years 51.1%, n=48). Native arteriovenous fistula (AVF) was the most common type of access used (75.5%) , followed by hypertension (17.0%), chronic glomerulonephritis (10.6%), and bilateral small size kidneys (10.6%) Table .The mean values of blood sample investigations are given in Table Hypotension was found to be the most common complication , followed by hypertension , nausea/vomiting , fever , and muscle cramps  , defined as a rise in SBP >10 mm Hg above the pre-dialysis value during, just at the end, or shortly after the session . Intradi, definedNausea/vomiting was found in 11.75% of patients in this study, i.e., higher than what was reported by another local study (3.22%) . InternaAnother significant complication reported in our data collection was fever  that occurred mostly in patients with temporary catheters due to line infection, first use dialyzers, membrane incompatibility, and sepsis. Another local study also reported the same , while aChest pain was found in 7.4% of our study population, a much lower percentage compared to that by Islam et al. (1.47%) , Rashid Hemodialysis is a lifeline for ESRD, a comparatively safe procedure with modern machines and technology, Intradialytic complications as enumerated in the results of this study can be prevented by proper counseling, less intradialytic weight gain, strict measures of infection control, appropriate dialysate temperature, adjustment of antihypertensive medications, and strict vigilance of vital signs during hemodialysis. These results are limited by the fact that the sample size cannot be representative of the entire population. Secondly, a prospective study should be done to evaluate and compare the number and type of complications (both acute and chronic).Blood pressure changes are critical while performing hemodialysis, just like we found hypotension as the most common intradialytic complication in our results, followed by hypertension. Others were fever, muscle cramps, and nausea/vomiting. a prospective follow-up study shall be done to have comparative and long-term results related to the acute and chronic complications of dialysis.


Objective: Intradialytic haemodynamic instability is a significant clinical problem, leading to end-organ ischaemia and contributing to morbidity and mortality in haemodialysis patients. Non-invasive continuous blood pressure monitoring is not currently part of routine practice but may aid detection and prevention of significant falls in blood pressure during dialysis. Brachial blood pressure is currently recorded intermittently during haemodialysis via a sphygmomanometer. Current methods of continuous non-invasive blood pressure monitoring tend to restrict movement, can be sensitive to external disturbances and patient movement, and can be uncomfortable for the wearer. Additionally, poor patient blood circulation can lead to unreliable measurements. In this feasibility study we performed an initial validation of a novel method and associated technology to continuously estimate blood pressure using pressure sensors in the extra-corporeal dialysis circuit, which does not require any direct contact with the person receiving dialysis treatment. Method: The paper describes the development of the measurement system and subsequent in vivo patient feasibility study with concurrent measurement validation by Finapres Nova physiological measurement device. Real-time physiological data is collected over the entire period of  dialysis treatment. Results: We identify a quasi-linear mathematical function to describe the relationship between arterial line pressure and brachial artery BP, which is confirmed in a patient study. The results from this observational study suggest that it is feasible to derive a continuous measurement of brachial pressure from continuous measurements of arterial and venous line pressures via an empirically based and updated mathematical model. Conclusion: The methodology presented requires no interfacing to proprietary dialysis machine systems, no sensors to be attached to the patient directly, and is robust to patient movement during treatment and also to the effects of the cyclical pressure waveforms induced by the hemodialysis peristaltic blood pump. This represents a key enabling factor to the development of a practical continuous blood pressure monitoring device for dialysis patients. I.Patients receiving hemodialysis treatment as a result of end-stage kidney disease (ESKD) are at a much higher risk of mortality due to cardiovascular disease (CVD) Intradialytic hypotension (IDH) is a sudden event, and generally defined as a decrease in systolic blood pressure greater than gold standard reference for continuous measurement of BP Arterial cannulation is widely regarded as the Three distinct methods for non-invasive monitoring of BP have occasionally been used in research settings. The first of these is arterial applanation tonometry The second method for non-invasive continuous estimation of BP is Pulse Transition Time (PTT) The third alternative is the volume clamp (or vascular unloading) method A.The iTrend  programme is a long-term collaborative project performed by a multidisciplinary research team from the Universities of Derby and Nottingham and the Royal Derby Hospital Renal Unit in the UK. The primary goal of the programme is to develop supporting technologies and real-time analysis of data to enable personalised and precision treatment in ESKD In this work, a feasibility study based around a novel method for continuously monitoring BP is described which involves the placement of pressure transducers onto the venous and arterial blood lines that connect a patient to a haemodialysis machine during treatment. This study is the first step to develop a continuous blood pressure estimating/measuring device for dialysis treatment. The resulting data is compared against standard BP measurements obtained via an occluding arm cuff and the volume clamp method, via the Finapres Nova , whose accuracy has been studied B.•to provide reliable and robust measurement of patient blood pressure before, during and immediately after haemodialysis treatment;•with regards to patient experience, to require no extraneous sensors to be attached directly to the patient;•the measurement method to be robust to patient movement during treatment;•the sensors to be cost-effective, non-bespoke and readily available as off the shelf items;•data aquisition and analysis hardware to be low physical footprint and low cost;•the system should not require any special interfaces to and should work equally well with any proprietary dialysis machine.This article describes the development of a continuous, non-invasive method to measure BP during renal dialysis sessions. Design objectives were as follows:••••The paper is divided into the following sections:For clarity, where a patient’s BP is mentioned, this should be taken to mean brachial blood pressure.II.The use of pressure signals from the arterial and venous blood lines of a dialysis machine has been shown in principle to enable continuous online monitoring of a patient’s heart rate, even for patients with low cardiac signal amplitude Our approach demonstrates a more robust approach to derive continuous BP signals from the arterial and venous dialysis lines and presents the initial results of its in-vivo verification via on-going patient studies in the Renal Unit at Royal Derby hospital.A.The aim of this feasibility study is to identify and experimentally derive relationships between the patient’s brachial BP, and the pressures recorded within the extra-corporeal blood lines to and from the dialysis machine. Typically, two such blood lines are provided during haemodialysis: an arterial line conducts blood from the patient to the dialysis machine, and a venous line that conducts blood from the dialysis machine back to the patient. Vascular access to the patient is provided by means of two large gauge needles (one on each line) into the patients ‘fistula’, a surgically enlarged blood vessel resulting from the connection of a vein onto an artery, typically located within the patients non-dominant arm.In order to develop a non-hardware specific generalised solution to the problem, additional pressure sensors were placed into the blood lines rather than making use of the pressure sensors present within the dialysis machines (as in previous studies). The primary function of these safety critical machine sensors is setup monitoring. This study utilised the existing ports and connection points which are common and standardised on most dialysis blood lines sets .FIGURE Starting on the blood return side  venous bAs will be seen, the blood flow rate through the extra-corporeal system is critical to analysis of the relationship between brachial and arterial line blood pressure measurements. A real-time measurement of blood flow is required for the calculations necessary for BP estimation. Flow rate is generally set at the beginning of treatment, and recorded manually. For various clinical reasons, medical professionals may adjust the flow rate during treatment which may or may not be recorded in patient notes.The pressure waveform measured by the pressure sensor connected to the venous bubble trap is dominated by the oscillations introduced by the lobes of the peristaltic blood pump Fourier trigonometric series for the function as; Considering a function As 5000 samples or 5 s wide. As the pump frequency is typically around quasi steady-state measurement. Frequency is converted to flow in units of microlitres/minute by The pump frequency is calculated and updated in real-time over a sliding window of data which is The additional pressure sensor on the arterial-line should be sited as close as possible to the patient’s vascular access, since the needle sits between positive pulsatile patient blood pressure at one end, and blood-pump dominated negative pulsatile pressure at the other end. Given that no suitable connector exists at the arterial needle end of the line, a ‘Y’ connector with 4 mm internal diameter is fitted to the tubing of the dialysis needle to allow access to both the dialysis line and the arterial line pressure sensor .FIGURE 5000 samples moving-average window, similar to the filter applied to the venous-line pressure data. With reference to Modelling the relationship between arterial-line pressure and brachial pressure is extremely complex with high levels of physiological differences between patients. In order to produce a tractable model, a number of approximations are included. The brachial cuff measurement is, in effect, a quasi-steady state measurement single-instance sample of systolic and diastolic pressure including no dynamic information, and hence the arterial line pressure is filtered by Assuming steady, incompressible flow with negligible losses, blood flow rate can be expressed using Bernoulli and Continuity equations A number of assumptions are inherent in this model; horizontal flow and fully developed flow at III.40PC015V2A 0 PSI to −15 PSI Arterial line, and Honeywell 40PC015G1A 0 PSI to 15 PSI Venous line) have been integrated  and storage is performed via a National Instruments A.Method: Participants > 18 years were recruited from the prevalent dialysis population at Derby Royal Hospital. Patient’s demographics, dialysis background, dialysis prescription, laboratory parameters pre- and post-dialysis at each session were recorded. All participants had continuous non-invasive monitoring of haemodynamics using pulse wave analysis (Finapres NOVA) during a single dialysis treatment of typically 4 hours duration, and this data was periodically verified by intermittent arm-cuff measurements. Two pressure sensors were attached to the dialysis lines as described: one between the arterial dialysis needle and dialysis line and the other directly onto the venous-line bubble trap. Data was continuously recorded from all sensors at a sampling rate of 1 kHz.The study protocol was approved by the West Midlands - Coventry and Warwickshire Research Ethics Committee and participants gave written informed consent.IV.In total 12 participants were recruited with 11 completed monitored dialysis sessions. 1 participant moved out of area before a session could be completed. 58.3% of participants were male, with a median age of 65 (IQR 48-78).Systolic, Diastolic and MAP) are saved to a master record with synchronised time stamps for comparison with the corresponding venous and arterial line pressures. This master record for the patient study enables the calculation of lumped parameter Serial brachial cuff blood pressure values were compared with synchronous pressure sensor data in Matlab (ver. 19b). Arterial line pressure sensor data was analysed for dialysis pump flow by fitting a Fourier model to the continuous venous line pressure signal. Derived pump flow, arterial and venous line pressures, and brachial cuff pressure measurements for a typical treatment session are shown in In this example , the dia•14: 14g Arterial 14g Venous•15: 15g Arterial 15g Venous•16: 15g Arterial 16g Venous where 14 is the normal gauge set, and 15, 16 used for new patients and access issues.In the Renal Unit at Royal Derby Hospital, where the patient studies are conducted, 14g is the standard and preferred gauge size for dialysis patients. Smaller diameter (larger gauge size) needles are used for new patients with recent fistula, and also for patients with needling problems.The gauge sizes used during this patient study are:With reference to −20. As predicted, the figure displays a correlated scatter for the population around a linear least squares fit with a gradient which represents a fundamental relationship between per patient basis (which again can be an updateable model).The experimental relationship between brachial cuff MAP and corresponding measured arterial line pressure for 11 sessions in the patient study is shown in −38. There are a number of salient features in this plot. Firstly, the gradient of the fit has only changed by 2.5% indicating a relatively accurate model for the machine and lines system. Secondly, the data In order to further examine this hypothesis, it is possible to negate the time varying effects in the data by taking a mean value for ments cf . HoweverFinally, although the majority of physical systems can be modelled adequately by linear, time-invariant models, there is much to be gained in future work developing time-variant, non-linear models of these specific systems. Overall, data from this first feasibility study indicates that a linearised model for individual patients, patient populations and machine sets can be calculated which defines a linear relationship between measured arterial line pressure and measured brachial artery pressure. The feasibility study thus confirms that it is practically possible to estimate brachial BP continuously and non-invasively during the period of a dialysis session in a clinical setting with measurement of venous and arterial line pressure, and occasional measurement of brachial blood pressure by arm cuff.V.The objective of this patient study was to answer a pressing question in dialysis treatment, whether a method could be developed which demonstrates the feasibility of continuous non-invasive blood pressure monitoring, without compromising patient experience and without requiring bespoke interfacing to the dialysis machine, or any additional sensing to be worn by the patient beyond current arm cuff monitoring requirements.An approximate mathematical model relating arterial line pressure, blood pump flow rate and brachial pressure was derived, which predicts a quasi-linear relationship between arm cuff measured pressure, and corresponding pressure measured in the arterial line near to the fistula. Interfaces, measurement devices and a data acquisition were designed and built to support an observational study during renal dialysis treatment.This is an early study, and we felt that a formal analysis of external disturbances would form part of a later study. At this time however, we can state that during each of the cases studied here, our method provided a continuous data record over the treatment period, whereas the data from the Finapres Nova was restricted to 30 minute sessions with 30 minute breaks due to discomfort. Additionally the Finapres Nova data exhibited many instances of waveform discontinuities and settling-time/re-calibration in the data sets.The results from this observational study suggest that it is feasible to derive a continuous measurement of brachial pressure from continuous measurements of arterial and venous line pressures via an empirically based and updated mathematical model. Potential exists to identify a more complex and hence more accurate parametric model.real-time for the complete duration of dialysis treatments. Further work will report on the outcome of these studies.The study presented here is critical to confirming that the fundamentals of this approach are feasible, and the results have confirmed that the methodology and technology has a practical future in renal units. There are a number of challenges following directly from this work which will be addressed in current and future algorithmic/technological developments and studies. In particular, iterative learning algorithms to update the mathematical models based upon incoming cuff BP measurements, improved mathematical models to increase estimation accuracy, and predictive models for hypotension. Patient studies are about to start at Royal Derby Hospital to demonstrate, analyse and improve the continuous estimation of brachial BP in


Only IM pattern (p = 0.015) resulted as an independent predictor of number of tacrolimus blood levels out of therapeutic range. RM pattern (p = 0.006) was inversely related to the administered dose. Therefore, genotyping could become a standard practice before tacrolimus prescription thus decreasing side effects, increasing efficacy and reducing the economic burden for the national health system.Precise tacrolimus treatment in transplanted patients is achieved in the clinical setting by performing therapeutic drug monitoring (TDM) and consequently adjusting therapy. The aim of this study was to retrospectively analyze the variability in tacrolimus blood levels throughout 2 years of observation in 75 transplanted patients and to investigate if tacrolimus blood levels correlate with presence of genetic polymorphisms, thus modifying tacrolimus pharmacokinetics. CYP3A5*1 (G6986A), CYP3A4*1B (A392G), CYP3A4*22, ABCB1 , SLCO1B1 (T521C), polymorphisms were analyzed. Based on the effect of their genotypes, patients were stratified into 5 groups: (1) reduced tacrolimus metabolism (RM), (2) increased metabolism (IM), (3) transporters polymorphisms (TM), (4) metabolism and transporter polymorphisms (AM) and (5) no mutations . The percentage of the samples out of therapeutic range was significantly higher in the IM group than in the WT group ( Tacrolimus is a calcineurin inhibitor widely used as an antirejection drug for patients who underwent liver or kidney transplantation. Tacrolimus is a macrolide that binds the FK binding protein 12 (FKBP-12), thus forming a complex that in turn engages calcineurin. This binding prevents the dephosphorylation and nuclear translocation of nuclear factor of activated T-cells, inhibiting IL-2 production and T-lymphocyte activation . Blood tp < 0.001 and p < 0.001, respectively). No differences by gender or allelic mutations were shown. Moreover, our study did not include patients in the early stage (1–6 months) after organ transplant and therefore no patient had renal insufficiency, warm ischemia time, delayed graft function, and chronic allograft dysfunction. All patients enrolled in our study had a kidney stable transplant and none experienced severe changes in renal function. Therefore, dosage adjustments were almost always secondary to the need to comply with the recommendations relating to maintaining blood levels within the therapeutic range and were guided by the information obtained from the therapeutic drug monitoring.Basic characteristics of the 75 patients included in this study were summarized in p = 0.001), as well as compared to the transporters polymorphisms (TM) group  (Median tacrolimus blood levels were 5.1 (4.6–6.1) in wild type (WT) subjects. No difference was observed between WT group and other groups in tacrolimus blood levels . At leas= 0.004) .p = 0.015) resulted as an independent predictor of number of tacrolimus blood levels out of therapeutic range, whereas reduced tacrolimus metabolism (RM) and TM patterns were not related to the increased risk of being out of therapeutic range. The presence of IM mutation (B = 0.206 (0.031/0.381); p = 0.021) influenced the probability of being out of therapeutic range also independently from the administered dose (Age of patients as well as gender did not influence the probability of being out of therapeutic range. IM pattern (B = 0.213 (0.041/0.384); red dose .p < 0.001) and TM (p = 0.043) groups than in WT group. No significant difference was shown between WT and IM groups (p = 0.574).Tacrolimus median dose was 3.5 (2.5–4.0) in WT group and 2.0 (1.5–5.0), 3.0 (2.0–4.5), 0.5 (0.5–0.5), in TM, IM, RM, respectively. Administered median dose was significantly lower in RM (p < 0.001) modified the dosage regimen. Only the presence of RM mutation (b = −0.513 (−0.876/−0.150); p = 0.006) was inversely related to the administered dose. No significant correlation was observed between the other groups of mutations and the tacrolimus dose ; mus dose . The post-hoc power calculation, including 75 patients as sample size stratified in four different groups and with an α error probability = 0.05, showed an effects size f = 0.3978 and a power (1-β error probability) = 81.3%.Inappropriate management of transplanted patients causes an incorrect therapeutic approach and an economic burden to the health care system. The results of the present study suggest that failure of achieving tacrolimus target blood concentration might be avoided by a wide genotyping of transplanted patients. Genotyping patients for the genes involved in tacrolimus metabolism and transport might allow the identification of subgroups of patients with drug concentration out of the therapeutic range.Indeed, the daily practice of drug monitoring reveals wide between-individual variability in tacrolimus pharmacokinetics and particularly in the dose required to achieve target blood concentrations. Polymorphisms of the genes coding for biotransformation enzymes (CYP3A4 and CYP3A5) and drug transporters (ABCB1 and SLCO1B1) were investigated to date. CYP3A5 expression may be dependent on genetic polymorphisms and CYP3A5 polymorphisms differently occur according to ethnicity . CYP3A5*Patients with one or more CYP3A5*1 allele showed a reduced tacrolimus concentration to dose ratio compared to non-expressors CYP3A5*3 in kidney, liver, lung, and heart transplant recipients . A studyIn our study, the number of the samples out of range was significantly higher in IM group than in WT or in TM group, due to low blood values of tacrolimus. Moreover, the presence of IM genetic mutation is directly related to the number of out of range samples. However, no correlation was observed between IM genetic polymorphisms and tacrolimus dose administered. Failure to increase the dose of tacrolimus administered could justify the observed results.The CYP3A4*22 C>T polymorphism was recently identified and studied in transplant patients: renal transplant patients, Caucasians, with T alleles needed lower tacrolimus doses compared to individuals with wild-type C allele . This SNAs for as CYP3A4 and CYP3A5, several SNPs have been identified in ABCB1 gene. The SNP in exon 26 C3435T) is in strict imbalance with two other SNPs located in exon 12 (C1236T) and exon 21 (G2677T/A), respectively . These t35T is inA total of 173 patients referring to the Toxicology and Drug Monitoring Unit of Messina University Hospital were enrolled from January 2017 to December 2018. In total, 75 subjects were included in the study. Exclusion criteria were as follows: patients with other type of transplant, in the early stage (6 months) of treatment after transplant, in therapy with other immunosuppressant (corticosteroid or mycophenolate mofetil), with previous transplant rejection, in therapy with drugs that increase tacrolimus blood levels , in therapy with drugs that reduce tacrolimus blood levels , with a concomitant transplant, with impaired vital functions. Inclusion criteria were as follows: patients with Kidney stable transplant , receiving tacrolimus as a primary immunosuppressant. All patients included in the study were genotyped as described below and, according to the effect of their genotypes, they were stratified into 5 groups: patients with (1) reduced tacrolimus metabolism (RM), (2) increased metabolism (IM), (3) transporters polymorphisms (TM), (4) metabolism and transporter polymorphisms (AM) and (5) no mutations . Informed consent was obtained from all the subjects or their legal representative. All subjects gave their informed consent for inclusion before they participated in the study. Tacrolimus dose was collected the same day of blood sampling and each patient was monitored at least once in two months for two years. The study was carried out in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Messina, project identification code N° 47/17 17/07/2017.Venous blood was collected in 3 mL tubes containing EDTA as anticoagulant. Tacrolimus concentrations were assayed in whole blood using the Siemens Dimension EXL-200 system. Genomic DNA was isolated from whole blood, cells were lysed in DNA buffer containing 10 mM Tris-HCl pH 7.4, 100 mM NaCl, 1 mM EDTA, 1 mM MgCl2. After centrifugation nuclei were lysed by the combined action of 10% SDS and proteinase K at 37 °C overnight. The cell debris from lysis, mainly protein, were captured by the organic solvents: phenol and chloroform. DNA was washed with 70% ethanol and resuspended in an adequate volume of RNAse/DNAse free water. DNA concentration in each sample was spectrophotometrically determined and stored for genotyping assay. For analysis of genotypes a common primer and two allele-specific primers were designed, with the 3’ base of each specific primer corresponding to either allele wild type or mutant, respectively . Dependip-value smaller than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics for Windows v22.0  and G Power 3.1 .Descriptive statistical analyses were performed to evaluate basal demographic and clinical characteristics of all patients. All results were expressed as median with interquartile range (Q1–Q3) for continuous variables, and absolute frequencies and percentages for categorical variables. Since most of the variables were not normally distributed (as resulted by Kolmogorov–Smirnov test), the nonparametric approach was used. Accordingly, the Mann–Whitney (comparison between two independent groups of patients) U test for continuous variables and the Pearson Chi Square test for categorical variables were applied. For each patient, all blood drug values, monitored during the study period, were recorded and the number of samples out of range was analyzed. Moreover, patients were stratified according to the occurrence of at least one tacrolimus blood level out of range or not. The out of range events were calculated as the ratio between the number of out range blood samples and the total number of blood samples, per patient. A generalized linear model (GLM) was estimated to identify significant predictors of out of range events. The considered predictors were as follows: sex and age (adult or child), transporters mutation (yes or no), reducing metabolism mutation (yes or no), increasing metabolism mutation (yes or no). The model was also estimated adjusting for administered dose. Moreover, a GLM was estimated to identify significant predictors of administered dose and the same covariates were considered. The results were expressed for each covariate as B coefficient with 95% Confidence Interval (95% C.I.). A post-hoc power calculation (F tests in fixed effects one-way ANOVA) was performed on tacrolimus blood levels, considering the whole sample size and assuming four different groups with an α error probability = 0.05. A


Background and Objectives: Abnormal arterial stiffness (AS) is a major complication in end-stage kidney disease (ESKD) patients treated by dialysis. Our study aimed to determine the significance of AS for survival of prevalent dialysis patients, as well as its association with cardiovascular parameters or vascular calcification promoters/inhibitors or both and AS. Materials and Methods: The study involved 80 adult hemodialysis patients. Besides standard laboratory analyses, we also determined promoters and inhibitors of vascular calcification (bone biomarkers): serum levels of fibroblast growth factor 23 (FGF23), soluble Klotho, intact parathormone (iPTH), 1,25-dihydroxyvitamin D3, osteoprotegerin, sclerostin, AS measured as ankle carotid pulse wave velocity (acPWV), Ankle Brachial Index (ABI), and vascular calcification (VC) score. Patients were monitored for up to 28 months. According to the median acPWV value, we divided patients into a group with acPWV ≤ 8.8 m/s, and a group with acPWV > 8.8 m/s, and the two groups were compared. Results: Values for bone biomarkers were similar in both groups. Mean arterial blood pressure (MAP), central systolic and diastolic brachial blood pressure, heart rate, and pulse pressure were higher in the group with acPWV > 8.8 m/s than in the group with acPWV ≤ 8.8 m/s. The mortality was higher for patients with acPWV > 8.8 m/s at any given time over 28 months of follow-up. In multivariable analysis, predictors of higher acPWV were age >60.5, higher pulse rate, and higher central systolic or brachial diastolic blood pressure. Conclusions: According to our results, we advise the measurement of acPWV preferentially in younger dialysis patients for prognosis, as well as intervention planning before the development of irreversible changes in blood vessels. In addition, measuring central systolic blood pressure seems to be useful for monitoring AS in prevalent hemodialysis patients. Abnormal vascular remodeling (VR) is a major complication of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) . The artVR results from a complex interaction between structural and functional changes in the vessel wall under the influence of traditional and nontraditional cardiovascular risk factors, especially oxidative stress, endothelial dysfunction, mineral metabolism disorders, and renal bone disease ,11,12,13Bearing in mind all these controversies, we conducted the present study with the aim to determine (a) the significance of AS for survival of prevalent dialysis patients, and (b) potential independent association between cardiovascular parameters or VC promoters/inhibitors or both and AS.The study involved 80 non-diabetic adults on hemodialysis (HD) selected from the pool of patients treated with chronic hemodialysis in two nephrology departments . Exclusion criteria were (1) hemodialysis duration of less than 6 months; (2) patients disagreed to participate in the study, which was approved by the institutional review board; (3) acute CV complications during the 6 months preceding entry into the study; (4) hemodynamically significant lower extremity artery occlusive disease; (5) atrial fibrillation at the time of pulse wave velocity (PWV) measurement; and (6) uncontrolled blood pressure.The participants were monitored from October 2015 until death or February 2020. The Ethics Committee of the Clinical Centre of Serbia evaluated and approved the study protocol , and all patients provided written informed consent. Biochemical, calcification, and vascular assessment were performed after signing the informed consent.Standard bicarbonate hemodialysis sessions lasted 12 h weekly. Dialysate calcium (dCa) was individualized to meet the specific requirements of each patient by optimizing management of serum Ca, phosphate, parathyroid hormone, and alkaline phosphatase levels and could be altered. Dialysate Ca at 1.5 mmol/L was commonly used; dCa of 1.25 mmol/L was applied to permit the use of vitamin D supplements and Ca-based phosphate binders in the setting of biochemically suspected adynamic bone disease; dCa higher than 1.75 mmol/L was employed for suppression of hyperparathyroidism, taking into account side effects. Management of renal osteodystrophy was adjusted on the basis of drug availability. Before the start of this cross-sectional study, the patients had received paricalcitol for 12 to 22 months, except for two individuals who had taken the drug for 4 months and 80 months, respectively. In addition, a smaller number of patients were prescribed sevelamer for up to 12 months. Cinacalcet was given to only a few patients for up to 6 months. During the study and in the following period, neither sevelamer nor cinacalcet were used. Additional variables of interest from the patients’ records were demographic ; underlying kidney disease; dialysis duration; systolic and diastolic blood pressures recorded during dialysis; and previous history of cerebrovascular disease and cardiovascular diseases, including coronary artery disease, congestive heart failure, peripheral vascular disease, parathyroidectomy, and medicaments ).Data were recorded for serum urea, creatinine, uric acid, total protein, C reactive protein (CRP), lipid profile, phosphate, calcium, alkaline phosphatase, hematological parameters, iron status, and intact parathormone (iPTH). Mean standard weekly Kt/V and urea reduction ratio (URR) were calculated. We also measured serum levels of 1,25-vitamin D3, fibroblast growth factor 23 (FGF23) and soluble Klotho, osteoprotegerin, fetuin A, and sclerostin.The routine biochemical parameters were determined using standard techniques, while stimulators or inhibitors of VC were analyzed in the same laboratory in the Clinical Centre of Serbia. Serum iPTH was measured by immunoradiometric assay , with normal values being 11 to 62 pg/mL. Serum levels of FGF23 were assayed with a commercially available kit  using an ETI-max 3000 . According to the manufacturer, the assay has a measurement range of 3.12–200 pg/mL with a lower limit of detection of 0.78 pg/mL. Intra-assay precision was <8%, and inter-assay precision was <10%. Serum levels of soluble Klotho were determined using a commercially available kit  and ETI-max 3000 . According to the manufacturer, the assay measurement range is 156–10 ng/mL, with a lower limit of detection of 0.039 ng/mL. Intra-assay precision was <8%, and inter-assay precision was <10%. A commercial chemiluminescent immunoassay  was employed to determine serum 1,25(OH)2D on a LIAISON Analyzer . The measuring range is 7.6–147.8 ng/mL, limit of quantification is 3.5 ng/mL, and the intra- and inter-assay coefficients of variation are 2.5% and 6.5%, respectively. Serum levels of osteoprotegerin were determined using a commercially available kit . According to the manufacturer, the assay range is 0–20 pmol/L (0–400 pg/mL), and the intra- and inter-assay coefficients of variation are ≤5% and ≤3%, respectively. Serum levels of sclerostin were determined using a commercially available kit . According to the manufacturer, the detection assay range is 62.4–4000 pg/mL, and the intra- and inter-assay coefficients of variation are <10%.Vascular calcification in the iliac, femoral, radial, and digital arteries in plain radiographic films of the pelvis and hands were evaluated by one person. A simple VC score was calculated as described by Adragao et al. . In brieBrachial blood pressure (BP) was measured in all patients in the non-fistula arm. Blood pressure was measured three times at 1-min intervals according to the European Society of Hypertension/Cardiology guidelines . A validA Complior SP system  was used simultaneously to assess the central systolic blood pressure (sSBP) and ankle carotid pulse wave velocity (acPWV) by two trained investigators. acPWV was measured 1 day between mid-week hemodialysis, utilizing two sensors  simultaneously to determine the velocity of the pulse wave in relation to the distance between the femoral artery and the suprasternal notch. Two measurements were taken, and the mean value was calculated. To determine the inter-observer variability of acPWV measurements, two experienced investigators independently analyzed 20 randomly selected patients. Interobserver variability was 7%.The Ankle Brachial Index (ABI) was determined 10–30 min before HD using an ABI-form device that automatically and simultaneously measured blood pressure in both arms and ankles with a Doppler device . Brieflyp-value) ≤ 0.05 was considered statistically significant.Continuous variables are presented as the mean (standard deviation (SD)) for normally distributed variables and as the median (interquartile range (IQR)) for non-normally distributed variables. Chi-square tests, ANOVA, or Kruskal–Wallis one-way ANOVA were used to examine differences in various baseline variables between the groups of patients. Patients were divided into two groups according to median acPWV value: ac PWV ≤ 8.8 m/s, and ac PWVT2 > 8.8 m/s, and were analyzed as a categorical variable. Univariate and multivariate Cox proportional hazard models were employed for determination of hazard ratios (HR) that variables have for all-cause and CV mortality. All variables that were statistically significant in the univariate analysis were included in the multivariate analysis. Model 1 was adjusted for age, sex, and brachial BP, while Model 2 was adjusted for age, sex, central systolic blood pressure (cSBP), and brachial systolic blood pressure (SBP). The Kaplan–Meier method was used for survival plots that were compared by log-rank tests. Receiver operating characteristics (ROC) curve analysis was performed using age as a continuous variable and acPWV as outcome in order to determine the most sensitive and specific patient age cut-offs for acPWV over 8.8 m/s. Statistical analysis was performed with SPSS 21.0 . The probability (p < 0.001) and revealed that 60.5 years was the most sensitive and specific  cut-off age value for the studied patients. There were no significant differences in dialysis vintage prior to inclusion in the present study, as was the case for body mass index, presence of hypertension, cardiovascular disease (CVD) and cerebrovascular insult (CVI) co-morbidities, treatment with ESA, phosphate binders, and antihypertensives between the two groups. The distribution of primary causes of ESRD were similar, but common renal calculosis in the group with acPWV ≤ 8.8 m/s and common Balkan endemic nephropathy in the group with acPWV > 8.8 m/s were found.The baseline characteristics, presence of co-morbidities, and treatment of the participants in two acPWV groups are shown in Data on blood vessel function and morphology and blood pressure parameters for the two groups are presented in Basal laboratory analyses are shown in During the follow-up period, 10 patients died due to heart failure, acute myocardial infarction, aorto-coronary bypass surgery, peripheral vascular disease with ulceration (four patients), cerebrovascular insult (one patient), systemic infection (two patients), colorectal cancer, and hepatocellular carcinoma and decompensated cirrhosis following hepatitis B virus infection (one case each).p = 0.002).Patient survival curves for the acPWV median groups are presented in Age, arterial hypertension, median acPWV, and Klotho were selected in univariate Cox regression analysis as predictors of mortality. However, having acPWV > 8.8 m/s was selected as an independent predictor for a fatal outcome in multivariate analysis . The proThe independent variables significantly associated with acPWV selected by logistic regression analysis are presented in The present study showed that acPWV is an independent risk factor for prevalent hemodialysis patients’ all-cause mortality, and the cut-off value for acPWV is above 8.8 m/s. In addition, increasing acPWV was positively associated with older age, higher pulse rate, and higher central systolic and brachial diastolic blood pressure.Our results are in accordance with previous studies, which have shown that acPWV contributes to increased cardiovascular morbidity and mortality in patients with CKD 2–5 and those treated by hemo- and peritoneal dialysis ,25,26,27The reference values for acPWV were assessed from 11,092 European subjects without overt CV disease, diabetes, treated hypertension, or dyslipidemia . It was We found that higher acPWV values were associated with older age. On the other hand, PWV > 8.8 m/s was seen in 11 patients younger than 60.5 years. These individuals could be at a particularly high risk for a fatal outcome due to AS developing earlier than expected. Similar results were presented by Ferreira and coworkers using the acPWV cut-off of 12 m/s recommended for the general population . TherefoMany authors point to an association of blood pressure and acPWV in the general population, as well as in CKD and dialysis patients ,41. ArteThe present analysis showed that acPWV is positively associated with the pulse rate, which is a variable that we can influence. An association between acPWV and pulse rate has been described in the general population and in CKD patients but not in the dialysis population. A recent study showed minimal physiologically relevant changes of acPWV for small changes in pulse rate, but larger differences in pulse rate could be considered as contributing to significant differences in acPWV . In addiAlthough statistically insignificant, higher iPTH, vitamin D, osteoprotegerin, and sclerostin on the one hand and lower FGF23 and Klotho on the other were found in our patients with acPWV > 8.8 m/s. The inclusion of these biomarkers in our analysis neither improved prediction of mortality of our patients nor selected them as independent variables for AS. Findings from previous studies are inconsistent. Some earlier studies showed that high levels of the biomarkers sclerostin, osteoprotegerin, FGF or FGF-KLOTHO axis, and/or vitamin D deficiency ,47,48 coWe failed to show any correlation between VC and AS. Moreover, significance of VC for patient survival was not confirmed in the multivariate analysis. However, the highest Adragao score of 8 was found in patients with acPWV over 8.8 m/s. In contrast to our analysis, others reported a close relationship between VC and AS, indicating that more calcified arteries lose their elasticity . FurtherThere are several limitations to this study that need to be noted. First, the number of patients enrolled was small and our findings need to be confirmed in a larger cohort. Second, a longer follow-up may have led to more events. Finally, this was an observational dataset, which cannot account for the presence of residual confounding factors, and causality can only be implied.Among prevalent patients treated with hemodialysis, we observed that AS, measured with acPWV, independently predicted all-cause mortality. A value for acPWV over 8.8 m/s was associated with a greater risk of patient mortality, especially in those younger than 60.5 years. Therefore, we can advise the measurement of acPWV preferentially in younger dialysis patients for prognosis, as well as intervention planning before the development of irreversible changes in blood vessels. In addition, measuring central systolic blood pressure seems to be useful for monitoring AS in prevalent hemodialysis patients.


Discrepancies exist between guidelines and real-life practice in severe asthma. Objectives: To establish profiles for severe asthma patients according to their maintenance therapies and identify unmet needs.2432 French lung specialists and allergists were invited to participate in a severe asthma survey between March and April 2018. Retrospective data were collected using an electronic case report form developed by IQVIA.anti-IgE, anti-IL5-pathway or anti-IL-4/IL-13 pathway therapy; 22 (13.2%) were ineligible for any current biologic according to biomarkers.71 respiratory physicians and/or allergists participated in the study, providing data for 736 severe asthma patients. The annual mean rates of hospitalization and exacerbation in the previous year were 0.65 (SD = 0.5) and 2.25 (SD = 1.0), respectively. One hundred one (13.7%) patients were treated with oral steroids; the mean dosage regimen was 16.1 mg per day (SD = 11.2). ICS-LABA-LAMA triple inhaled therapy was reported for 288 patients (39%); 231 patients (31.4%) had one biologic in their maintenance treatment. Among patients hospitalized at least once in the previous year (n = 311), 89 (28.5%) were currently treated with biologics, and 61 (19.6%) with oral steroids. One hundred sixty-six patients with uncontrolled asthma and no current biologic therapy had data for “T2 status”; 78 (47%), 89 (53.6%) and 137 (82.5%) of them had treatment criteria respectively for an Our study updated “real-life” therapeutic management data for severe asthma in France in 2018. We highlighted a need for improved patient-phenotyping. This work also gives a striking insight of the position of current and forthcoming biologics. Asthma is a heterogenous disease whose main feature is chronic airway inflammation. Novel biologics such as IL5 and IL-4/IL-13 pathway-targeting therapies have made essential the phenotyping of severe asthma, according to GINA guidelines. This strategy aims to drastically decrease annual exacerbation rates and the need for oral steroids, while improving levels of asthma control.,,,Beyond the various reactions to the evidence base for asthma care, the implementation of current recommendations by respiratory physicians is not always optimal.Subsequently, real-world studies documenting asthma treatment strategies in situations unaffected by “NICE-like” prescription restrictions, and where the medication costs are not an issue for either the prescriber or the patient, take on increasing interest. This is the case for France, where several biologics have been sequentially introduced to the market between 2009 and 2019, and data concerning their usage should provide an insightful vision of the current level of asthma control, medication use and biomarker-elicited profiles. This likely helps at drafting tomorrow's landscape which can be extremely helpful for all the severe asthma stakeholders.We then aimed to depict the profile and therapeutic management of severe asthma patients in the real world, identify unmet needs, and relate this to the use of current and futures therapies.Two thousand four hundred thirty-two French lung specialists and allergists were invited to participate in a retrospective survey focusing on severe asthma between March and April 2018. Physicians were selected using OneKey, a regularly updated directory of 15 million healthcare professionals (HCP), 1 million healthcare organizations (HCOs) and their affiliations from over 100 countries.Patient characterization included sex, age, employment status, and body mass index. Disease characteristics included the duration of severe asthma in years, asthma phenotype, blood eosinophil count before current maintenance therapy, type and dosage regimen of maintenance therapy. Atopy was defined by at least 1 positive skin prick test and/or a specific IgE concentration higher than 0.35 kUI/l directed against the commonest aeroallergens of the region.The specialty, type of activity , and location for the diagnosing physician were also collected.In order to assess the hospitalization costs for asthma exacerbation, we obtained the overall hospitalization data for asthma occurring in France in 2018,  were assessed using ANOVA tests for quantitative variables and Chi-squared or Fisher tests for qualitative variables. A bilateral p value < 0.05 was considered statistically significant. All calculations were carried out using the R statistical programming environment.Seventy-one respiratory physicians and/or allergists, of whom 63% worked part or full-time in a hospital environment, answered the survey. Physicians that responded were more likely to be men (71.8% versus 61.3% of non-responders) and less likely to work in the Paris area than non-responders (28.1% versus 21.3%)  years. The mean BMI was 25.9 (SD = 5.23) kg/m3 (n = 515 patients). Atopy was reported in 83% of patients with severe asthma.At the time of diagnosis, the mean FEV1/FVC ratio was 0.60 (SD = 12.2). Mean blood eosinophilia was 396 cells/mmThe annual mean rates of hospitalization and exacerbation in the previous year were 0.65 (SD = 0.90) and 2.25 (SD = 1.85), respectively. A history of admission into an intensive care unit was reported for 21% of patients. The most recent mean ACT score was 16.6 (SD = 4.4).The percentages of never, active and former smokers were 55%, 13%, and 29.5%, respectively; 2.5% were using electronic cigarettes. Regarding comorbidities, 27% had allergic rhinitis, 22% gastroesophageal reflux disease (GERD), 19% anxiety disorders, 10% cardiovascular diseases, and 7% diabetes .Table 1POne hundred one (13.7%) patients were treated with a maintenance daily dose of oral steroids with a mean dosage regimen of 16.1 mg per day (SD = 11.2) of prednisone equivalents. ICS-LABA-LAMA triple inhaled therapy was reported for 288 patients (39%). Two hundred thirty-one patients (31.4%) had one biotherapy in their maintenance treatment. Of note, 29 (4%) had no inhaled corticosteroids . Among p3; among them, 152 (29.6%) patients were admitted at least once during the last 12 months. Among the latter 52  were receiving biologics in their current maintenance therapy. These results are quite similar for patients with no history of admission to the hospital in the past 12 months, except for the proportion of patients treated with oral steroids, regardless of serum eosinophil count, which was less important in this group  (In patients with available eosinophilia data before initiation of current therapy (515/736), 315 (61.2%) had a blood eosinophil count ≥300 cells/mms, 9.4%) , Table 4anti-IgE and/or anti-IL5) were hospitalized at least once in the previous year. The latter corresponded to a total of 136 hospitalizations representing a cost of 192,304€  .Among the 736 patients of the study, 311 (42.3%) were admitted at least once in the previous year, representing a total of 475 hospitalizations for a mean annual cumulative cost of 671,650 €/year. Among the 515 with available T2 biomarkers , 100 who were eligible for biologics  despite optimal inhaled therapy, 305 had no biologics. Among these 305 patients, 166 had data indicating a “T2 status”; 78 (47%), 89 (53.6%), and 137 (82.5%) patients, respectively, had criteria for being treated an biologic .Fig. 1Pr,,This study describes severe asthma management in secondary or tertiary care in France in 2018. Demographic and clinical data are consistent with the recent literature.Among the 736 patients, approximately three quarters had been “phenotyped” for T2 status and around one third were treated with biologics. The vast majority of the latter were treated with omalizumab, which is obviously due to its earlier development and commercialization.According to the above observations, biomarker assessment is still not systematic in routine clinical practice (around 30% missing data for eosinophilia in our study). Eventually, the rise of FeNO evaluations, which are still not refunded in France and thus rarely performed, will increase awareness for the added-value of biomarkers in general. Historically, skin prick tests were the only biomarker of atopy used for characterizing asthma, and it seems that this part of history is still present.anti-IL-4/IL-13 therapy, which is not market-approved at this time in France, corresponds to the vast majority of indications for biologics in “under-treated” patients. This fact is certainly of interest when we think about how each therapy fits into an optimized decision-making process .One important issue highlighted by our study is the “under-management” in secondary care of the most severe patients who were recently hospitalized because of their asthma. Indeed, around 66% were eligible to receive an IL5-targeting drug but did not. More generally, a large proportion of them were not initiated with biologics despite being eligible and suffering from frequent exacerbations and poor asthma control. These observations are consistent with those made in primary care, in severe and non-severe patients. In the REALISE survey (8000 patients from 11 european countries), 45% of respondents had uncontrolled asthma.Consequently, another insightful result of our study is the cost of severe asthma. Indeed, among 736 patients, we computed a potentially avoidable cost of 671,650€ mainly driven by the number of hospitalizations in patients with suboptimal therapeutic management according to current guidelines. Obviously, these results should be cautiously extrapolated to the general population of severe asthmatic patients as our conclusion relies on declarative data. In a recent case-control study using a national French medical claims database, the estimated medical direct cost of severe asthma was $9227/year versus $3950/year for matched patients without asthma.,There are several limits to this study that should be taken in account. First, as for any survey, there is an obvious potential for selection bias. Indeed, only 3% of the contacted physicians were recruited. This may be explained by the length and completeness of the questionnaire, which in turn provides us with precise and valuable information. In addition, the observed patient characteristics correspond well with those of the most recent randomized controlled double-blind trials.Our study updates data for “real-life” therapeutic management in a French severe-asthma population for the year 2018. We highlighted a need for better phenotyping and subsequent treatment tailoring, which could lead to a substantial improvement in public health costs, in addition to an obvious improvement in clinical outcomes. High rates of eligibility for biologics in approved indications suggests that the unmet need represented by low-T2 patients corresponds to only one third of the severe asthma population. Finally, there is clearly room for improving communication between severe asthma expert centers and secondary/primary care. The latter may be achieved through continuing medical education, active participation in multidisciplinary meetings or to the constitution of a register for severe asthma.ACT, Asthma Control Questionnaire; FeNO, Fraction Expired of Nitric Oxide; FEV1, Forced Expiratory Volume in 1st Second; FVC, Forced Vital Capacity; GINA, Global Initiative for Asthma; ICS, Inhaled CorticoSteroids; IgE: Immunoglobulin E; IL5, Interleukin 5; IL5R, Interleukin 5 receptor; IL4/13, Interleukin 4/13; LABA, Long Acting Bêta Agonist; LAMA, Long Acting Muscarinic AgonistThe data that support the findings of this study are available from the corresponding author upon reasonable request.No ethics approval was needed for this survey.No fundings supported this study.The authors have no conflicts of interest to declare in relation with this work. They all contributed equally to this work and give their consent for the publication of this article.