Gene coding mutations found in sodium glucose co-transporters (SGLTs) are known to cause renal glucosuria. SGLT2 inhibitors have recently been shown to be effective hypoglycemic agents as well as possessing cardiovascular and renal protective properties. These beneficial effects have to some extent, been attributed to weight loss and reduced blood pressure. The aim of the current study was to evaluate the prevalence of renal glucosuria amongst a large cohort of Israeli adolescents and to investigate whether renal glucosuria is associated with lower body weight and lower blood pressure values.Medical and socio-demographic data were collected from the Israeli Defense Force’s conscription center’s database. A cross-sectional study to evaluate the association between conscripts diagnosed as overweight [BMI percentiles of ≥ 85 and < 95 and obesity (≥ 95 BMI percentile)] and afflicted with renal glucosuria was conducted. In addition, we assessed the association of renal glucosuria with elevated diastolic and systolic blood pressure. Multinomial regression models were used.The final study cohort comprised 2,506,830 conscripts of whom 1108 (0.044%) were diagnosed with renal glucosuria, unrelated to diabetes mellitus, with males twice as affected compared to females. The adjusted odds ratio for overweight and obesity was 0.66 (95% CI 0.50–0.87) and 0.62 (95% CI 0.43–0.88), respectively. Adolescents afflicted with renal glucosuria were also less likely to have an elevated systolic blood pressure of 130–139 mmHg with an adjusted odds ratio of 0.74 (95% CI 0.60–0.90).Renal glucosuria is associated with lower body weight and obesity as well as with lower rates of elevated systolic blood pressure. Kidneys play a major role in glucose homeostasis. Up to 50% of fasting gluconeogenesis may be attributed to the kidney cortex , 2. In aThe benign nature of FRG, as well as the nearly exclusive expression of SGLT2 in the kidney, has rendered the SGLT2s an intriguing pharmacological target in the development of novel hypoglycemic medications , 9. SubsThe aim of our study was to illustrate in a large population-based cohort of Israeli adolescents, the prevalence of non-diabetic renal glucosuria (RG) and investigate whether these subjects were less likely to exhibit cardiovascular risk factors such as increased body weight and elevated BP levels.All male and female Israeli adolescents, eligible for mandatory military service in the Israeli Defense Forces (IDF), are obligated to undergo a medical health assessment approximately 1 year prior to conscription. The medical assessment for military service candidates comprises a detailed medical history based on a status report completed by the candidates’ primary care physician and a thorough physical examination. Basic ancillary tests also include height, weight, BP measurements and a dipstick urinalysis. Valid computerized data relating to RG have been available since 1974. A glucosuria diagnosis is based upon a positive repeated qualitative urine dipstick prompting an evaluation to rule out DM and kidney disease which includes a morning fasting glucose, a 2-h oral glucose tolerance test and a biochemistry evaluation including serum creatinine and electrolytes. In the event of any missing data or abnormal findings during the initial assessment, the examinees were sent for a further, more comprehensive medical evaluation. All confirmed diagnoses were numerically coded by a trained military medical board.Complete valid computerized data regarding BP measurements have been available since 1977. BP was measured in a sitting position, after a 5–10 min rest period, by a manual sphygmomanometer with an appropriately-sized cuff placed on the right arm, at heart level. Data as to socio-demographic characteristics were collected through personal interviews with all examinees. Our study included subjects aged 16–19 years, examined between January 1, 1974 and December 31, 2016. We excluded adolescents diagnosed with DM (n = 3113) and proteinuria (n = 4743)  was used for statistical analyses in our study. Univariate and multivariable logistic regression models evaluated the crude, adjusted odds ratio (aOR) and the 95% confidence interval (95 CI%) for RG, amongst males and females. The multivariable models were adjusted for year of examination, age at the time of examination, country of origin, body mass index (BMI), socio-economic status (SES) and years of education.Univariate and multivariable multinomial regression models were conducted to evaluate the crude, the adjusted OR and the 95% CI, respectively, for weight status and systolic blood pressure (SBP) and separately for diastolic blood pressure (DBP). We adjusted the multivariable models for variables associated with the outcomes in the univariate analyses and for variables known to be associated with the outcome based on previous research. Several multivariable analyses were performed; the first, Model 2, was adjusted for the year of examination. Model 2A,  was adjusted for year of examination and BMI. Model 3, was also adjusted for sex, age at the time of examination, country of origin . Model 4, in addition to the variables of the former models, was also adjusted for SES based on the examinee’s place of residence which was divided into three groups based on a scale taken from the Israeli Central Bureau of Statistics .Years of education were divided into four groups ; weight status into seven BMI percentile groups according to the Centers for Disease Control and Prevention Growth Charts : < 5% . BMI percentile distribution in those diagnosed with RG and those without RG are shown in Fig. Mean BMI was 20.91 kg/mThe relationship between RG and BP was assessed in 2,374,157 examinees  of whom 1058 [786 males (74.3%)] had been diagnosed with RG. The mean BP was 118/72 mmHg in the RG group and 117/71 mmHg in the non-glucosuric group . Compared to a reference of SBP 110–119 mm/Hg in the final adjusted model, the aOR was 0.74 (95% CI 0.60–0.90) for SBP of 130–139 mm/Hg  had a higher mean BMI, SBP and DPB compared to non-glucosuric subjects . HoweverOur study has several notable limitations. Firstly, we had no data as to the severity of glucosuria amongst examinees diagnosed with RG. Secondly, study participants were analyzed as a homogenous group regardless of the specific genetic mutation associated with RG. Theoretically, different mutations may be associated with varying degrees of glucosuria, thereby, inducing variable body weight and BP reductions. Furthermore, our glucosuria estimation was qualitative and not quantitative, hence, we could not draw any conclusions as to the effects of increasing urine glucose and any measured outcomes. Thirdly, the BP values analyzed in our study were derived from a single BP office measurement taken in a potentially stressful environment (known to increase the probability of white coat-associated elevated BP measurement) . Yet, moTo the best of our knowledge, the current study is the largest trial to date evaluating the prevalence of RG in a late-adolescent population without DM. Our data indicate that in adolescents, RG is more common in males and is significantly associated with lower body weight, less obesity and lower rates of SBP values in the hypertension range. These findings may support the assumption that SGLT2 inhibitors may reduce weight and BP in non-diabetic individuals. Well-powered large scale studies are essential in order to clarify whether these RG-associated beneficial metabolic effects in adolescence have any ramifications on future cardiovascular morbidity and mortality. Well-powered large scale studies are essential in order to clarify whether these RG-associated beneficial metabolic effects in adolescence have any ramifications on future cardiovascular morbidity and mortality rates.Additional file 1: Figure S1. Flow chart describing the study cohort (1974–2016). Figure S2. BMI percentile group distribution amongst males N = 1,469,718 (1974–2016). Figure S3. Systolic blood pressure groups distribution amongst the general population N = 2,374,157 (1977–2016). Figure S4. Systolic blood pressure group distribution amongst males N = 1,384,360 (1977–2016). Table S1. Glucosuria and BMI percentiles in males only (1974–2016). N = 1,469,718. Results of multinomial regression models. Table S2. Glucosuria and blood pressure in males only. (1977–2016). N = 1,384,360. Results of multinomial regression models.


A potential mechanism underlying cigarette smoke-induced airway disease is insufficient tissue repair via altered production of matrix metalloproteinases (MMPs). Osteitis is a signature feature of recalcitrant chronic rhinosinusitis (CRS) and often results in revision surgery. The present study aimed to investigate MMP expression in the nasal tissues of asthmatic patients with CRS and any association with cigarette smoking and osteitis. Thirteen smokers with CRS and asthma, 16 non-smokers with CRS and asthma, and seven non-smoker asthmatic patients without CRS were prospectively recruited. The expression of MMPs and associated immunological factors in surgically-obtained nasal tissues was evaluated via real-time PCR and western blotting. Maximal bone thickness of the anterior ethmoid (AE) partition was measured in axial sinus computed tomography (CT) sections. MMP-1 and MMP-9 expression was increased in the nasal tissues of smokers with asthma and CRS via real-time PCR and western blot. Maximal AE partition bone thickness was greater in smokers with CRS and asthma than in non-smokers with CRS and asthma. MMP-1 and MMP-9 levels were correlated with maximal AE bone thickness. Cigarette smoking was associated with the up-regulation of MMP-1 and MMP-9 in the nasal tissues of patients with airway inflammatory diseases, and with AE osteitis, and with therapeutic resistence. Type 2 inflammatory cytokines, such as IL-5 and IL-13, are considered key drivers of airway inflammation in patients with CRS and asthma3. However, the IL-17A mediated immune response has been linked to neutrophil recruitment, airway remodeling, and resistance to corticosteroid-based therapy in airway disease cases6. A recent study by our group revealed that cigarette smoking was related to IL-17A activation in the nasal tissues of asthmatic patients with CRS and attenuated improvements in asthmatic patients after nasal surgery8. Cigarette smoke contains over a 1,000 chemicals, and chronic obstructive pulmonary disease (COPD)-like airway injury and remodeling occur in chronic cigarette smoke exposure rodents models10. A potential mechanism for cigarette smoke-induced airway disease is insufficient tissue repair via altered production of matrix metalloproteinases (MMPs)11.Chronic rhinosinusitis (CRS) and asthma are common inflammatory airway diseases and frequently comorbid, as per the “unified airway” concept2+-activated, zinc-dependent endopeptidases, which may be produced by airway epithelial cells, fibroblasts, and inflammatory cells12. MMPs play an essential role in the degradation of basement membranes and extracellular matrix proteins including collagens IV, V, VII, X, and XIV; gelatin; and elastin. MMPs contribute to the tissue edema and remodeling seen frequently in inflammatory diseases of the airway including asthma, COPD, and CRS14.MMPs comprise a family of Ca15. Higher levels of MMP-9 are associated with increased asthma severity and decreased lung functioning. MMP-12 is also an elastolytic proteinase found in the alveolar macrophages of cigarette smokers16 and is relevant to cigarette smoke-induced emphysema17.Tissue remodeling in the lower airway has been extensively studied in asthmatics and in patients with COPD. For example, MMP-9, also known as gelatinase B or 92 kDa gelatinase, is a critical elastolytic enzyme produced by alveolar macrophages in COPD patients. It is also secreted by neutrophils, epithelial cells, mast cells, and fibroblasts18. Elevated MMP-1,-2,-7,-8, and -9 have also been noted in the sinonasal tissues of CRS patients20. In particular, MMP-9 is significantly lower in patients with good mucosal healing after sinus surgery compared to those with poor healing21. MMP-9 plays an important role in the pathophysiology of osteitis in CRS22. Osteitis, a form of neo-osteogenesis due to inflammation rather than infection, is a common factor in recalcitrant CRS and is associated with revision sinus surgeries and CRS severity, indicated by elevated Lund-Mackay computed tomography (CT) scores25. IL-17A, a signature CRS cytokine27, promotes MMP-9 expression by activating the NF-κB signaling pathway in the nasal tissues of patients with CRS and nasal polyps28. As a result, the relationship between cigarette smoking, IL-17A, and MMPs is worthy of investigation.Recent studies have indicated that sinonasal tissue remodeling occurs secondary to CRSGiven the above background, we hypothesized that IL-17A-mediated immune responses and MMPs expression might be associated with cigarette smoke-related airway inflammation, osteitis formation, and resistance to current therapeutic regimens. The present study aimed to investigate the expression of MMPs in the nasal tissues of asthmatic patients with CRS and its association with cigarette smoking and osteitis.29 and CRS was defined using the criteria established in the European CRS position paper30 and was based on subjective symptoms and objective findings from nasal endoscopy and sinus CT. Participant inclusion criteria included a diagnosis of asthma (1) with regular follow-up for at least 1 year; (2) failed medical treatment for nasal symptoms; and (3) plans to undergo nasal surgery. Exclusion criteria included previous nasal surgeries or major medical comorbidities such as diabetes, nephrotic diseases, autoimmune disorders, immunodeficiencies, malignancies, and other chronic illnesses. Seven non-smoker asthmatic patients without CRS (confirmed by sinus CT) were enrolled in the control group during septomeatoplasty and/or turbinoplasty. Participants provided informed consent prior to study enrollment. All research was performed in accordance with the relevant guidelines and regulations and all Institutional Review Board requirements.The Institutional Review Board of the Chang Gung Memorial Hospital approved of all study procedures undertaken here (IRB Numbers: 101-5069B and 103-7085B). Asthmatic patients with CRS were prospectively recruited between August 2013 and June 2016. Asthma diagnoses fulfilled Global Initiative for Asthma (GINA) asthma diagnosis guidelines31.Patient clinical characteristics were determined at enrollment and at a 6 month follow-up appointment. Patients were asked if they regularly used cigarettes or other forms of tobacco pre-operatively. Patients were considered to be smokers if they reported regular or on-going smoking in the last 12 months and non-smokers were considered to be those who never regularly used cigarettes1), and FEV1/FVC ratio, were measured before and 6 months after nasal surgery. The severity of sinonasal symptoms and the level of asthma control were evaluated by the Sino-Nasal Outcome Test-22 (SNOT-22)32 and Asthma Control Test (ACT) questionnaires33, respectively.A preoperative nasal endoscopy examination and sinus CT, which were scored using the Lund-Kennedy endoscopy score and Lund-Mackay CT score, were completed in all patients. The maximal thickness of the bony partition of the anterior ethmoid sinuses (AE) was measured on an axial sinus CT section for each patient Fig. . PulmonaNasal mucosal specimens were obtained during nasal surgery and rinsed in phosphate-buffered saline (pH 7.6), stored in liquid nitrogen at −70 °C, and then processed for immunoblotting and real-time polymerase chain reaction (PCR).Frozen nasal tissues from all 36 participants were homogenized . Total RNA was extracted from nasal specimens using the RNeasy Mini Kit  and quantified by NanoDrop . Reverse transcription was performed with random hexamer primers using the High-Capacity cDNA Reverse Transcription Kit . Real-time PCR was done using the TaqMan assay with primers specific to each target gene Table  and glycNasal tissues from 21 participants with adequate specimens, including seven smokers with asthma and CRS, nine non-smokers with asthma and CRS, and five asthmatic non-smokers without CRS were processed for western blot analyses of MMPs. Total protein was prepared using a 1% IGEPAL lysis buffer . Cellular proteins (10 μg) were fractionated by SDS-PAGE and electroblotted onto polyvinylidene difluoride membranes. Primary antibodies including MMP-1 , MMP-9 , MMP-12 , and β-actin  were used to assess differences in protein levels by enhanced chemiluminescence. Protein bands were visualized using a gel documentation system . Relevant band intensities were quantified via densitometric analyses and normalized to β-actin.х2 or Fisher’s exact tests, as appropriate. Continuous variables were analyzed using the Mann-Whitney U test or Kruskal-Wallis H test when comparing between two or three groups. Correlations were determined using the Spearman’s correlation coefficient (r). Statistical significance was set at p < 0.05.Data are presented as mean ± standard deviation (SD) and statistically analyzed using GraphPad Prism 5 . Categorical variables were compared using Participants included 13 smokers, 16 non-smokers, and 7 non-smokers with asthma and without CRS. Participant characteristics are summarized in Table The mRNA expression of MMP-1  between cigarette smoke and neo-osteogenesis in AE with asthma and CRS. Taken together, these results reveal that cigarette smoking may have association with an IL-17A-mediated inflammatory response and increased MMP-1 and MMP-9 expression in the nasal mucosa of patients with asthma and CRS. This may then results in tissue remodeling, which involves neo-osteogenesis or osteitis of the sinus, and thus poorer outcomes following sinus surgery.Osteitis was initially defined as bony thickening of the sinus walls in CRS37. Exposure to diesel exhaust particles, traffic-related air pollution, and PAH induces IL-17A production and can lead to severe asthma38. Th17 polarization is initiated in an AhR-dependent manner through the stimulation of atmospheric particulate matter (PM) in the murine lung. PAHs in the PM are likely sources of Th17-promoting activity39. Recent work also demonstrated that IL-17A promotes the expression of MMP-9 by activating the NF-κB signal pathway, revealing a crucial role for IL-17A in the pathogenesis of CRS and associated tissue remodeling28. MMP-9 also plays a critical role in the pathophysiology of osteitis in CRS and MMP-9 overexpression, which is steroid-independent, suggesting its relevance to therapeutic resistance22. Taken together, MMPs from IL-17A-mediated inflammation via the AhR activation induced by cigarette smoke exposure may thus contribute to neo-osteogenesis and recalcitrant disease in patients with CRS and asthma.Cigarette smoke contains many AhR-activating ligands such as polycyclic aromatic hydrocarbons (PAHs)3 and are thus correlated with these objective severity measurements of CT and endoscopy. Furthermore, MMPs such as MMP-1 and -9 may be predictors of lower airway obstruction and resistance to contemporary steroid-based medical treatment in patients with CRS and asthma. Therefore, defining the role of MMPs and their association with immune pathways is imperative in designing, implementing, and tailoring therapeutics to successfully treat these patients. Future novel therapeutics that target MMP-related inflammatory responses may thus be beneficial to those with asthma or CRS that is refractory to current standard treatment protocols. For example, antibiotics such as doxycycline are established MMP-9 inhibitors may be beneficial to this group of patients.In the current study, MMP-1 and MMP-9 levels were correlated with FEV1/FVC (% predicted), while IL-5 and IL-13 mRNA levels were associated with the CT scores and endoscopy scores, respectively. These results implicate MMPs, which might be induced by cigarette smoke, in lower airway obstruction and sinus osteitis, which were not evaluated via CT and endoscopy scores here. Type 2 inflammatory cytokines such as IL-5 and IL-13 are key mediators of airway inflammation in patients with CRS and asthma24, we suggested it might be suitable for recurrent rather than our primary CRS cases. It not common for bony thickening >3 mm or >5 mm in primary CRS cases. We measured the maximal AE partition bone thickness on CT images to evaluate the severity of neo-osteogenesis instead and AE was selected because it is possible the most exposed sinus to the inhale cigarette smoke. Third, cigarette smoking data was collected by patient self-report, which is not always valid. Quantification of serum nicotine and cotinine levels and analysis of their relationships with cytokine expression should also be further considered to clarify the immune response associated with cigarette smoke exposure of the airway.While it offers potentially significant insights into the improved treatment of asthmatic patients with CRS, the present study has several limitations that warrant some consideration. First, this study would have benefited from the inclusion of patients without airway diseases and CRS in a normal control group. However, inclusion of such a group was not permitted by our institutional ethics committee due to the requirement for an invasive biopsy of the nasal mucosa. Second, a larger-scale study is necessary for further subgroup analyses, such as that of CRS patients with and without polyps or patient stratification by the severity of osteitis. Although scoring system of osteitis such as global osteitis scoring scale have been proposedCigarette smoking was associated with the up-regulation of MMP-1 and MMP-9 in the nasal tissues of patients with airway inflammatory diseases and with neo-osteogenesis of AE in the present study.supplementary data


Obstructive sleep apnea (OSA) is a condition characterized by recurrent episodes of partial or complete upper airway obstruction during sleep. Hypertension (HTN) is defined by the presence of a chronic elevation of systemic arterial pressure above a certain threshold value (≥140 mm Hg systolic or ≥90 mm Hg diastolic). On the surface, OSA and HTN appear very different from one another. Despite this, they share several common risk factors including obesity, male gender, and advancing age. In 2003, the Seventh Joint National Committee (JNC VII) recognized OSA as a secondary cause of HTN. As physicians, our goal is to understand the OSA-HTN association better through academic study regarding its epidemiology, its pathophysiology, and its treatment.  Over the years, there has been some overlap between patients of obstructive sleep apnea (OSA) and hypertension (HTN) with about 50% of HTN patients also having concomitant OSA . As physOSA is a condition described as recurrent episodes of upper airway inspiratory collapse during sleep, leading to hypopnea (breathing reduction) or apnea (breathing cessation) episodes that cause transient hypoxemia (low oxygen levels in the blood) and hypercapnia (elevated carbon dioxide levels in the blood) . The patHTN is a condition that refers to a sustained increase in BP beyond certain systolic (SBP) and diastolic blood pressure (DBP) levels. The majority of current definitions define HTN as SBP ≥140 mm Hg and/or DBP ≥90 mm Hg . The curEpidemiology of OSA and HTNOSA is a highly prevalent sleep disorder that is estimated to affect 15% to 24% of all adults, but that the number is believed to be incorrect because OSA is still greatly underdiagnosed . In 2017According to a report from AHA, between 2011 and 2014, the prevalence of HTN in the United States adults was 45.6%  . This waPast research studies have been successful in demonstrating epidemiological evidence of the OSA-HTN relationship. They have determined that OSA is not only a predisposing factor for HTN but there is also a greater incidence of OSA in hypertensive patients -15. OSA PathophysiologyOSA and HTN are both multifactorial diseases . They shSleep Inefficiency Due to OSAp = 0.004) and short sleep duration (p = 0.003) were both significantly associated with HTN, whereas poor sleep was not (p = 0.756) [Impaired sleep quality (sleep inefficiency and shorter sleep duration) can lead to OSA development . There i= 0.756) .Nocturnal Fluid Shift in OSAAnother significant pathophysiological mechanism is nocturnal fluid redistribution . During The Autonomic System Counterregulatory Mechanisms Against Apneic EpisodesOSA patients have apneic episodes caused by airway collapse during sleep . These eThe Inflammatory and Cytokine-mediated Effects of HypoxemiaOSA causes intermittent nocturnal hypoxemia and hypercapnia that causes oxidative stress and inflammation . The oxiNegative Intrathoracic Pressure Putting Stress on the HeartOSA causes intermittent negative intrathoracic pressure in patients . This paThe Renin-Angiotensin-Aldosterone SystemOSA causes hypoxemia leading to an activation of the renin-angiotensin-aldosterone system (RAAS) . RAAS stManagementWith OSA and HTN, the goals of initial evaluation are to determine the patient’s baseline, evaluate for target organ damage, screen for potentially curable causes, identify risk factors that are present, determine the prognosis, and choose a therapy that is specific to the patient’s needs . A complCPAP TherapyFor all cases of OSA, CPAP remains the main therapy utilized but its effect on BP reduction has not been proven to be completely effective . In prevLifestyle ModificationsObesity is one of the few risk factors commonly seen in both OSA and HTN. Because of this, a reduction in weight can help reduce the OSA severity and BP in an HTN patient. A 2000 cohort study found that a weight gain of 10% led to a 32% increase in AHI and a six-fold increase in the odds of developing moderate to severe OSA . In addiAntihypertensive DrugsAntihypertensive medications can be prescribed to all patients with HTN who have mild to moderate OSA (who do not require CPAP therapy) . They caOral AppliancesP = 0.04) and 2.7 mm Hg , respectively [In mild to moderate OSA, oral appliances can be recommended as an alternative treatment to CPAP . A meta-ectively .Upper Airway SurgeryUpper airway surgery is also a treatment option for OSA patients who require BP reduction . These oMore and more OSA patients present or need treatment for co-existing HTN. The OSA airway collapse leads to the BP being driven up, and without treatment, the patient continues in a self-perpetuating pathophysiological cycle that leads to an increase in their cardiovascular and cerebrovascular risk. Although enormous collected data and treatments are available for OSA requiring BP reduction, more strategies are critically needed. The only way to make this happen is to create a path for more research and larger clinical trials. As physicians, we must spearhead this cause because more and more of our patients will come in with this condition.


High blood pressure is the leading risk factor for premature deaths and a major cost to societies worldwide. Effective blood pressure-lowering drugs are available, but patient adherence to them is low, likely partly due to side effects. To identify patient-specific differences in treatment effects, a repeated cross-over design, where the same treatment contrasts are repeated within each patient, is needed. Such designs have been surprisingly rarely used, given the current focus on precision medicine. The Precision HYpertenSIon Care (PHYSIC) study aims to investigate if there is a consistent between-person variation in blood pressure response to the common blood pressure-lowering drug classes of a clinically relevant magnitude, given the within-person variation in blood pressure. The study will also investigate the between-person variation in side effects of the drugs. In a double-blind, randomized, repeated cross-over trial, 300 patients with mild hypertension will be treated with four blood pressure-lowering drugs  in monotherapy, with two of the drugs repeated for each patient. If the study indicates that there is a potential for precision hypertension care, the most promising predictors of blood pressure and side effect response to the drugs will be explored, as will the potential for development of a biomarker panel to rank the suitability of blood pressure-lowering drug classes for individual patients in terms of anticipated blood pressure effects and side effects, with the ultimate goal to maximize adherence. The study follows a protocol pre-registered at ClinicalTrials.gov with the identifier NCT02774460. High blood pressure is the leading risk factor for premature deaths worldwide  and accoEffective blood pressure-lowering drugs are available, with the first-line drug classes—angiotensin-converting enzyme (ACE)-inhibitors, angiotensin receptor blockers, calcium channel blockers, and thiazide diuretics—considered equally effective on average. Most of their protective effects depend on the amount of blood pressure reduction achieved, and there are few class-specific protective effects . They doPoor adherence is likely the main cause of poor blood pressure control, with as little as 1 in 2 patients estimated to be adherent to prescribed treatment in developed countries . BecauseThe concept of precision medicine promises maximization of treatment benefit and minimization of treatment harm using subtle characteristics  of patients with the same trait to guide treatment decisions. If the promise holds true widely, hypertension would be an optimal field, with a handful of first-line drug classes that all have similar average blood pressure-lowering effects, and each has common side effects that hamper adherence.For hypertension, the concept needs answers to several important questions. The most important question is if there is a clinically relevant and repeatable between-person difference in blood pressure response or side effects to a given drug . If therIf this study indicates that there is a potential for personalized blood pressure-lowering treatment, we will explore the most promising predictors of blood pressure and side effect response to the drugs, using peripheral blood analyses in combination with clinical data. If feasible, we will then explore the potential for development of a biomarker panel to rank the suitability of each of the blood pressure-lowering drug classes for the individual patient in terms of both anticipated blood pressure effect and side effects, with the ultimate goal to maximize adherence.The primary objective is to establish the potential for precision hypertension care, by investigating if there is a consistent between-person variation in blood pressure response to the common blood pressure-lowering drug classes of a clinically relevant magnitude, given the within-person variation in blood pressure.To investigate the between-person variation in side effects of blood pressure-lowering drugs in contrast to the within-person variation in side effects.To investigate patient treatment preferences when presented with: i) their individual ratings for each drug class; ii) a combination of their individual ratings and blood pressure effect of each drug class.To develop a prediction model based on biomarkers and clinical characteristics for patient treatment preferences.To develop and evaluate a point-of-care tool using this prediction model, in order to inform treatment decisions in the clinical setting.To evaluate between- and within-person variation in response in mean and standard deviation of daytime, nighttime, and 24-h blood pressure and heart rate to the common blood pressure-lowering drug classes.To evaluate between- and within-person variation in self-reported symptoms and quality of life in response to the common blood pressure-lowering drug classes.To evaluate between- and within-person variation in pulse wave characteristics and estimated central blood pressure in response to the common blood pressure-lowering drug classes.To evaluate between- and within-person variation in DNA methylation, RNA, proteins, and metabolites in response to the common blood pressure-lowering drug classes.To investigate associations of DNA genomic variation, DNA methylation, RNA, proteins, and metabolites with blood pressure effects and self-reported symptoms and quality of life.To investigate the associations of self-reported symptoms and quality of life collected using an electronic diary with patients’ treatment preferences and adverse events reported in the clinic.To identify the patient-by-treatment interactions and hence investigate the patient-specific differences in treatment effects, a repeated cross-over design, where the same treatment contrasts are repeated within each patient, is needed. This has been convincingly suggested for decades , but sucThe study needs to be double-blind, and the order of the treatment periods randomized, in order to avoid obvious sources of bias.Evidence-based titration and target doses have been chosen for all four drug classes included in this protocol . Within The study is outlined in The first patient was randomized in the first quarter of 2017; last patient out is expected in the fourth quarter of 2021.Visit 1. The screening visit (visit 1) will occur at least two weeks before randomization (visit 2). Written informed consent is obtained, eligibility criteria  in accordance with national guidelines (SBU 2007) is provided to all participants.Placebo run-in period. After the screening visit, the patient stops taking any concomitant blood pressure-lowering drugs and starts on a placebo run-in period of two weeks to establish an untreated baseline to be used for characterization of the study sample.Visit 2. At visit 2, eligibility criteria are checked once again. Assessments made at this visit include fasting venous and capillary blood sampling, questionnaires, and pulse wave analysis, and 24-h blood pressure and ECG monitoring is initiated.If all criteria are met, the patient is randomized and given the first study drug. The study drug is to be taken once daily.The day after visit 2, the patient returns the 24-h blood pressure and ECG equipment to the clinic.Treatment period. Between visits 2 and 3 patients are dosing study drug at home, and fill out the side effects questionnaire at home at specific time points.Visit 3. At visit 3 of each treatment period  the patient comes fasting to the clinic for blood sampling, body weight, concomitant medication, and adverse events (AE) checks, office BP measurement, and initiation of 24-h blood pressure and ECG measurement. The patient fills out two paper questionnaires: the side effect questionnaire  and a treatment preference rating questionnaire. The patient returns all unused study drug (ensuring that they have full coverage of study drug until the completion of visit 4) and receives the next treatment kit, which starts with a 7-day placebo wash-out period before the next active drug treatment period starts.In rare cases, if a patient due to unbearable side effects of a specific treatment so wishes, bailout visits 3 and 4 can be carried out and the treatment period terminated prematurely so that the next treatment period can begin.Visit 4. At visit 4, the day after visit 3, the 24-h blood pressure and ECG measurement ends and the patient returns the equipment to the clinic. The treatment periods and visits 3 and 4 are repeated for a total of 6 times.Visit 5. Visit 5 occurs 1–2 weeks after the sixth and last visit 4. At visit 5, the patient is asked by an independent physician to do an overall treatment preference rating including all treatment periods, based on a summary of the patient’s own reported side effects, treatment preference ratings for all treatment periods, and ambulatory daytime blood pressures. All data in the summary have been validated by data management personnel, signed by the PI and locked before being presented to the patient. As a final step, the independent physician breaks the randomization code for each completed patient, and prescribes the drug preferred by the patient for continuous use.Intention-to-treat analyses will be used for all side effects, including all patients taking at least one dose of the study drug in a new treatment period. As-randomized analyses will be used for blood pressure endpoints, including all patients having had a treatment adherence of more than 90% during that treatment period.p values. P < 0.05 will be considered statistically significant.The primary analysis of individual variation in treatment differences in visit 4 daytime systolic blood pressure will be performed using a random effects model with correlated random intercept and treatment contrasts, allowing correlation between all random effects, and with treatment period as a fixed effect. All available periods with >90% treatment adherence from all randomized patients will be used. The global hypothesis—that there is a contribution from patient-specific differences in relative treatment response to the variation in on-treatment blood pressure in the analysis set—will be tested using a likelihood ratio test based on the maximum-likelihood fit of that model compared to a model with random intercept (only) and treatment contrasts and treatment period as fixed effects. Since variance parameters must be non-negative, the null hypothesis lies on the border of the parameter space of the larger model. Hence the usual assumption of chi-square distribution in the likelihood ratio test is not valid, and the test statistic will be compared to a reference distribution obtained by parametric bootstrapping to obtain a Appropriate methods will be used to present estimates of treatment contrast variances, covariances, and residual variance. Homoscedasticity of the residual variance will be investigated. A detailed statistical analysis plan for pre-defined analyses will be finalized before unblinding. Problems with model convergence or other changes to the analysis will be recorded in a statistical report.X and Y), descriptive plots and tables will be produced based on the patients that had repeated periods with both treatment X and Y. A pre-defined pairing of the periods for each patient, into what amounts to two cross-over trials in the same patient, will be used to produce two independent measurements of the treatment contrast X–Y within each patient.For each pair of treatment regimens  to address the causal role of the identified biomarkers for blood pressure response and side effects, which is unimportant for prediction purposes, but key for further investigation of new druggable targets.p values was computed using 1000 bootstrap iterations for the reference distribution of the test statistic , and packages lme4 v. 1.1–10  and pbkrtatistic . P < 0.0n = 240 patients, the trial has a power of 82% for detecting individual treatment effects if only one treatment arm differs from the others by having an individual variation in effect with SD =7.5 mmHg, and a very high power if two or three treatments have patient-specific effects on that level.Two scenarios were simulated. In the first, normally distributed uncorrelated individual treatment effects were added to between one and four of the treatment arms, with a standard deviation of 5, 7.5, or 10 mmHg. With The second scenario is intended to describe a simplified on/off switch for effect. We assume that for one of the treatments 20%, or 50%, of the patients experience an effect that is 10, 20, or 30 mmHg higher (or lower) than the remaining patients. The trial has 90% power to show if a subgroup of 20% of patients has an effect that differs by 20 mmHg on one of the treatments. In terms of SD of treatment effects, the power is similar to the simulations under normal distribution (the SD is the subgroup effect times 0.5 for the 50% case and times 0.4 for the 20% case).The study was approved by the Ethics Committee of Uppsala University (Dnr 2016/135) and the Swedish Medical Products Agency . The study follows a protocol pre-registered at ClinicalTrials.gov with the identifier NCT02774460. The study is conducted in accordance with the protocol, applicable regulatory requirements, GCP, and the ethical principles of the Declaration of Helsinki as adopted by the 18th World Medical Assembly in Helsinki, Finland, in 1964 and subsequent versions. Written informed consent will be obtained from all patients prior to enrolment in the study.The study will be patient-, investigator-, study nurse-, UCR study team-, and sponsor-blinded. Clinical examinations, interpretations of 24-h blood pressure and ECG measurements, and assessments of side effects, treatment preferences, and other questionnaires will be performed by persons unaware of the treatment allocation.The order of the different active treatments is randomized for each patient. The patients are assigned consecutive randomization numbers according to their inclusion order, and clinical staff will record the numbers being used. The randomization list is prepared at Uppsala Clinical Research Center (UCR).The investigational products are manufactured and packaged in inconspicuous blister packaging and labelled by Apotek Produktion och Laboratorier AB (APL) in accordance with good manufacturing practice (GMP) and local regulatory guidelines.Electronic case report forms (eCRF) are used for all data collection, in accordance with a pre-specified data management plan. In accordance with GCP principles, monitoring of the study is arranged by the sponsor, and carried out by UCR, in accordance with a pre-specified monitoring plan.This study uses two study databases, database #1 for the majority of the study, and database #2 for visit 5. On an individual patient level, after the last visit 4, database #1 is validated by data management personnel, signed by the PI, and locked, before being presented to the patient by an independent physician. After each patient has provided a new overall treatment preference rating, the independent physician signs the eCRF, breaks the randomization code for that patient, and enters the eCRF data into database #2. Upon study completion databases #1 and #2 are merged.In the PHYSIC trial, we use the only design that can study the potential for precision medicine for blood pressure-lowering treatment . The cru


Hypertension is a common cardiovascular disease at present. Uncontrolled blood pressure leads to further complications including heart attack, stroke and chronic kidney disease. In Thailand, most of the information related to this issue is collected by hospitals or hospital-based organizations rather than at the community level. The objectives of this study were to determine the prevalence of uncontrolled hypertension and to assess the relationship between patient characteristics  and uncontrolled blood pressure among hypertensive patients in the rural communities in the central areas in Thailand.This was a cross-sectional study conducted in Na-Yao and Phra-Pleong rural communities of Thailand in 2018 using the total design method. In all, 406 individuals aged ≥18 years were interviewed using structured questionnaires related to demographic information, higher risk behavior, comorbidities and arthrometric measurement. Blood pressure was assessed for all participants. Uncontrolled hypertension was defined as BP ≥140/90 mmHg.The prevalence of uncontrolled hypertension was 54.4% . Uncontrolled blood pressure was associated with neck circumference more than 35.75 cm for males and 32.75 cm. for females , sedentary behavior more than 5 hours a day  and missed doctor appointments .Approximately one half of hypertensive patients in these rural communities had uncontrolled blood pressure. The Ministry of Public Health and health care providers should provide further strategies to prevent uncontrolled blood pressure’s complications. Nowadays, hypertension is a common and primary risk factor for cardiovascular diseases.  It is onNevertheless, in Thailand, most information related to hypertension is collected in hospitals or hospital-based organizations rather than at the community level. A half of areas in Thailand are still rural (47%) where the healthcare infrastructure and healthcare provider characteristics differ from those of urban vicinities especially in remote rural areas.  FurthermThis study was conducted in two rural communities of the central areas in Thailand, 160 kms from Bangkok Metropolitan: Na-Yao rural community in Chachoengsao province and Phra-Pleong rural community in Sakaeo province. These remote communities are housing approximately 12,000 people with agriculture as the major occupation. A cross-sectional study was conducted in January 2018. A total survey was used to collect the information from the target population. The registered patients presenting hypertension in these rural communities were retrieved from the databases of PHC units and community hospitals. All of 406 patients with hypertension were interviewed. Inclusion criteria of the study comprised presenting hypertension, receiving medical treatment in a PHC unit or a community hospital for the past 12 months and aged ≥18 years. The patients would have been excluded from the study if they had been pregnant or at their postpartum stage (within eight weeks).The healthcare system in Thailand can be categorized into two types comprising (1) the healthcare system under the Ministry of Public Health and (2) the private healthcare system such as private clinics and hospitals. All Thais have healthcare coverage schemes such as the universal coverage scheme, social insurance scheme and government officer scheme.The 420 participants were recruited to the study from PCU officers. Participants were identified by a computerized search of medical records, undertaken by the PCU staff and were asked to participate in the study. Posters in front of the PCU also reminded patients and encouraged them to be interested in participating in the study. The participants visited the PCU to join the study. Moreover, the research team seek for the patients at their houses to encourage them to join the study. From all of 420 patients, 406 hypertensive patients were included in the study. 14 participants were excluded from the study because 2 of them were post-partum women and 12 hypertensive patients did not live in the target areas at the period of studying. The informed consent in Thai was obtained before conducting the research. In case participants could not read the information sheet, the research team would read the information to them and then the participants could use their finger print to confirm their agreement on the consent form. The participants did not receive any incentive for participating in the study. During the study, one participant spent 30 minutes to provide complete information. Face-to-face interviews were conducted by using standardized questionnaires to obtain the required information from patients with hypertension. The interviewers were well trained.Standardized questionnaires, developed by the research team, covered information on demographics, self-reported comorbidities including diabetes mellitus, dyslipidemia, gout, chronic kidney disease, antihypertensive medication used, physical activities, sedentary behaviors including sitting and sleeping at home, smoking and alcohol consumption. Ex-smoker and Ex-drinker were defined by smoke-free and alcohol-free for 12 months, respectively. Never alcoholic drinking was defined by alcoholic drinking for life-time period. Never smoker were patients who has never smoked, or who has smoked less than 100 cigarettes in his or her lifetime.  The sedeWe measured systolic blood pressure (SBP), diastolic blood pressure (DBP), weight (in kilogram) and height (in centimeters), body mass index (BMI) (in kilogram/meter-squared), waist circumference (in centimeters) and neck circumference (in centimeters). Antihypertensive agents were identified and categorized into the following classes: (1) diuretics, (2) anti-adrenergics [α- and ß-blockers], (3) calcium channel blockers [CCBs], (4) angiotensin converting enzyme inhibitors [ACEIs] and (5) angiotensin receptor blockers (ARB).2. BMI was classified in five groups including <18.5kg/m2 (underweight), 18.5–22.9kg/m2 , 23.0–24.9kg/m2 (overweight), 25.0–29.9 kg/m2 (obesity I), and ≥30kg/m2 (obesity II). [Hypertension was defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) hypertension guidelines, i.e., a high blood pressure (SBP ≥140 mmHg or DBP ≥90mmHg). Uncontrolled hypertension was defined by JNC 7 hypertension guidelines, as the hypertensive patients, with medical treatment, have a blood pressure of SBP ≥140 mmHg or DBP≥90 mmHg.  Blood prity II).  Waist ciity II).  Waist ciity II).  Neck cirity II). t-test. Demographic characteristics, behavioral data and co-morbidity were stratified by sex. Binary logistic regression analysis was used to determine the risk factors associated with uncontrolled hypertension. The magnitude of association was presented as crude odds ratios (ORs) with 95% confidence interval (CI). A p-value less than 0.05 was considered as statistically significant. Differences identified between subgroups of patients are considered hypothesis-generating and require confirmation in independent studies. The multivariate analysis was performed to adjust confounders by using logistic regression analysis with enter method which is a default function of SPSS software for simultaneous adding independent variables in the model. Maximum Likelihood (ML) estimation has been used to obtain beta coefficients from logistic regression analysis.We checked the collected data by using double-data entry for accuracy and completeness and then coded, entered and analyzed by using IBM SPSS Statistics for Windows, Version 23.0. Frequency distribution of demographic characteristics, behavioral data and comorbidities were calculated to determine descriptive statistics of the sample. Chi-square test was used to compare frequency distribution of categorical variables by strata. Kolmogorov-Smirnov test has been used to assess the normality of the continuous data. Normally distributed continuous data were compared by using Student’s 1(age in years) + β2(gender) + β3(community) + β4(scheme) + β5(occupation) + β6(smoking) + β7 + β8(dyslipidemia) + β9(gouty) + β10(diabetes mellitus) + β11(chronic kidney disease) + β12(hypertension duration in years) + β13(neck circumference) + β14 (fish sauce use) + β15(sedentary behavior) + β16(missed doctor appointments) + β17(lifestyle modification) + β18(number of antihypertensive drugs). The multicollinearity was tested. The variables significant in univariate analysis and in established relationship with the outcome were included in multivariate analysis. The Hosmer-Lemeshow goodness-of-fit of the logistic regression models was performed with p-value = 0.648.The final model was Y = -0.424 + βThis study was reviewed and approved by the Royal Thai Army Medical Department Institutional Review Board, reference number R142q/60_Exp. The participants consented in agreement with the WMA Declaration of Helsinki–Ethical principles for medical research involving human subjects.The sample size of the study totaled 406 patients with hypertension. Descriptive characteristics of the study sample is presented in p-valuemale = 0.112 and p-valuefemale = 0.468) . Among males and females, uncontrolled hypertension was 59.8%  and 52.4% , respectively. The prevalence of uncontrolled hypertension in Na-Yao community and in Phra-Pleong community was 55.1%  and 53.9%  respectively. No significant difference was found in prevalence of uncontrolled hypertension between both rural communities.  The prev= 0.468) Univariate and multivariate logistic regression analysis were performed to determine the factors associated with uncontrolled hypertension . After aThis study found the high prevalence of uncontrolled hypertension in the rural communities. The risk factors for uncontrolled hypertension comprised an increase in neck circumference of patients with hypertension, the length of time spent on sedentary behavior and missed doctor appointments. The present study has shown that the prevalence of uncontrolled hypertension among patients with hypertension was 54.4%, lower than that in a related study conducted in the Thai rural community (61.6%).  Thai guiThe present study found that patients with hypertension, having a neck circumference more than 35.75 cm  and 32.75 cm , are more likely to increase the risk of uncontrolled blood pressure significantly. The similar information was reported in Chinese studies about the relationship between neck circumference and hypertension. , 21 MoreThe hypertensive patients with sedentary behavior for more than 5 hours a day had increased risks for uncontrolled blood pressure. Similarly, a related cohort study in Spain found that noninteractive sedentary behavior more than 7.9 hours a day was directly associated with a higher risk of hypertension.  The stud26 (5.2%) out of 406 hypertensive patients missed doctor appointments. The study found that missing doctor appointments exhibited a significant association with uncontrolled blood pressure. We used subgroup analysis for factors regarding missing doctor appointments. We found that the patients concerning about the side effects of anti-hypertensive medication and believing that medicine was not effective for the treatment are more likely to miss doctor appointment. Moreover, some patients with hypertension believed that they had been cured of the disease already, which is the reason why they lost follow-up with their physicians. All of the subjects possessed misperceptions regarding the knowledge and understanding of hypertension treatment and the lack of awareness of the complications of uncontrolled blood pressure. The study by Knight EL et al., found the lack of knowledge by the patients regarding their target SBP was a dependent predictor of poorly controlled blood pressure. The study employed a cross-sectional design, which made it difficult to establish a cause-and-effect relationship between associated factors and uncontrolled hypertension. Our findings suggested that modifiable risk factors for uncontrolled blood pressure should be improved. Patients with hypertension especially those residing in rural communities should be targeted for more educational interventions in raising awareness about hypertension, its complication and treatment. Moreover, this finding implied that screening for and managing multiple risk factors should be considered. Nevertheless, the potential of multicollinearity may against the overall fit of the model. The multicollinearity may result due to population unrepresentative sample or insufficient information in the sample.  Our studIn the study, approximately one half of the patients with hypertension residing in rural communities in the central areas in Thailand have had uncontrolled blood pressure. Neck circumference may be used to independently predict uncontrolled blood pressure. In addition, the sedentary behavior more than 5 hours a day may increase the risk for uncontrolled hypertension. Moreover, patients missed the doctor appointments resulting from their misperceptions and the lack of awareness about hypertension complications and treatment. Further, residing in a rural community may reflect poor access to health literacy, so the Ministry of Public Health and health care providers should develop comprehensive guidelines and strategies to allow the hypertensive patients to have access to the standard healthcare system and be educated on hypertension and its complications.S1 Table(DOCX)Click here for additional data file.


Dear Editor,We read with great interest the study by Fornier and colleagues  in which2) value decreased to 40% or for a maximal period of 10 min”. It was therefore possible that the minimum StO2 value in some patients was higher than 40% after 10 min in the vascular occlusion test, which may have led to faster tissue oxygen re-saturation speed [The authors stated: “A rapid arterial occlusion of the upper limb was provoked by inflation of the pneumatic cuff at 50 mmHg above the systolic arterial pressure, until either the tissue oxygen saturation StO value deThe authors further stated that “all patients were monitored with a five-lead electrocardiogram with computerized analysis of repolarization and invasive or non-invasive arterial blood pressure”. This means that arterial blood pressure was determined using different methods among the patients, and this variation of arterial blood pressure determination may have contributed to the results. Compounding this method-related variability is the fact that atrial fibrillation patients show relatively large short-term blood pressure fluctuations because of variability in left ventricular stroke volume.2 [Four patients in the study were treated with norepinephrine, yet the dose was not reported. Norepinephrine affects StO2 , so dose2 . These iStudies like those of Fornier and colleagues  should a


Design and Setting. Prospective observational study in cardiac intensive care unit. To test if splenic Doppler resistive index (SDRI) allows noninvasive monitoring of changes in stroke volume and regional splanchnic perfusion in response to fluid challenge. Fifty-three patients requiring mechanical ventilation and fluid challenge for hemodynamic optimization after cardiac surgery. SDRI values were obtained before and after volume loading with 500 mL of normal saline over 20 min and compared with changes in systemic hemodynamics, determined invasively by pulmonary artery catheter, and arterial lactate concentration as expression of splanchnic perfusion. Changes in stroke volume >10% were considered representative of fluid responsiveness. A <4% SDRI reduction excluded fluid responsiveness, with 100% sensitivity and 100% negative predictive value. A >9% SDRI reduction was a marker of fluid responsiveness with 100% specificity and 100% positive predictive value. A >4% SDRI reduction was always associated with an improvement of splanchnic perfusion mirrored by an increase in lactate clearance and a reduction in systemic vascular resistance, regardless of fluid responsiveness. This study shows that SDRI variations after fluid administration is an effective noninvasive tool to monitor systemic hemodynamics and splanchnic perfusion upon volume administration, irrespective of fluid responsiveness in mechanically ventilated patients after cardiac surgery. Fluid resuscitation is a cornerstone of perioperative management of patients undergoing cardiac surgery. The effects of extracorporeal circulation, together with the underlying cardiac disease, are often associated with substantial changes in intravascular volume and hemodynamic status, resulting from possible inflammation processes, hormonal influences, and pharmacological interactions. Hypovolemia and tissue hypoperfusion may occur after surgery and remain undetected, thus leading to postoperative complications, multiorgan dysfunction, prolonged hospital stay, and increased mortality –6. On thThe aim of the present study was to explore the association between changes of splanchnic perfusion inferred by SDRI and changes of stroke volume in response to fluid challenge during mechanical ventilation following major cardiac surgery.2O or fraction of inspired oxygen >50%.The study was approved by the Review Board of our University Hospital (Protocol no. 812/2014). Study protocol and aim were explained to patients before elective cardiac surgery and written informed consent was obtained. Fifty-three consecutive patients admitted to the intensive care unit after elective cardiac surgery were prospectively included . No statAll patients were sedated with continuous infusion of propofol and mechanically ventilated with tidal volume of 6 mL/kg of predicted body weight. The eligible patients were studied when a fluid challenge was required to optimize hemodynamic status. SDRI measurements were obtained before fluid challenge (T0) and 5-10 min after 500 mL of normal saline had been centrally infused for 15–20 min by pressure bag (T1). Investigators who performed the SDRI measurements were not involved in patient care, and the physicians in charge of patient care were blinded to SDRI results. The following data were recorded before and after fluid challenge: stroke volume (SV), central venous pressure (CVP), mean arterial pressure (MAP), pulmonary artery occlusion pressure (PAOP), systemic vascular resistance index (SVRI), mixed venous oxygen saturation (SvO2), and arterial lactate level (cLac). Percentage changes between T0 and T1 were calculated. Patients were defined as fluid challenge responders when stroke volume at T1 was ≥10% than at T0.2 . The correct positioning of the catheter was confirmed by the waveform of the pressure curve, catheter length, and a chest X-ray.Patients were positioned 30° supine and all pressure transducers were referred to mid chest at the level of right atrium. All patients were monitored with invasive arterial blood pressure by radial  and pulmonary artery catheters . Clinical data were collected from bedside monitors . Cardiac output was measured by intermittent thermodilution with 10-mL normal saline injected into the superior vena cava via pulmonary artery catheter. Three consecutive injections were randomly performed during the respiratory cycle. When measurements differed by >10%, the cardiac output was further measured twice and the average value was calculated after exclusion of the highest and lowest values. In order to reduce interoperator variability, saline was always injected by the same physician. Thermodilution curves were retained if they showed stable baseline temperature, undisturbed rapid rise, and exponential decay without signs of early recirculation. Blood samples (2 mL each) were collected from the tip of pulmonary artery catheter to measure SvOUltrasonographic examinations were obtained with a 2.5-MHz phase array transducer, provided with a color-pulsed wave Doppler device for studying of the spleen by last-generation US equipment . Patients were placed in a supine position and, after a preliminary examination of abdominal cavity and organs, the complete spleen visualization was obtained in a coronal view including the hilum. Doppler US measurements were obtained by an anesthesiologist (F.C.) with 15 years of experience in Doppler ultrasound. The transducer was positioned on the left intercostal spaces. Color Doppler allowed identification of the main branches of the splenic artery, which were measured just past the hilum, at a distance of 1 cm from it, inside the spleen in a straight tract of the vessel, avoiding more peripheral vessels . The sam t-test were used for comparisons between and within groups, respectively. Fisher's exact test was used for comparisons of frequencies. A sample size of at least 51 patients was required for a paired t-test with power = 0.8, α = 0.05, effect size = 0.4, and a two-sided alternative hypothesis. Correlations were determined by Pearson's test. To assess the diagnostic accuracy of SDRI values in the prediction of an increase in SV of 10% or higher, sensitivity receiver operating characteristic (ROC) curves were constructed and the following parameters determined: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).All results are expressed as means ± standard deviations, counts, percentages, odds ratio (OR), and 95% confidence interval (CI). The Shapiro-Wilk test was used to evaluate the normal distribution of continuous variables. Unpaired and paired Student's p value <0.05 was assumed as statistically significant. Statistical analyses were performed by using SPSS software , GraphPad Prism 6.00 , and the R software/environment .The percentage changes between T0 and T1 of main hemodynamic and clinical variables were entered into univariate logistic regression models with responsiveness to fluid challenge as the dependent variable. The variables that reached statistical significance at univariate analysis were entered into a multivariate logistic regression model. The le Cessie-van Houwelingen-Copas-Hosmer test was used to assess the goodness-of-fit for each logistic regression model . A two-s2 , and cLac . However, stroke volume  and CVP  were lower in responders than nonresponders, whereas SVRI was higher .Before fluid challenge, SDRI was not significantly different between responders and nonresponders . The same was true for MAP , PAOP , SvO2 (p = 0.012) were significantly increased and SDRI (p<0.001) and SVRI (p<0.001) significantly decreased, while CVP, MAP, PAOP, and cLac did not change significantly. In nonresponders, stroke volume was also increased (p<0.001) while SDRI (p = 0.006) and cLac (p = 0.017) decreased significantly. No significant changes were observed for CVP, MAP, PAOP, SVRI, and SVO2  were fluid challenge responders. Stroke volume change after fluid challenge was 23±13% in responders and 5±3% in nonresponders (p<0.001). In responders, stroke volume (p<0.001) and SVOand SVO2 .r = –0.51; p<0.001). The area under the ROC curves (AUC) was significant for SDRI percent reduction . A SDRI reduction >9% was a marker of fluid responsiveness, with 100% specificity, 100% positive predictive value, 63% sensitivity, and 68% negative predictive value. A SDRI reduction <4% excluded fluid responsiveness, with 100% sensitivity, 100% negative predictive value, 61% specificity, and 77% positive predictive value. No responder had SDRI reductions < 4%, and conversely none of the nonresponders had SDRI reductions >9%  and nonresponders . By contrast, in nonresponders only cLac significantly decreased from 1.5 ± 0.6 mmol/L before fluid challenge to 1.2 ± 0.5 mmol/L after fluid challenge (p = 0.009), while SVRI was insignificantly changed from 1893 ± 628 before fluid challenge to 1739 ± 545 dyne-sec/cm−5/m2 after fluid challenge (p = 0.184).Twenty patients had SDRI reduction between 4% and 9%. Eleven of them were responders and 9 nonresponders. In the former, cLac significantly decreased from 1.8 ± 1 mmol/L before fluid challenge to 1.3 ± 0.6 mmol/L after fluid challenge (p = 0.022) and SVRI from 2663 ± 1089 before fluid challenge to 2175 ± 780 dyne-sec/cm−5/m2 after fluid challenge; p = 0.551)Patients with SDRI reduction <4% showed no further reduction in cLac levels  or SVRI , cLac  and SVO2  before and after fluid challenges.SDRI measurements were statistically correlated with stroke volume . However, this correlation was significant in nonresponder  but not in responder  group. In 9 out of 23 patients with a stroke volume increase <10% after fluid challenge there was a decrease of cLac from 1.4 ± 0.8 to 1.2 ± 0.6 mmol/L (p = 0.017), and SDRI from 0.67 ± 0.12 to 0.63 ± 0.11 (p <0.001), suggesting an improvement in splanchnic perfusion.Fluid challenge caused an increase of SDRI ≥4% in 39 patients but a stroke volume increase ≥10% only in 30 of them (p < 0.001). The occurrence of SDRI percent reduction >4% was 100% in responders and 39% in nonresponders. The percent increase of stroke volume was significantly correlated with the percent decrease of SDRI in the whole population  an SDRI reduction >9% was a marker of fluid responsiveness, with 100% specificity and 100% positive predictive value; (2) an SDRI reduction >4% was always associated with an improvement of splanchnic hypoperfusion mirrored by an increase in lactate clearance and reduction in systemic vascular resistance, regardless of fluid responsiveness; and (3) a SDRI reduction <4% excluded fluid responsiveness, with 100% sensitivity and 100% negative predictive value, without improvement in splanchnic perfusion.Stukely firstly suggested in 1722 that the spleen was a “diverticulum of the systemic circulation, filling and empting with blood, thus acting as a controller of blood volume” . In animThe reduction of arterial lactate concentration observed in nonresponder patients to fluid challenge confirms previous experimental data, suggesting  that splA number of indexes that allow predicting fluid responsiveness have been already proposed , but the2. Therefore, if fluid administration is exclusively based on changes in stroke volume, the opportunity to revert ongoing vasoconstriction and improving splanchnic perfusion might be missed.Our study has a number of strengths. For the first time, it describes the relationship between invasive stroke volume and noninvasive SDRI after fluid administration in the postoperative period. Furthermore, our results provide evidence that improvement in splanchnic circulation occurs in either the presence or absence of stroke volume responsiveness, and SDRI percent reduction is representative of active vasodilation in the splanchnic circulation, as confirmed by its correlation with cLac and SVOOur study has several limitations. First, it was not designed to evaluate the influence of confounding factors, such as age and abnormal arterial stiffness, which may have affected SDRI. Second, in this study only normal saline was used for fluid challenge, which makes the results not directly applicable to conditions where different fluids are infused or in patients receiving nutritional supplementation. Third, our recording period was relatively short because the aim was to study acute physiological responses to fluid challenge, thus possibly missing late physiological responses due to fluid balance restoration or fluid redistribution. Fourth, the study was not powered to assess differences in clinical outcomes. Fifth, inflammation and ensuing increases in splenic blood flow could possibly be a potential confounding factor, especially in cardiac surgery patients due to CEC procedure.Significant changes in splenic Doppler resistive index assessed with Doppler ultrasonography mirror significant hemodynamic variations induced by fluid challenge and allow a valuable and repeatable bedside method to assess splanchnic perfusion regardless of fluid responsiveness.


The measurement of the ankle-brachial pressure index is a straightforward method for the detection of peripheral disease in the lower limbs. Only a few old studies with small numbers of patients have been conducted comparing the gold standard, ankle-brachial pressure index measurement, with strain gauge plethysmography and reactive hyperaemia for detecting peripheral arterial disease. The purpose of this study was to evaluate the feasibility and accuracy of strain gauge plethysmography values compared with the Doppler ultrasound method, ankle-brachial pressure index, in the assessment of peripheral arterial disease, especially in patients with severe aortic stenosis.221 ankle-brachial pressure index measurements and strain gauge plethysmography measurements of patients with suspected peripheral arterial disease, diagnosed peripheral arterial disease with or without aortic stenosis were compared.Irrespective of aortic stenosis in patients with and without peripheral arterial disease, the resting arterial blood flow was within the normal range. In patients with aortic stenosis, the time-to-peak flow couldn’t detect peripheral arterial disease and was found to be a false negative. In patients without aortic stenosis, time-to-peak flow correlated well with the ankle-brachial pressure index for detecting peripheral arterial disease. Peak flow at 5 seconds was the one of the flow values that correlated with ankle-brachial pressure index and detected peripheral arterial disease in patients with and without aortic stenosis.Peak flow at 5 seconds is one of flow value that correlated well with ankle-brachial pressure index in detecting peripheral arterial disease in patients with and without aortic stenosis. Detection of peripheral arterial disease in patients with severe aortic stenosis seems to be less sensitive with flow measurements than with ankle-brachial pressure index. Peripheral arterial disease (PAD) is a manifestation of generalized arteriosclerotic disease and leads to a range of clinical conditions from asymptomatic disease to critical ischemia.The standard, quantitative, noninvasive test to assess the severity of PAD is the measurement of ankle-brachial pressure index (ABPI). It is an accurate, simple, and noninvasive measurement and considered to be the most accurate noninvasive diagnostic methode for PAD and its assessment. An ABPI below 0.9 has been widely accepted as evidence of PAD in most epidemiological studies .The American College of Cardiology/American Heart Association (ACC/AHA), Society for Vascular Surgery (SVS), and European Society of Cardiology (ESC) guidelines recommend ABPI determination as the first-line noninvasive test to establish a diagnosis of PAD because of its high sensitivity and specificity , 3, 4.Beside ABPI, clinical signs, 6 min Walking test, treadmeal excercise, and other nonivasive techniques have assumed an important role in detection of PAD. Both Ultrasound and plethysmography, segmental oscillography allow objective evaluation of vascular disorder by measurement of segment limb blood pressure, analysis of blood velocity disturbance, recording of digit or limb pulse waveforms. Also imaging of vascular disease, with or without Doppler flow analysis or color-flow mapping are useful methods. In patients with aortic stenosis and pre-TAVI, pre-procedural CT-angiography is clinically useful, allowing precise pre-procedural TAVI planning with accurate assessment of iliac and femoral arteries.Only a few studies with small numbers of patients or healthy subjects have been conducted that compare ABPI measurement (as the gold standard) with Strain-gauge plethysmography—reactive hyperemia (SGP-RH) for detecting PAD , 6.There are no data regarding detecting PAD with SGP-RH in patients with AS. The presence of PAD is significantly associated with increased rates of major vascular complications as well an immediate and late mortality in patients with AS undergoing TAVI. Assessment of PAD before TAVI is essential to choose an access strategy and to predict clinical results and avoide major complications.The purpose of the present study was to examine and compare the accuracy and predictive values of SGP-RH measurements with the Doppler ultrasound method ABPI and toe-brachial index (TBI) as a gold standard in the assessment of known or suspected PAD, in patients with and without severe aortic stenosis (AS), thus determining the feasibility of predicting peripheral arterial disease in this group.Between October 2015 and October 2017, a total of 221 patients were referred for a vascular check with suspected PAD, with already diagnosed PAD for follow-up, or for PAD screening in patients with AS before undergoing Transcatheter aortic valve implantation (TAVI) in the Department of Angiology. Data from these subjects were collected retrospectively and included into this single center study .According to the standard care for PAD, study subjects underwent ABPI measurements in both legs (reference for presence of PAD ≤ 0.9). They underwent bilateral SGP-RH when they were not able to perform an exercise test, such as a treadmill test, for any reason, or depending on the physician’s decision. Ethics approval for this retrospective study was not necessary. Our local ethic committee of the faculty of medicine of the University of Bonn (Germany) confirmed that ethical approval was not needed in this case. Patients records used in our retrospective study were all fully anonymized before we accessed them and anlayzed it.The assessment of the ABPI is a simple, non-invasive clinical test to diagnose PAD.ABPI was performed by measuring the systolic blood pressure from both brachial arteries and from the posterior- (PTA) and anterior-tibial (ATA) or the dorsalis pedis arteries. All measurements were performed with the use of appropriately sized pneumatic cuffs for both the ankle and the arm. The systolic ankle pressures were recorded with a handheld 5 MHz bi-directional pocket Doppler instrument by continuous wave (cw) velocity detection . The ABPI was calculated for each lower limb as the ratio of the lowest pressure from the right or the left PTA and ATA  over the greatest brachial systolic pressure according to the following formula:For each patient, only the lowest ABPI recorded in the two ankles was used for categorization into non-PAD and PAD groups. Ratios of > 0.90 to < 1.4 are considered normal, and ratios ≤ 0.9 indicate the presence of PAD ,7,8,9. FIn patients with an ABPI ≥ 1.4, which were considered to have medial calcific sclerosis with non-compressible arteries, the criteria for the classification into the PAD or non-PAD group were determined by additional toe-pressure measurements .In many cases, TBI is useful in medical conditions associated with medial calcifications , such as advanced age, longstanding diabetes, or chronic kidney disease, which can lead to unreliable ABPIs due to non-compressible vessels . HoweverThe TBI was determined as the ratio of the pressure from the right and the left big toe, measured by means of a photoplethysmograph (PPG) infrared light sensor , over the greatest brachial systolic pressure measured. Ratios less than 0.70 are considered appropriate to define PAD [The assessment of SGP-RH is a simple method for measuring peripheral blood flow that has been in use for more than 100 years and allows physicians to diagnose and further evaluate PAD. Despite its lengthy history, its current importance/prevalence for both clinical use and research is rather low and mostly limited to the assessment of venous diseases of the lower legs , becauseSGP-RH is based on the principle of post-occlusive reactive hyperaemia (RH), and offers the examiner the opportunity to register blood flow and volume changes after a certain period of hyperaemia by applying controlled pressure to a cuff around a segment of the limb. These measurements are, in turn, designed to provide information on the ability of the arterial inflow to respond to an ischemic stimulus  especialBefore the peripheral blood flow measurements, the patients were invited to rest in a supine position for at least 15 minutes. The patient’s legs were positioned in such a way that the knee was neither flexed nor hyperextended while lying on the examination couch, and the lower legs were placed slightly above heart level (at an angle of approximately 30 degrees) by supporting the heels with the use of specially tailored foam cushions and pillows. Constant room temperature was maintained at an average of 20°C. Peripheral blood flow measurements were conducted in both legs simultaneously. For the testing, both appropriately sized pneumatic occlusion cuffs were wrapped around the patient’s thighs and the strain gauge detectors were circularly placed on the thickest part of the calf and connected to a plethysmography device .This method enables the evaluation of the following parameters:Resting flow (RF) in ml / 100ml / min Peak flow (PF) in ml / 100ml / min Time-to-peak flow (tPF) in sec The peripheral blood flow measurements consisted of two stages:For the measurement of the resting flow (RF), the pneumatic occlusion cuffs of the thigh were inflated up to 60 mmHg to guarantee venous occlusion. For the testing, three consecutive pressure inflations were performed (three times per minute) for 5 seconds each with a 15 second interval in between each occlusion in which the cuff was instantaneously deflated. As a result, RF values were obtained at 0, 15, and 30 seconds.Normal RF values can reach 3–4 ml / 100ml / min. In patients with mild or moderate PAD (Fontaine’s stage II/III), the blood flow at rest remains within in the normal range, whereas a reduction of the RF becomes apparent in patients with severe PAD and pain or discomfort while resting .For the measurement of reactive hyperaemia (RH), the pneumatic occlusion cuffs on the thigh were inflated to a suprasystolic pressure to exclude peripheral circulation . After three minutes, the arterial occlusion was released. Hereafter, five consecutive pressure inflations up to 60 mmHg (to guarantee venous occlusion) were performed for 5 seconds each, with a 15-second interval in between each occlusion in which the cuff was instantaneously deflated. As a result, RH values were obtained at 5, 15, 25, 35, and 45 seconds.After a three-minute period of interruption of blood flow, the normal arterial blood inflow may reach 20–40 ml / 100ml / min in healthy adults. This value correlates with the severity of the disease and decreases steadily with progression through the stages of PAD: In patients with Fontaine’s stage II PAD, the arterial blood inflow ranges between 4–10 ml / 100ml / min, whereas in patients with advanced stage PAD (Fontaine’s stage III or IV), the arterial blood inflow is considerably reduced (1–5 ml / 100ml / min) . The cutA subsequent computer-assisted analysis factored in first flow, peak flow (PF), and time-to-peak flow (tPF). The first flow was defined as the first arterial blood inflow during hypaeremia after three minutes of circulatory arrest (in ml / 100ml / min). The PF was recorded as the maximal arterial inflow during hypaeremia after three minutes of circulatory arrest (in ml / 100ml / min). The tPF was specified as the time (in seconds) until the peak flow had been reached.The PF and the tPF are normal if the greatest arterial inflow occurs following the first occlusion maneuver and constantly decreases during subsequent maneuvers. If the arterial inflow behaves differently, then the PF is pathological. The same applies to the tPF; a healthy, no-PAD patient will have reached the maximum within 5 to 15 seconds. Any discrepancies thereof  are considered pathological. In the present study, the cut-off for pathological tPF was >15 seconds. In conclusion, a PF greater than 12 ml/ 100ml / min and a tPF within 15 seconds with a fast decrease afterwards indicates a good peripheral arterial perfusion reserve. Deviations from this indicate the presence of PAD , 14.Data for continuous variables are given as the mean ± standard deviation. Categorical variables are given as frequencies and percentages. For comparisons between two groups, a Student’s t-test was performed for continuous variables and a Chi-square test for categorical data; the Chi-square test was also used for categorical variables. Sensitivity and specificity were calculated with 95% confidence limits. ROC curves for PF and tPF were plotted to show the predictive potential of these variables with respect to PAD. Statistical analyses were conducted with SPSS Statistics Version 22.0 .The investigators initiated the study, had full access to the data, and wrote the manuscript. All authors vouch for the accuracy and completeness of the data and analyses and confirm that the study was conducted according to the protocol.Patients’ baseline characteristics, according to vascular status, are summarized in Irrespective of AS in patients with and without PAD, the resting arterial blood flow showed the highest level after 0 seconds and constantly decreased afterwards. At 0 seconds, the RF was within the normal range and reached 3–4 ml / 100ml / min, irrespective of whether PAD was present or not, however PAD patients showed lower values than non-PAD patients , Fig 3.(2.1) Assessment of peak flowRegardless of whether PAD was present or not, the peak flow (PF) showed the highest level after 5 seconds and constantly decreased afterwards. PAD patients showed a significantly lower value . In PAD patients, all PF values were below the standard level. In non-PAD patients, the PF at 5 seconds was within the normal range , Fig 3. (2.2) Assessment of time-to-peak flowIn patients with PAD and without PAD, the time-to-peak flow (tPF) was within the normal range , but significantly prolonged in PAD patients  in patients with low-gradient AS didn´t correlate well with ABPI in detecting PAD .However PF at 35sec and 45sec correlated better with ABPI (AUC 0.604 and 0.608) in patients with low flow low gradient stenosis, but not in Patients with high flow gradient.In AS population aortic valve area (AVA) correlated parametically well with tPF (p = 0.042). The scatter plot  shows poIrrespective of whether PAD was present or not, the RF at 0 seconds was within the normal range in both groups and reached 3–4 ml / 100ml / min. RF measurements appear to be a rather unspecific parameter, which did not provide any substantial information. These values are considered normal and are consistent with previous findings: research from Bossaert et al.  has estaFinally, at this time, it is not possible to give a reliable statement on the importance of RF in terms of the peripheral perfusion.Our study shows that peak flow at 5 seconds was the only flow value, that correlated well with ABPI in detecting PAD in patients with  and without AS . Reactive hyperaemia is a reproducable method to assess the extent of artrial inflow initiated by an ischemic stimulus ,19. NormIn our study population with and without AS, PAD was not detected in tPF values with a cut-off point of > 15 sec, but it was significantly prolonged in the PAD group, compared with non-PAD, and there was a significant correlation with the ABPI measurement . Fig 6 sIn subjects with PAD atherosclerotic changes and endothelial dysfunction can alter the strain-gauge measurements, as compared to healthy individuals . A decreTo the best of our knowledge, this is the first study to evaluate SGP-RH parameters in AS patients. Physiological changes in pressure and flow within the arteries, spanning from the ascending aorta to the anterior tibial artery, show that in presence of a “healthy” aortic valve and with increasing distance from the heart, the maximum pressure impulse increases slightly at the detriment of the flow pulse (14). In cases of pre-existing high-degree aortic valve stenosis with reduced cardiac output the respective values are markedly reduced and may become difficult to detect PAD. In vascular patients; however, a prolonged tPF would have been reasonably expected because of narrowing of the arteries. The fact that expectations were not met in AS group might be due to the fact that PAD-patients may compensate disturbed and/or impaired blood circulation in small vessels by reducing peripheral vascular resistance. However in Patients with AS and low flow low gradient stenosis the PF at 35 and 45sec corraletd well with ABPI in detecting PAD, but not the PF at 5sec. Reasons for this will amongst others originate from abnormal haemodynamic flow patterns in low flow low gradient stenosis, local regulatory processes in AS patients and reduced ejection fraction that were in fact not yet known. We can only speculate that the diagnostic method is insufficiently sensitive in this group.On the other hand, pathological changes like atherosclerosis and endothelial disfunction are assumed to be mechanisms by which patients with PAD may result with lower peak-blood-flow values and delayed peak-blood-flow response . These rThe strain gauge has been utilized in validity and reliability testing since the late 1800s. However, this method has proven to be prone to errors and artefacts, making the interpretation of results difficult. Precise analysis is dependent upon accurate equipment set-up and limb positioning in order to prevent the over- or underestimation of peak blood flow while maximizing reliability. Salisbury et al.  emphasizThis study was designed to examine the feasibility and accuracy of SGP-RH values compared with the Doppler ultrasound method, ABPI, in the assessment of known or suspected PAD, especially in patients with severe aortic stenosis in our vascular center. This was a single-center experience that started in 2016. As such, the clinical assessment of peripheral arterial disease using objective clinical vascular tests was limited to only a small number of patients, therefore, we cannot reasonably address this issue. Given the small sample size, the proportion of PAD patients were not well balanced in terms of PAD severity, the majority of the PAD patients had only mild to moderate forms of peripheral arterial disease. For further verification and generalization of our results, larger studies that include more patients with higher-stage PAD are required. In the case of SGP-RH, however, the artefacts observed, which made interpretation of the results difficult, could be due to patients that do not tolerate the suprasystolic pressure of the pneumatic occlusion cuffs for the thigh and the resulting pain-triggered contractions of the lower-leg musculature. Other causes may include poor fit of the strain-gauge detectors or movement of the patients during the measurements.The result of the study shows fair accuracy and agreement between parameters of SGP-RH peak flow at 5 seconds and ABPI for the detection of peripheral artery disease in the lower limbs in patients with and without AS. Time-to-peak flow values had a better predictive potential in detecting PAD in patients without AS. In patients with AS, it is less sensitive. There is a significant correlation between tPF in PAD patients with ABPI values less than 0.7All in all, flow measurements have a limited predictive potential for the detection of PAD in patients with severe aortic stenosis than ABPI.From the economic point of view and availability, the Doppler ultrasound may be the method of first choice for measurement, but when the results are in contrast to the clinical findings or patients are unable to perform an exercise treadmill test, referral to SGP-RH measurement might be considered. Especially in patients with low ABPIs, the Doppler method often failed, most frequently at the dorsal pedal artery. Furthermore, SGP-RH measurement is a useful methode in evaluating the prognosis and assessing the efficacy of therapeutic interventions in patients with PAD.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.