Loop diuretics are among the most widely used drugs worldwide and are commonly employed in the management of complications associated with acute kidney injury (AKI), namely volume overload and electrolyte management. The use of loop diuretics in critically ill patients with AKI is paramount to preventing or treating pulmonary edema. The naturetic response to a loop diuretic is based on its unique renal pharmacology. Our review article summarizes the pharmacology of furosemide in the intact nephron and discusses how this response might be altered by the presence of AKI. We discuss the increasing body of literature on the latest clinical utility of furosemide namely, it’s challenge test, known as the furosemide stress test which has highlighted a new and novel role for furosemide over the past number of years. This test assists with the identification of AKI subjects at higher risk of AKI progression and the need for renal replacement therapy. The stress test can also predict cessation of continuous renal replacement therapy in patients with established AKI. On the basis of the evidence presented in this review, we propose future potential studies of furosemide in AKI. Acute Kidney Injury (AKI) is a common and serious complication that is associated with several adverse outcomes including death, need for renal replacement therapy (RRT), increased length of hospital stay, chronic kidney disease and rising health care costs ,2. Even N-(2-furyl-methyl)-5-sulfamoyl-anthranilic acid) is a potent natriuretic drug that is chemically synthesized and does not occur naturally (lasts Six hours) and 2 h after single-dose intravenous administration however these times can vary dramatically ) of 0.87 (0.05) with a sensitivity and specificity of 87% and 84%, respectively, for the progression to AKIN Stage 3. More importantly, it was determined that the FST was feasible, safe and well tolerated in critically ill patients  774 mL/h.) vs. 117 mL/h. (IQR 158 mL/h.), p = 0.003). In 25 patients in the furosemide group and 27 patients in the placebo group showed recovery of renal function at ICU discharge (p = 0.46). This recovery work along with data from heart failure patients (independent of AKI status) points to the utility of the response to furosemide as a clinically useful prognostic biomarker for adverse patient outcomes. The performance of the FST in adults to predict both severity of AKI and the recovery on AKI is remarkably consistent and the ROC AUCs are typically greater than 0.85 . Additionally, the 6 h urine output of 500 mL after the FST provided an AUC of 0.86 providing a sensitivity and specificity of 85% and 76% [The FST has been used in the prediction of delayed graft function (DGF) post deceased donor kidney transplantation (DDKT) . In this and 76% . In a sm and 76% . The 4-hThe FST effectively interrogates the nephron with a focus on tubular function and a clinical readout which is the urine output over a period of time . When the FST is deconstructed, it can be sub-divided into four components . To dateThe use of urinary sodium concentration and FEM to enhance the diagnostic capacity of the FST is theoretical and requires validation. The suggested use of urinary sodium and FEM is a proposed framework on how to expand the utility of this test.via kidney biopsy which may be too invasive for routine serial assessment. However, we postulate that since tubules comprise the majority of renal mass and reduced kidney size correlates with worsening CKD, that tubular atrophy and fibrosis are a part of the fibrotic pathway and represent the loss of tubular function. Thus, measures of tubular function and reserve are likely to be robust measures of fibrosis in CKD.CKD is a serious public health hazard worldwide and risk assessment and prognostication is typically conducted by measuring equilibrated GFR (eGFR) and level of proteinuria. Both these tools have significant limitations because the eGFR equation requires standardized creatinine measurement and can have higher levels of bias at higher level of GFR. Proteinuria is an excellent predictor of risk, but many patients with CKD do not have significant proteinuria. In CKD, the development of kidney fibrosis is considered one of the most potent risk factors for renal disease progression, independent from the CKD etiology, as it represents a final common pathway from injury . In aggrSome evaluation tools to assess tubular function have been tested such as dilution capacity, concentration ,32 and u2). Similar to the forced exhaled volume (FEV1) in pulmonary function testing, a healthy person can expire most of the air from their lung in 1 s. Whereas a patient with lung disease often demonstrates a decreased FEV1. Similarly, a healthy person with a full complement of functioning nephrons should be able to promptly eliminate furosemide into the urine. However, when tubular dysfunction is present as the case with tubular-interstitial fibrosis, the fibrosed kidney will not be able to efficiently move furosemide out of the plasma and into the tubular lumen. This type of functional testing may form the basis of assessing tubular function in a noninvasive fashion.We postulate that the FST may be a useful tool to evaluate tubular function and reserve and may be able to serve as a noninvasive tool to assess kidney fibrosis. We have conceived the concept of the furosemide excreted mass at 2 h  especially given increasing use of these loop diuretics in the context of acute heart failure. In addition, further studies on the use of the FST in later stages of AKI other than early stage AKI is justified. Frequently, patients with severe AKI receive a high dose of intravenous furosemide to prevent or treat oliguria. This information is frequently used to predict if a patient is a ‘responder’ or ‘non-responder’ to furosemide and the subsequent need for RRT. This approach should be standardized in advanced stage 3 AKI to avoid delayed definitive therapy or RRT and may be clinically relevant use of the FST when compared to it’s use in early stages of AKI. In conclusion, the FST has been demonstrated to safe and effective predicting the severity of AKI across multiple cohorts and investigators over three continents and its overall performance has been consistent. In addition, the FST appears to have the capacity to predict severity in sub-types of AKI such as DGF and also appears to predict recovery. FST may also have a role as a diagnostic in CKD.


Peripheral arterial disease (PAD) is one of major vascular diseases which frequently coexists with coronary arterial disease and cerebrovascular disease. The patients with PAD have a poor prognosis when it progresses. A new blood pressure testing device enables to simultaneously measure brachial blood pressure (BP), central BP, and several vascular parameters, with easy and non-invasive, in a short time. Here, we aimed to evaluate these arterial stiffness parameters in patients with PAD.In this study, 243 consecutive patients who were suspected of having PAD and referred to our hospital from September 2016 to June 2019, were registered. Several parameters, such as brachial BP, central BP, aortic pulse wave velocity (aPWV), total vascular resistance (TVR), augmentation index (AI) and augmentation pressure (AP), were determined by Mobil-O-Graph. Ankle-brachial pressure index (ABI) was used to define PAD (ABI ≤ 0.9 as PAD). The relationship between PAD and central BP, aPWV, TVR, AI, or AP were investigated.P < .05, 125 ± 22 mmHg vs 119 ± 18 mmHg, P < .05, respectively). TVR, AI, and AP were significantly higher in the PAD group . No significant differences in diastolic BP, central diastolic BP, and aPWV were found between the groups. Multivariate logistic regression analysis revealed that PAD was significantly associated with TVR, AI, and AP .One hundred sixty-two patients (67%) were categorized as the PAD group and 81 patients (33%) as the non-PAD group. In the PAD group, the systolic brachial BP and central systolic BP were significantly higher than those in the non-PAD group (138 ± 24 mmHg vs 131 ± 19 mmHg, TVR/AP/AI were significantly higher in the PAD group than in the non-PAD group. Peripheral vascular disease (PAD) is a condition in which arteriosclerosis mainly occurs in blood vessels of the limbs and is usually determined by ankle-brachial pressure index (ABI).,2,4,5 The main causes of PAD are lifestyle-related diseases, such as hypertension, diabetes, dyslipidemia, chronic kidney disease, smoking, and obesity. It is well known that the cause of increased mortality when PAD progresses to foot amputation.,4In recent years, the increase of lifestyle-related diseases largely associated with metabolic syndrome has been remarkable.–9Arterial stiffness can be assessed by a variety of methods. Increase of arterial stiffness is associated with higher risk for the development of arteriosclerosis and recognized as a prognostic marker beyond standard risk factors. Currently, arterial stiffness is able to be measured non-invasively and reproducibly.,11 Flow mediated dilatation represents vascular endothelial function.,13 Cardio-ankle vascular index is used for estimating the extent of arterial stiffness and atherosclerosis.–16 Augmentation index is used as a surrogate measure of arterial stiffness.–19 Multiple measurements for these parameters for evaluation of vascular function provide a clue of arteriosclerosis. These parameters are widely used in clinical practice worldwide, however, the accuracy of these methods is unsatisfactory especially in the patients with PAD. Vascular catheterization can evaluate hemodynamics in patients with PAD, such as vascular resistance and arterial central blood pressure, but invasive. Recently, Mobil-O-graph has been developed and it enables non-invasive and simultaneous measurement of several vascular parameters with shorter procedure duration.,21 So far, the evaluation of PAD using Mobil-O-graph has not been reported.To date, to evaluate vascular dysfunction, an early stage of arteriosclerosis, several devises have been developed. Pulse wave velocity (PWV) is widely used in clinical practice as a parameter for arterial stiffness.Therefore, in this study, we aimed to examine the association of several parameters determined by Mobil-O-graph, such as central blood pressure, brachial blood pressure, aortic PWV (aPWV), total vascular resistance (TVR), augmentation pressure (AP), and augmentation index (AI), with PAD. Among them, TVR, AP, and AI were found to have a significant association with PAD.22.1This was a single-center, and cross-sectional observational study.2.2The participants were recruited from outpatients who were suspected of having PAD and referred to our hospital from September 2016 to June 2019, and who were 20 years old and over, and obtained informed consent of the present study. Patients who disagreed to participate in this study were excluded.Based on physician's charts, characteristics of each participant was evaluated, including age, sex, body mass index, smoking, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, ischemic heart disease, cerebral infarction, and medications. Lab data were collected as following: serum creatinine, calcium, phosphorus, hemoglobin, fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol.Participants received a test under fasting, alcohol-free, and non-smoking, or refraining smoking at least 12 hours condition.2 or urinary protein≥±. In the dipstick test, ± is considered equal to 0.15 g/gCr.The definition of disease is as follows; diabetes mellitus was defined by receiving medication for diabetes mellitus or fulfilling the diagnostic criteria: postprandial plasma glucose levels ≥200 mg/dL and/or HbA1c ≥6.5%. Dyslipidemia was defined by receiving medication for dyslipidemia or fulfilling the diagnostic criteria: LDL-cholesterol ≥140 mg/dL, HDL-cholesterol <40 mg/dL, triglycerides ≥150 mg/dL. Chronic kidney disease was defined as eGFR <60 mL/min/1.73 mHypertension was defined by receiving anti-hypertensive agents or ≥140/90 mmHg. Ischemic heart disease was defined as symptomatic and having history of percutaneous coronary intervention treatment and/or surgical operation of coronary artery bypass grafting. Cerebral infarction was defined as symptomatic and requiring hospital treatment. Smoking included both current and past habitat of smoking.2.3,23 Cuffs were applied to both upper arms and ankles. ABI was calculated dividing the ankle SBP in each leg by the higher SBP of upper arm. The lower ABI value was used as representative ABI of each participant.ABI was determined with BP-203RPE II form  or VaSera VS-1500A , followed manufactural instruction. In brief, ABI was measured after resting in a supine position for 5 minutes in a temperature-controlled (22–25 °C) room. Blood pressure was measured using oscillometric method. Oscillometry was based on the assumption that maximum oscillations occurring in the vessel in slow cuff deflation correspond to mean arterial pressure from which mathematical formulas can deduct the systolic and diastolic blood pressure.2.4PAD was defined as ABI ≤0.9.2.5Several vascular parameters were measured using Mobil-O-Graph ; brachial systolic blood pressure (bSBP), brachial diastolic blood pressure, brachial pulse pressure (bPP), central systolic blood pressure (cSBP), central diastolic blood pressure, central pulse pressure (cPP), aPWV, TVR, AP, AI, stroke volume, cardiac output, and cardiac index. Each participant laid on the bed in a spine position for >5 minutes in a quiet and temperature-controlled room, then, the measurement was performed in accordance with the manufacturer instruction.The Mobil-O-Graph had an inbuilt ARCSolver . After brachial BP was measured, the cuff was instantly inflated, and brachial artery pressure waves were recorded, holding the diastolic BP level for 10 seconds. Brachial artery pressure wave was digitized with a high-fidelity pressure sensor connected to a 12-bit A/D converter. Central AI and AP were calculated using a generalized transfer function. The ARCSolver transfer function includes an algorithm for checking the signal quality. We analyzed only excellent or good-quality results, that is, >80% or >50% of signals used for the transfer function, respectively.This running 1st pulse wave gets reflected from distal branching point of aortic wall and generates 2nd reflected wave. Arterial stiffness mainly determines the morphology of reflected 2nd wave. AIX and PWV were obtained with the help of algorithm and mathematical model in the inbuilt software by using amplitude and time difference of 1st and 2nd wave.2.6This study followed the Declaration of Helsinki  on medical protocol and ethics. Informed consent was obtained from all participants. The ethics committee of the Institutional Review Board in Okayama University Hospital approved the protocol (Ken1609-029).2.7t test or chi-squared test where appropriate. Multivariate logistic regression analyses were performed to investigate the association of TVR, AP, and AI with PAD. Statistical significance was defined as P < .05. All data were analyzed using JMP .All data are presented as the mean ± standard deviation or number (%). Differences between the 2 groups were examined by a student 33.1P = .0272) and usage of antiplatelet drugs (P = .0007).Characteristics of the participants are shown in Table 3.2P = .0129, 125 ± 22 mmHg vs 119 ± 18 mmHg, P = .0295, 57 ± 17 mmHg vs 51 ± 12 mmHg, P = .0047, 42 ± 15 mmHg vs 38 ± 11 mmHg, P = .0260, respectively). TVR, AI, and AP were significantly higher in the PAD group . No significant differences in brachial diastolic blood pressure, central diastolic blood pressure, aPWV, stroke volume, cardiac output, nor cardiac index, between the groups.Vascular parameters are shown in Table 3.3P = .0178), as well as AP and AI  adjusted with age, sex, and body mass index. These significant association remained adjusted with model 1 covariates plus smoking (Table P = .0496).Multivariate logistic regression analyses were performed to investigate the association of PAD with TVR, AP, and AI. As shown in Table 4In this study, we found that bSBP, cSBP, bPP, and cPP in the PAD group were significantly higher than those in the non-PAD group. In addition, TVR, AI, and AP were significantly higher in the PAD group compared with non-PAD group. Moreover, a multivariate logistic regression analyses demonstrated that PAD was significantly associated with TVR, AP, and AI adjusted with established multiple risk factors. Especially, elevated TVR was observed in older women. It is also reported that high TVR is associated with mortality, heart failure, and CVD events. Thus, increased TVR may further enhance the accumulated risk for cardiovascular disease. As expected, in the current study, higher TVR is associated with the presence of PAD. This might be simply because the risks for PAD are common compared with other heart and vascular diseases such as heart failure, ischemic heart disease, and stroke. Indeed, the patients with PAD are known to have high CAD risk.,27 The other reason is that the mean arterial BP elevated in patients with arterial sclerosis and several patients with PAD have a low cardiac output due to CAD. Consequently, TVR may increase by reflecting peripheral arterial stenosis and low cardiac output. Therefore, TVR well-represents the vascular condition of atherosclerosis throughout the body.TVR basically presents resistance to blood flow that occurs in blood vessels. The definition of TVR is calculated as follows; TVR is equal to mean arterial BP divided by cardiac output. TVR is significantly higher in women than in men. The central AP determined by the Mobil-O-Graph was reported to be associated with age and sex in the European community-based population. Higher central AP is associated with increased risk of development of CAD in younger and middle-aged men. Thus, AP may reflect the accumulation of cardiovascular risks in association with aortic wall stiffening. In the current study, AP in the PAD group is significantly higher than that in the non-PAD group. aPWV is also known as one of the surrogate markers for aortic stiffness. However, our study showed no difference in aPWV between the PAD group and the non-PAD groups. This result suggests that aPWV may not reflect the peripheral vascular condition but represents central vascular condition. AP may be a better way to evaluate arterial stiffness than aPWV.AP represents changes in central hemodynamics and pressure wave characteristics resulting from increased aortic wall stiffening and aortic remodeling.,30 Several papers have reported the clinical significance of AI. An increase in central AI is related to a risk of increase of cardiovascular events and all-cause mortality.,31 AI can predict clinical cardiovascular events independent of peripheral pressures. AI is recognized as one of useful markers of arterial stiffness in patients with PAD. AI is higher in patients with PAD as compared with control patients. In consistent with these studies, AI in the PAD group is significantly higher than that in non-PAD group in the present study, although all participants were referred to our institute to be suspicious for PAD. This result suggests that higher value of AI may be linked to vascular stenosis or occlusion in the peripheral artery. In this sense, AI can represent from mild to severe vascular condition.AI presents an indirect measurement of arterial stiffness.Several limitations in this study are noted. Firstly, this study was conducted in a single-institution study, with a small number of participants. Secondly, since all participants were referred to our hospital to be suspicious for PAD, the background of all participants were bias. That is, all participants in this study had, at least one or more risks for atherosclerosis. No healthy person was examined. Future study will be required to conduct a study in the general population. Third, since the current study was a cross-sectional observation study, the effect of the interventional treatments for PAD on the changes in these parameters were not clarified. Fourth, in this study, PAD was defined only by ABI value, however, ABI alone cannot provide a precise diagnosis of PAD in clinical setting. Fifth, in the present study, ABI value was determined by the oscillometric method, not by the doppler method. Future study will be required to further confirm whether TVR/AP/AI are valuable markers for PAD.5TVR, AP, and AI were significantly higher in the PAD group than in the non-PAD group. Non-invasive, easy, and reproducible tool is desirable to assess arterial stiffness.The authors would like to thank Dr. Hiroaki Otsuka and Dr. Kentaro Ejiri from Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences for patient recruitments, and Dr. Shugo Okamoto, Dr. Yasuhiro Onishi, Dr. Mariko Tsuchida-Nishiwaki, Dr. Natsumi Matsuoka-Uchiyama, Dr. Nozomu Otaka, Dr. Yuki Kakio, Dr. Hidemi Takeuchi, and Dr. Yoshiko Hada from Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences for helpful comment.Conceptualization: Rika Takemoto, Haruhito A. Uchida.Data curation: Rika Takemoto.Formal analysis: Rika Takemoto, Haruhito A. Uchida.Investigation: Rika Takemoto, Haruhito A. Uchida, Hironobu Toda.Writing – original draft: Rika Takemoto.Writing – review & editing: Haruhito A. Uchida, Hironobu Toda, Ken Okada, Fumio Otsuka, Hiroshi Ito, Jun Wada.


To clarify the relationship between serum urate (SU) decrease and visceral fat area (VFA) reduction in patients with gout.We retrospectively analyzed 237 male gout patients who had two sets of body composition and metabolic measurements within 6 months. Subjects included had all been treated with urate-lowering therapy (ULT) . All patients were from the specialty gout clinic of The Affiliated Hospital of Qingdao University. The multiple linear regression model evaluated the relationship between change in SU  and change in VFA .p <0.001) accompanied by a decrease in median (interquartile range) VFA . By multiple regression model, ΔSU was identified to be a significant determinant variable of decrease in VFA .ULT resulted in a mean (standard deviation) decrease in SU level (464.22 ± 110.21 μmol/L at baseline, 360.93 ± 91.66 μmol/L at the final visit, The decrease in SU level is positively associated with reduced VFA. This finding provides a rationale for clinical trials to affirm whether ULT promotes loss of visceral fat in patients with gout. Patientcontrols . A cross< 0.001) .p = 0.003) and change in waist circumference , even though the change in SU was relatively small   clinical electronic medical record system. Every patient voluntarily provided their written informed consent to import their electric health records into the BIMS, further used in scientific research.Data were extracted for patients who met the following criteria: (a) received ≥ 2 body composition measurements within 6 months; (b) age ≥ 18 years; and (c) male, to minimize the influence of gender confounding as the sex differences in fat distribution  and acceClinical characteristics included age, systolic and diastolic blood pressure (BP), comorbid disease, and concomitant medications. Fasting blood samples were collected from 7:00 to 9:00 a.m. Serum samples were analyzed on an automatic biochemical analyzer . Routine laboratory measurements included SU, alanine aminotransferase, aspartate aminotransferase, glucose, triglyceride, total cholesterol, creatinine, and blood urea nitrogen. BP was measured on the arm with an automatic sphygmomanometer while the participant was seated (Omron Colin).We extracted body composition data, including body fat (BF), percentage of body fat (PBF), VFA, and skeletal muscle mass (SMM), from an InBody S10 body composition analyzer , a BIA device that is portable, non-invasive, and non-radiation. The effectiveness of bioelectrical impedance analysis in body composition measurement agrees well with the gold standard method—computed tomography (CT) . Include2), and ≥24 kg/m2 was defined as overweight and ≥28 kg/m2 as obesity, according to Chinese criteria (−0.411 × (0.993)age; Cr > 0.9 mg/dl, eGFR = 141 × (Cr/0.9) −1.209 × (0.993)age  clinical practice guidelines age . Chronict-tests or Wilcoxon rank tests as appropriate. To observe the relationship between ΔSU and ΔVFA, participants were divided according to quartiles of ΔSU . Changes in visceral fat area, body fat mass, waist circumference, and body mass index were analyzed for each quartile of ΔSU.All analyses were performed using SPSS version 26.0 . Two-tailed probability values <0.05 were considered statistically significant. Before statistical analysis, continuous variables were tested for a normal distribution using the Kolmogorov–Smirnov test or Shapiro–Wilk test. Data were presented as mean ± standard deviation (SD), median , or number (percentage). Changes (Δ) were calculated as the (baseline level) – . Comparisons of variables between baseline level and final visit level were undertaken using paired-sample p < 0.20 were selected in multiple linear regression analysis. To control for the potential confounding effects of concomitant medication, antihypertensive, lipid, glucose-lowering, and liver–kidney-protecting medication use were adjusted in Model 2. Tophus, fatty liver, chronic vascular disease, and medication use were included in regression analysis as dichotomous variables, and others were continuous variables. The dichotomous variables were coded 1 for the presence and 0 for the absence of the factor.Simple linear regression analyses were conducted to evaluate the respective associations of changes in metabolic parameters between visits, baseline characteristics, medical history, and concomitant medication uses, with change in visceral fat area between visits. Multiple linear regression analysis was performed to examine relations among variables by using ΔVFA as a dependent variable to evaluate the role of the parameters in VFA loss. Variables with A total of 3,162 gout patients were screened. Patients were excluded because of the following criteria: individuals without  or only a single body composition measurement (n = 562), taking antiobesity drugs (n = 12), age <18 years (n = 17), follow-up interval <2 weeks or >6 months (n = 155) and female (n = 13). After exclusion, 237 individuals were considered eligible for this study  of the patients had already taken urate-lowering agents at the time of the baseline body composition evaluation. Of all, 86 were treated with febuxostat (range from 20 to 80 mg/day), and 151 were treated with benzbromarone (range from 25 to 50 mg/day). The SU levels were decreased from 464.22 (110.21) μmol/L at baseline to 360.93 (91.66) μmol/L at the final visit. Accordingly, the proportion of patients achieving the SU target (<360 μmol/L) was increased from 20.7% to 59.9% (p < 0.001) (2 (p < 0.001) . Significant decreases were also detected in other body composition parameters, including body fat (p < 0.001) , WC (p < 0.001) (p < 0.001), and lipid profiles—triglyceride (p = 0.001) and cholesterol (p = 0.003). Although statistically significant differences were shown in hepatic and other renal-related parameters at baseline and final visit, the average levels of these indicators were within the normal range throughout ULT  SU dropped from 464.22 (110.21) μmol/L to 360.93 (91.66) μmol/L  .In simple linear regression analysis, changes in serum urate, glucose, triglyceride, AST and baseline serum urate, and baseline visceral fat area were significant predictors of changes in visceral fat area . As our previous study showed, SU levels were reduced by ~160 μmol/L in gout patients taking low-dose febuxostat (20 mg/day) or benzbromarone (25 mg/day) within 12 weeks  had a statistically significant decrease in VFA when compared to Q1 (<25 μmol/L), Q2 (25–109 μmol/L), and Q3 (109–189 μmol/L). A positive statistical association between visceral fat variance and serum urate decrease also was observed after adjustment for potential confounding variables and concomitant medication use  inhibitor, ULT uricosuric drug benzbromarone, can reverse this effect by reducing lipogenesis in adipocytes and decreasing triglyceride content , which plays a key role in urate homeostasis in the proximal tubule , is alsoogenesis , bufferiogenesis . Both ne content . In addi content . In thisp < 0.001), which indicated that gout patients with more visceral fat could lose more fat. Interestingly, a slight improvement in skeletal muscle mass was observed . Elevated insulin resistance was observed to be associated with greater loss of lean body mass . Moreover, adherence to diet-based weight loss strategy is usually low and difficult to sustain owing to the difficulty adapting to the physiological and neurohormonal aspects of weight loss . Third, dietary and physical information was not collected in our study. Participants seeking to start gout care may have changed their activity patterns and dietary intake, which would weaken the magnitude of association between changes in serum urates and changes in visceral fat. Currently, it is difficult for us to rule out the possibility of diet and exercise. Finally, we analyzed the data as a whole by ignoring ULT dosages and duration details. The effects of ULT duration on visceral fat improvement and the maximum reduction by lowering SU need to be evaluated prospectively.In summary, our results indicate that decrease in serum urate level is associated with loss in visceral fat, especially in gout patients with an initially high baseline level of visceral fat. Our finding provides new insight into the improvement of abdominal obesity in patients with hyperuricemia and gout, which may provide additional emphasis to support initiation and adherence in ULT.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the research ethics committee of the Affiliated Hospital of Qingdao University (#QYFYWZLL 26298). The patients/participants provided their written informed consent to participate in this study.CL and JL contributed to the study concept and design. CW, XX, and TZ contributed to the acquisition of data. ZR, JL, XX, LH, TM, RT, and CL contributed to drafting and modifying the manuscript. ZR, XL, LC, HL, AJ, and ZL interpreted the data. ZR, YH, JL, XX, and SH worked on the sample processing and the statistical analysis. CL has full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the article and approved the submitted version.This work was sponsored by the National Natural Science Foundation of China (#81770869 and #31900413), National Key Research and Development Program (#2016YFC0903401), Shandong Province Key Research and Development Program (#2018CXGC1207), and Shandong Province Natural Science Foundation (#ZR2018ZC1053). Prof. Robert Terkeltaub was supported by NIH (#AR060772 and #AR075990) and the VA Research Service.RT is funded by a research award from Astra-Zeneca and has consulted with Horizon, Selecta, SOBI, and Astra-Zeneca.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The significance of renal arteriosclerosis in the prediction of the renal outcomes of diabetic kidney disease (DKD) remains undetermined.We enrolled 174 patients with DKD from three centres from January 2010 to July 2017. The severity and extent of arteriosclerosis were analysed on sections based on dual immunohistochemical staining of CD31 and α-smooth muscle actin. An X-tile plot was used to determine the optimal cut-off value. The primary endpoint was renal survival (RS), defined as the duration from renal biopsy to end-stage renal disease or death.2, and the average 24-h urine protein was 4.52 (2.45 ~ 7.66) g/24 h. The number of glomeruli in the biopsy specimens was 21.07 ± 9.7. The proportion of severe arteriosclerosis in the kidney positively correlated with the Renal Pathology Society glomerular classification , interstitial fibrosis and tubular atrophy (IFTA) , urine protein , systolic BP , and age  and significantly negatively correlated with baseline eGFR . In the multivariable model, the primary outcomes were significantly correlated with glomerular class , IFTA  and the modified arteriosclerosis score . After risk adjustment, RS was independently associated with the baseline eGFR , urine proteinuria  and the modified arteriosclerosis score , and the nomogram exhibited good calibration and acceptable discrimination .The baseline estimated glomerular filtration rate (eGFR) of 135 qualified patients was 45 (29 ~ 70) ml/min per 1.73 mThe severity and proportion of arteriosclerosis may be helpful prognostic indicators for DKD.The online version contains supplementary material available at 10.1186/s12882-021-02492-x. Diabetic kidney disease (DKD) is the most common complication in patients exposed to long-term hyperglycaemia . In ChinIn 2010, the Research Committee of the Renal Pathology Society (RPS) developed a pathologic classification system of diabetic nephropathy . HoweverDKD is a common vascular complication of diabetes. Renal ischaemia and endothelial injury play important roles in the pathological processes that promote renal fibrosis and CKD –19. AlthIn the current study, we hypothesized that the proportion of damaged arteries to all arteries in the tissue may contribute to the prognosis of DKD. To validate the significance of renal artery damage in the prediction of renal outcomes of DKD, we employed dual immunoperoxidase staining to better identify arteries with or without lesions and developed a modified arteriosclerosis score for the severity and proportion of all counted arteries. Nomograms were then used to predict the risks of DKD with all clinical characteristics as well as the pathological score –22.This was a multi-centre, retrospective study of patients with DKD diagnosed by renal pathology. Patients were enrolled between January 2010 and July 2017 from three hospitals . Of the 174 patient-included cohorts, 135 patients were eventually enrolled. The exclusion criteria included patients with DKD coincident with other patterns of kidney injury and inadequate renal tissue samples  .All demographic and clinical data were carefully documented from electronic medical clinical records of three hospitals. Demographics included age at the time of biopsy and sex. Clinical parameters collected included body mass index (BMI), blood pressure, hypertension, diabetic retinopathy (DR), diabetes duration, smoking, glycosylated haemoglobin (HbA1c) level, total cholesterol (Chol) level, serum albumin (ALB) level, urine protein (UPRO) level, eGFR, follow-up time, and follow-up serum creatinine (sCr) level. Hypertension was considered in patients with systolic blood pressure greater than 140 mmHg, diastolic blood pressure greater than 90 mmHg or antihypertensive drug administration. DR was defined as the presence of any characteristic lesion as described by the International Clinical Diabetic Retinopathy Disease Severity Scale, which is a grading standard designed according to the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). Hyperuricaemia was defined as serum uric acid ≥420 μmol/L in males or ≥ 360 μmol/L in females. Urinary protein was expressed in g per 24 h. The eGFR was estimated using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation .The clinical outcomes were considered to evaluate the predictive value of renal pathology variables, ESRD , or all-cause death. The follow-up time was defined as the duration from renal biopsy to ESRD or all-cause death , 25, theAll renal biopsies were performed and processed by standard techniques , 25. TheGlomerular lesions and interstitial lesions were scored according to the DKD pathologic classification issued by RPS , 25. ForTo assess the proportion of all involved arteries distributed in the tissues, severe arteriosclerosis, which was defined as arteries with thickening exceeding the intima thickness, to all arteries in sections was calculated. Since the proportion of severe arteriosclerosis was a continuous variable, X-tile software was used to find the best cut-off value and convert it to hierarchical data , 28. EveWithout knowledge of the clinical outcomes, two experienced nephropathologists (Qifeng Jiang and Yifan Zhang) were assigned to independently evaluate and score light microscopy slides. Pathological scoring disagreements were resolved by consensus.Student’s t-test between groups, one-way analysis of variance (ANOVA) in multiple groups, or Pearson’s test for correlation analysis. Nonparametric variables are presented as the medians and interquartile ranges (IQR) and were analysed with the Mann–Whitney test between groups, Kruskal–Wallis test in multiple groups, or Spearman rank correlation test. Categorical variables were expressed as percentages and compared using the Pearson χ2 test.Variables with a normal distribution are presented as the means and standard deviations and were subjected to unpaired Kaplan-Meier (KM) survival curves with log-rank tests and the Cox proportional hazards model to identify the potential association between clinical and pathologic variables and outcomes. Variables with a significance of P < 0.1 in the univariate models were included in the multivariable models [P < 0.1 in the univariate models. The second multivariable model  included only those pathological variables significant to P < 0.1 in the univariate models. The “Fully Risk-Adjustment Model” incorporated clinical variables significant at P < 0.05 in the clinical model, as well as pathological variables significant at P < 0.05 in the pathological model. Then, the AUCs of different risk variables and two models in predicting RS were estimated using time-dependent receiver operating curves (ROCs).The modified arteriosclerosis score cut-off value was analysed using the X-tile plot . Survivae models . Three mTo estimate median and individual postdiagnosis renal survival probabilities at 1, 3, and 5 years, a nomogram was constructed based on the “Fully Risk-Adjustment Model” . ValidatP-value < 0.05 considered statistically significant. All statistical analyses were performed using X-tile software version 3.6.1 (http://tissuearray.org), GraphPad Prism 7 software (GraphPad Software) or R version 3.6.3 .All tests used were two-sided, with a Of 174 patients with biopsy-proven DKD, 37 patients were excluded due to coincidence with other kidney diseases, and 2 patients were excluded due to inadequate tissue samples. Finally, 135 patients were enrolled in this study. The mean number of glomeruli for each biopsy specimen was 21.07 ± 9.7. During the 21-month follow-up  , 10 pati2. The median duration of diabetes was 7 (3–11) years, with HbA1c of 7.72 ± 3.88%, SBP of 157.12 ± 25.92 mmHg, and total cholesterol of 5.89 (4.9–6.81) mmol/L. The median urine protein at enrolment was 4.52 (2.45–7.66) g/24 h, with a median baseline eGFR of 45 (29–70) ml/min per 1.73 m2.The baseline clinical data of 135 DKD patients are listed in Table The pathological characteristics of the patients are tabulated in Table r = 0.28, P<0.012) and IFTA   but significantly positively correlated with urine protein , SBP , and age . Univariable and multivariable Cox regression analyses were used to explore the association between clinical characteristics and renal survival (ESRD or death). Only clinical variables that showed significance in the univariate analysis (P < 0.1) were included in the multivariable clinical model. The only clinical variables to remain significant in the multivariable clinical model were baseline eGFR, urine proteinuria and albumin , IFTA , arteriosclerosis score  and modified arteriosclerosis score  were correlated with shorter RS time in DKD patients.As shown in Table P < 0.05 in univariate analysis were also used to construct two multivariable models. In the pathological model, only RPS glomerular class and IFTA were statistically significant if RPS glomerular class , IFTA  or arteriosclerosis scores  were included. However, if the modified arteriosclerosis score  was used instead of the arteriosclerosis score in the model, all three variables were statistically significant. In the second multivariable model, clinical features  and RPS glomerular class, IFTA or modified arteriosclerosis score were included. The full risk-adjustment model showed that only baseline eGFR , urine proteinuria  and modified arteriosclerosis score  were independently associated with RS. The forest plot in Fig. Pathological variables with Figures A prognostic nomogram for 1-, 3-, and 5-year RS was established Fig. a. BaseliIn terms of discrimination, the C-index for renal survival was 0.82 (95% CI: 0.75–0.87). The calibration curve for the probability of survival at 1, 3 or 5 years after biopsy showed optimal agreement between the prediction by the nomogram and the actual observation  and provided a prognostic nomogram and score . As a toOur study has multiple strengths. The main strength of our study is that we illustrated the modified arteriosclerosis score vascular lesion as an independent marker of time to diabetic ESRD with a modified definition. Our method could identify DKD patients with a worse prognosis. Furthermore, the new immunohistochemical method we performed showed more comprehensive characteristics of vascular lesions than conventional staining, which may be used as a reference for the pathological score of DKD in the future. Third, our study was constructed in the framework of a multicentre cohort study with a broad spectrum of parameters available at diagnosis. Multicentre studies can better represent real-world heterogeneity and are more generalizable than single-centre studies. Moreover, we created a nomogram for DKD patients to help nephrologists make clinical decisions. Nomograms have the ability to generate an individual probability of a clinical event by integrating diverse prognostic and determinant variables, which meets our desire for biologically and clinically integrated models and fulfils our drive towards personalized medicine. Finally, the blinded evaluation of renal biopsy is another strength of this study.Despite these strengths, some limitations must be considered when interpreting our findings. First, it was a retrospective study. However, all end points were based on objectively measured laboratory values that reduced the chance for bias. Second, it was a small sample size. Therefore, our findings are hypothetical and need to be reexamined with a larger data set. Third, we did not evaluate the therapeutic interventions during follow-up, which may have had miscellaneous impacts on renal prognosis. Finally, histologic changes were assessed based on a simple classification, but diabetic glomerulopathy is far more complicated.In conclusion, we present here a novel renal survival prediction model based on three key independent prognostic factors. Other studies are required to determine whether the modified arteriosclerosis score can be applied as a novel, independent marker of time to ESRD for DKD patients. The prognostic nomogram and the score proposed may help offer the opportunity to define risk-adapted strategies for DKD management in the future.Additional file 1: Figure S1. Time-dependent ROC of different risk factors for RS at 24 months of follow-up. Abbreviations: AUC, area under curve; CI, confidence interval; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MAS, modified arteriosclerosis score; UPRO, urine protein.Additional file 2: Figure S2. Time-dependent ROC of different models for RS at 24 months of follow-up.


Lung-protective ventilation is key in bridging patients suffering fromCOVID-19 acute respiratory distress syndrome (ARDS) to recovery. However,resource and personnel limitations during pandemics complicate theimplementation of lung-protective protocols. Automated ventilation modes mayprove decisive in these settings enabling higher degrees of lung-protectiveventilation than conventional modes.2O, peak pressure <30 cmH2O,peripheral oxygen saturation ≥88% and dynamic mechanical power <17J/min.Prospective study at a Swiss university hospital. Critically ill,mechanically ventilated COVID-19 ARDS patients were allocated, bystudy-blinded coordinating staff, to either closed-loop or conventionalmechanical ventilation, based on mechanical ventilator availability. Primaryoutcome was the overall achieved percentage of lung-protective ventilationin closed-loop versus conventional mechanical ventilation, assessedminute-by-minute, during the initial 7 days and overall mechanicalventilation time. Lung-protective ventilation was defined as the combinedtarget of tidal volume <8 ml per kg of ideal body weight, dynamic drivingpressure <15 cmH2/ FiO2 ratio of 92 [72-147] mmHg and a staticcompliance of 18 [11-25] ml/cmH2O, were mechanically ventilatedfor 11 [4-25] days and had a 28-day mortality rate of 20%. During theinitial 7 days of mechanical ventilation, patients in the closed-loop groupwere ventilated lung-protectively for 65% of the time versus 38% in theconventional group  and for 45% versus 33% of overall mechanical ventilation time.Forty COVID-19 ARDS patients, accounting for 1,048,630 minutes (728 days) ofcumulative mechanical ventilation, allocated to either closed-loop (n = 23)or conventional ventilation (n = 17), presenting with a medianpaOAmong critically ill, mechanically ventilated COVID-19 ARDS patients duringan early highpoint of the pandemic, mechanical ventilation using aclosed-loop mode was associated with a higher degree of lung-protectiveventilation than was conventional mechanical ventilation. Closed-loop mechanicalventilation could help clinicians in the systematic implementation oflung-protective ventilation in CARDS patients, while significantly reducing theirworkload.11 INTELLiVENT®-ASV is such a closed-loop ventilation mode.Based on peripheral oxygen saturation and end-tidal carbon dioxide concentrationmeasurements, it automatically adjusts minute ventilation, the fraction of inspiredoxygen (FiO2) and the positive end-expiratory pressure (PEEP)breath-by-breath.11 INTELLiVENT®-ASV has been shown to safely ventilatepatients in a variety of pathologies and to maintain ventilation settings and lungmechanics within the limits of protective mechanical ventilation, while reducing thenecessity for medical and nursing adjustment.1214Closed-loop mechanical ventilation modes enable a fully automatized and optimizedfunction of the mechanical ventilator, thus reducing the necessity for manualadjustment.The objective of the present study was to assess the performance, in terms oflung-protective ventilation, of a closed-loop ventilation mode as compared toconventional mechanical ventilation in the resource-constrained setting of theCOVID-19 pandemic.This prospective study was performed between March and May 2020 at the Institute ofIntensive Care Medicine of the University Hospital Zurich, an academic tertiary carereferral center. The study was approved by the cantonal ethics committee of Zurich(BASEC: 2020-01681) and informed consent was obtained from the patients or fromtheir next of kin. The study complies with the Declaration of Helsinki, theGuidelines on Good Clinical Practice (GCP-Directive) issued by the EuropeanMedicines Agency as well as with Swiss law and regulatory authorityrequirements.15 and (II) a criticalmanifestation of COVID-19 requiring admission to an intensive care unit andtreatment with invasive mechanical ventilation due to profound hypoxemia,complying with the Berlin definition for ARDS.16Patients were prospectively included in this study if they presented with (I) aSARS-CoV-2 infection that was laboratory confirmed by nucleic acid amplificationaccording to the WHO-issued testing guidelines,2) overFiO2 ratio (P/F ratio) <200 mmHg, the use of neuromuscularblocking agents in patients with a P/F ratio <150 mmHg or presenting anuncontrollable respiratory drive and vigorous breathing efforts under deepsedation, as well as the use of an esophageal pressure probe in patients at thelimit of lung-protective ventilation or with a clinically assessed abnormalchest-wall compliance.In the setting of the COVID-19 pandemic, resources at the Institute of IntensiveCare Medicine had to be expanded to allow for care of a higher number ofinvasively ventilated COVID-19 patients. Therefore, in addition to the standardHamilton-S1®  mechanical ventilator, DraegerEvita® Infinity® V500 machines  had to be employed tomechanically ventilate COVID-19 patients. The standard mode of ventilationemployed on the Hamilton-S1® ventilator was INTELLiVENT®-ASV 1.1 (closed-loopventilation), and Biphasic Positive Airway Pressure Ventilation on the DraegerEvita® Infinity® V500 . Weaning from the Hamiltonventilator was approached via the INTELLiVENT®-ASV mode. For the Draegerventilator, Biphasic Positive Airway Pressure and Spontaneous ContinuousPositive Airway Pressure ventilation could be used. Ventilation times on otherventilation modes, during patient transport and during interventions, weredisregarded in the final analysis to prevent potential biases. Physician andnursing staff in charge of treatment and care in the ICU were the same for bothtypes of mechanical ventilator; no differentiation or splitting of teamsdependent on ventilator expertise was undertaken. Medical and nursing staff werefamiliar with the use of both devices and ventilation modes as part of theirdaily routine, and had received an intensified refresher course on mechanicalventilation focusing on lung-protective ARDS ventilation in both closed-loopventilation and conventional ventilation modes at the beginning of the pandemic.Institutional standard procedures were the same for both closed-loop andconventional mechanical ventilation, including but not limited to the proning ofpatients with a partial pressure of arterial oxygen  were algorithmically assessed on a minute-by-minute basis; thus,non-equal, temporally concomitant settings were noted as a change. To assureoptimal ventilation and oxygenation of all patients, at least 1 blood gasanalysis per 6 hours ICU was performed. Static driving pressure was measured atthe time-point of endotracheal intubation as the difference of aninspiratory-and an expiratory-hold maneuver, subsequently ÷ static compliancewas calculated as tidal volume static driving pressure. However, in order toenable a continuous, minute-by-minute assessment of driving pressure andmechanical power, we chose to employ their dynamic approximations in analogy tothe previously published study by Urner et al.17 Peak inspiratory pressurewas thus employed as a surrogate for plateau pressure. Consequently dynamicdriving pressure was calculated as peak inspiratory pressure − positive endexpiratory pressure, dynamic compliance as tidal volume ÷ dynamic drivingpressure and dynamic mechanical power as 0.098 × respiratory rate × tidal volume× (peak inspiratory pressure − (0.5 × dynamic driving pressure)).All mechanical ventilators were attached to the patient data management system enabling a prospective, minute-by-minutecollection of all mechanical ventilator settings and measurements. Changes inventilator settings  ≥88%23 under permissivehypercapnic ventilation with a lower pH limit of 7.25.24 Further, a mechanicalpower <17 J/min was defined as lung-protective for the setting of thisstudy.25Lung-protective mechanical ventilation was defined and institutionally targetedas: a maximal tidal volume of 6-8 ml per kg of ideal body weight.P < 0.05 was consideredstatistically significant. For longitudinal analysis of mechanical ventilatorparameters, lung mechanics and blood gas analyses, differences between timepoints and ventilation modes were tested using linear mixed effects modelanalysis. As independent variable fixed effects, time point and ventilation modewere entered into the model, respectively, with and without interaction terms,which were retained only if they were found to contribute to the model. Asrandom effects, intercepts for subjects as well as per-subject random slopes forthe effect on dependent variables were employed. P values werecalculated using a likelihood ratio test of the full model, with the effect inquestion, against a “null model,” without the effect in question.P values for individual fixed effects were obtained bySatterthwaite approximation in a multi-dimensional model comprising time pointand outcome status. Statistical analysis was performed via a fully scripted datamanagement pathway using the R environment for statistical computing version3.6.1.26 Values are given as medians with interquartile rangesor counts and percentages as appropriate.Due to the breakthrough nature of this cohort study during the ongoing healthcrisis, no power calculations were undertaken. Comparisons of populationcharacteristics were performed using the Wilcoxon Signed Rank and chi-squaredtest, as appropriate. A 2-sided 2O/ L, as presented in Forty-seven patients with CARDS were admitted to the intensive care unit duringthe study period. Of these, 40 patients required invasive mechanicalventilation, were included in the study and allocated by study-blindedcoordinating staff to either conventional ventilation (ConV) in 17 cases orclosed-loop ventilation (CLoop) in 23 cases, as illustrated in 2) at a clinicallycomparable pH as opposed to the ConV group   .P < 0.001). This was accompanied by adecreased alveolar dead space and alveolo-arterial gradient in the CLoop group(P < 0.001)  .P< 0.001), respiratory rate (P < 0.001), dynamic drivingpressure (P < 0.001) and dynamic mechanical power(P < 0.001), while achieving higher dynamic compliance(P < 0.01) and lower alveolar dead space(P < 0.002) than did patients in the ConV group, asevidenced in During the initial 7 days post intubation, patients in the CLoop groupexperienced systematically lower peak inspiratory pressures and 49% (P < 0.001), respectively, for dynamic drivingpressures in the ConV group (P < 0.001); this difference was also patent when theoverall ventilation time between groups was compared (P <0.001). Additionally, the percentage of time with a peak inspiratory pressure<30 cmH2O (P < 0.001) was also higher in theCLoop group. Simultaneously, paO2 levels remained ≥7.33 kPa for 99%and the SpO2 ≥88% for 99% of the ventilation time in the CLoop groupversus 99% (P < 0.001) and 97% (P <0.001) in the ConV group, respectively. Finally, patients in the CLoop groupwere successfully ventilated in a fully protective fashion, with conjoint tidalvolumes <8 ml/kg IBW, dynamic driving pressures <15 cmH2O, peakinspiratory pressures <30 cmH20, SpO2 ≥88% and dynamicmechanical power <17 J/min, over 45% of the time, 63% during the first week,as opposed to 33%  and38% , respectively, inthe ConV group.The dynamic driving pressure in the CLoop group was maintained at <15cmHP = 0.02). In comparison, theautomated algorithm in the CLoop group adapted the ventilator settings every 2.8[2.3-3.6] minutes.In patients ventilated in the ConV group 7 [3-12] changes per day had to bemanually implemented to adapt mechanical ventilator settings as opposed to 4[2-7] in the CLoop group  was comparedwith conventional mechanical ventilation (ConV) in COVID-19 ARDS (CARDS) on aminute-by-minute basis. The CLoop group was fully protectively ventilated concerningtidal volume, driving pressure, peak inspiratory pressure, peripheral oxygensaturation and mechanical power, for 65% of the first week and 45% of their overallventilation time, as opposed to 38% and 33%, respectively, for those in the ConVgroup. This was achieved with a concomitant decrease in the need for manualadjustment of the ventilator settings in the CLoop compared to the ConV group.3 In this setting, reduced tidalvolume ventilation patterns with 4 to 8 ml/kg IBW tidal volumes have become standardof care.19 Nonetheless,the implementation of these standards is still not universal; in the recent LUNGSAFE study only two-thirds of the ARDS patients received tidal volumes below 8 ml/kgIBW27and recent data show only 23% of patients with CARDS being ventilated with tidalvolumes below 6 ml/kg IBW.28 The present study reports a limitation of tidal volumesbelow 8 kg/ml IBW for 90% and below 6 ml/kg for 57% of the mechanical ventilationtime in the ConV group, reflecting the excellent training and understanding ofprotective ventilation among ICU staff. Nonetheless, and regardless of the evidentproficiency of the medical and nursing staff, CLoop was superior to ConV concerningsettings for inspiratory pressure and dynamic driving pressure. These 2 variablesact as surrogate parameters for transpulmonary pressure and pulmonary distension,and their limitation at 30 cmH2O21 and 15cmH2O,20 respectively, has been correlated with systematic mortalityreductions in ARDS. Further, recent research has emphasized the importance ofelevated cycling frequencies as amplifiers of the static strain induced by tidalvolumes and driving pressures leading to the stress failure of stress-bearingalveolar micro-elements.29 The observed reduced respiratory rate in the CLoop group duringthe acute phase of CARDS ventilation, as opposed to the higher respiratoryfrequencies in the ConV group, could thus be a further protective factor.Interestingly, and in contrast to ConV, CLoop enabled normoxic ventilation at higherP/F ratios while reducing FiO2 levels. Elevated FiO2 settingshave been previously postulated as an exacerbating variable to alveolar barrierdysfunction, aggravating the degree of VILI, while their limitation has shownprotective effects.3033Protective invasive mechanical ventilation has become a clear goal in ARDS therapy inorder to limit strain to the “baby lung” and prevent VILI.35 Mechanicalpower combines the effects of all main ventilatory variables, and powers above 17J/min have been associated with worse outcomes in ARDS.25 Even though mechanical powercalculation is not included in the CLoop algorithm, this type of ventilation modemanaged to limit mechanical power to under 17 J/min for 79% of ventilation timewhile ConV did so for only 50% of the time, a value similar to the mechanical powerreported in large ARDS cohorts.17 Interestingly, the percentageof time under lung-protective mechanical ventilation in the CLoop group, especiallyregarding mechanical power, was reduced during the first week in comparison to theoverall time, probably indicating the difficulty of the closed-loop algorithm tocounterbalance spontaneous ventilation.The concept of mechanical power is a relatively new and holistic approach toquantifying the energetic strain delivered to the lung during ventilation.36 The pandemic triggered by SARS-CoV-2 has overwhelmed hospitals,leading to a lack of personnel and resources in ICUs.57 Mortalities in mechanicallyventilated CARDS patients have been reported to oscillate between 20%-80% in thissetting,38 with mostlying substantially above the 30% reported in classic ARDS.10 Reasons forthe variability of mortality are manifold, probably reflecting the heterogeneity oftreatment strategies, especially regarding off-label therapies, patient triagebefore ICU, variable degrees of resources and staffing limitation as well asventilation strategies, including ventilator sharing, among others.3739 Nonetheless, the elevatedincidence of barotraumas in CARDS as compared to classical ARDS may mainly be rootedin the exhaustion of personal resources, coupled with the recruitment of staff whoare inexperienced in ARDS treatment.40 The thorough implementationof lung-protective protocols could explain the exceptionally low 28-day mortality ofonly 20% in this cohort. Most notably no ventilator associated barotraumas wereobserved in this cohort and only 1 patient died of refractory respiratoryfailure.Integrating lung-protective ventilation approaches into routine mechanicalventilation is a complex and resource-intensive endeavor, even for experiencedclinicians and nurses.12 This addedefficiency could reduce strain on nursing and medical staff, especially within theframework of the COVID-19 pandemic. Further, it allows inexperienced ICU staff toimplement lung-protective ventilation strategies without the need for exhaustivetraining and considerations of the high heterogeneity of CARDS.41 Experienced caregivers arerare and the implementation of their know-how is resource-intensive.36In analogy to previous studies on CLoop, the number of manual changes in mechanicalventilator settings by caregivers was lower with CLoop than with ConV.43 Fifth, the use of peakpressure as a surrogate parameter for plateau pressure may be a relevant confounderfor the interpretability of the data. Nevertheless, and as previously shown, dynamicdriving pressure and mechanical power have a clinical repercussion on outcomesimilar to static driving pressure and mechanical power.17 Further, there is no currentmethod for faithfully assessing static plateau pressure in a continuous approach.Sixth, it could be argued that ICU staff were not accustomed to pressure-controlledventilation and lung-protective strategies, leading to the observed inferiority ofConV. However, the implementation of mechanical ventilation refreshers for the ICUstaff previous to this study’s initiation as well as the high degree ofimplementation of lung-protective strategies in the ConV group compared to what ismentioned in the literature, argue against this point. Finally, while theimplementation and acceptance of closed-loop ventilation is widespread in the ICUsetting in which this study was performed, the de-novoimplementation of this tool in other ICUs may face resistance due to its novelty andan intrinsic reluctance to use automatic tools in ICU settings. As shown here, thesafety and efficacy of closed-loop ventilation as well as the reduction of workloadshould be strong enough arguments to support a supervised implementation of thistechnology, especially in the setting of a pandemic.The present study has to acknowledge certain limitations. First, this study was not aclassic and truly randomized controlled trial; nevertheless, the study design chosenwas devised to maximally reduce biases. Second, the primary end-point of the study,albeit of pathophysiological relevance, does not prove a clinical benefit of CLoopover ConV. Nonetheless, this study describes continuous, minute-by-minute sampledventilatory data, something unaccomplished before over such a long period ofmechanical ventilation in ARDS. This, in turn, allows a faithful representation ofboth ventilation strategies over time, as opposed to the reporting of daily sampledventilation data, and counterbalances the relatively low number of recruitedpatients. Third, the relevance of the reduction in ventilator interactions describedwas not directly correlated to the bedside experience of the ICU staff; as such, thedegree of reduction in effective strain on medical and nursing personnel is notquantifiable. Fourth, it can be argued, that the present study only regarded CLoopcomparing it with pressure-controlled ventilation, and disregarding the still widelyused volume-controlled ventilation. However, there is no clear evidence favoring anymode over pressure control in ARDS.In conclusion, closed-loop ventilation, when compared to conventional mechanicalventilation, is associated with a higher degree of lung-protective ventilation,coupled with less hypoxemic time, while reducing the number of mechanical ventilatorsetting adjustments necessary in CARDS during an early highpoint of the COVID-19pandemic.Click here for additional data file.Supplemental Material, sj-pdf-1-jic-10.1177_08850666211024139 for Closed-LoopVersus Conventional Mechanical Ventilation in COVID-19 ARDS by Pedro DavidWendel Garcia, Daniel Andrea Hofmaenner, Silvio D. Brugger, Claudio T. Acevedo,Jan Bartussek, Giovanni Camen, Patrick Raphael Bader, Gregor Bruellmann,Johannes Kattner, Christoph Ganter, Reto Andreas Schuepbach and Philipp KarlBuehler in Journal of Intensive Care Medicine


Background: In order to reduce the risk of invasive blood pressure monitoring and improve the safety and efficiency, this article mainly analyzes the effectiveness and safety of using positive-pressure connector for invasive blood pressure monitoring in patients with coronary artery interventional therapy, so as to improve the invasive blood pressure monitoring method.Aim: To study and analyze the application of positive-pressure connector in invasive blood pressure monitoring in coronary interventional therapy.Methods: From October 2017 to October 2019, a total of 120 patients admitted to Cangzhou Central Hospital, Cangzhou, Hebei, China, for coronary interventional therapy with invasive blood pressure monitoring were selected and divided into a control group and an experimental group by drawing lots with 60 patients in each group. Positive-pressure connector was used for invasive blood pressure detection in the experimental group, and heparin cap connector was used for invasive blood pressure detection in the control group. The effectiveness and safety of blood pressure monitoring in the two groups were compared, and the influence of different joints on invasive blood pressure monitoring was analyzed.Results: The influencing factors of puncture efficiency in the experimental group (6.67%) were significantly lower than those in the control group (30.00%) (P < 0.05). There was no significant difference in catheter bending between the experimental group and the control group (P > 0.05). The experimental group exhibited a remarkably higher puncture safety rate (93%) compared to the control group (67%) (P < 0.05). There was no significant difference in arterial blood pressure between the two groups with different indwelling time (P > 0.05). The frequency of extubation and reinsertion in the experimental group was significantly lower than that in the control group (P < 0.05). Factors influencing puncture safety in the experimental group were significantly lower than those in the control group (P < 0.05).Conclusion: The use of positive-pressure connector for invasive blood pressure monitoring in patients with coronary artery interventional therapy can greatly improve the safety of blood pressure monitoring and reduce the suffering of patients. Therefore, the application of positive-pressure connector in invasive blood pressure monitoring is worthy of promotion and application in clinical practice. Invasive blood pressure monitoring is widely applied in clinical practice of blood pressure monitoring. It is a method to measure continuous arterial blood pressure by inserting a puncture tube directly into the artery. Invasive blood pressure monitoring is more accurate than non-invasive blood pressure monitoring and is not affected by measurement manipulation and other factors. In addition, this technique features constant and dynamic change and is affected neither by artificial compression, nor cuff width and tightness. Importantly, the measurement is accurate and reliable and can be obtained at any time . This meIn this study, 120 patients admitted to our hospital for coronary interventional therapy with invasive blood pressure monitoring from October 2017 to October 2019, Cangzhou Central Hospital, Cangzhou, Hebei, China, were selected and divided into a control group and an experimental group by drawing lots.P > 0.05). See The study used propensity score (PS) nearest neighbor matching, the most basic method of propensity score match (PSM), that is, directly looking for one or more individuals with the same or similar PS value from the control group to match the experimental group . There wPatients who received coronary interventional therapy and applied invasive blood pressure monitoring in our hospital;No other organic diseases;No drug allergy or abuse history, no bad addiction, normal cognitive function;Did not receive other analgesic drugs recently;Left main trunk diameter stenosis >50%, proximal anterior descending branch diameter stenosis >70%, two or three coronary artery diameter stenosis >70%, and left ventricular function impairment < 40%, extensive ischemia.Any coronary artery diameter stenosis >70%, manifested as activity-induced angina or equivalent symptoms, and poor drug treatment.Unstable blood pressure and blood sugar control;Coronary heart disease with other organic diseases;Recent history of infection;The results of Allen test  did not This study was approved by the ethics committee of the hospital, and all patients volunteered to participate in the study and signed informed consent, IRB: 2016-03-423.In order to ensure the safety and effectiveness of the measurement results, this study has unified management, and there is a relatively complete internal treatment control process, wherein all links are well-considered.The starting time is when the puncture was successfully inserted into the pressure measuring tube, and the ending time was when the indwelling needle is removed. In the control group, heparin cap connector was used to connect the pressure sensor with the indwelling needle. Before puncture, it was checked whether each joint of the pressure sensor can be used normally. Alcohol cotton was used to disinfect the front and side of each joint, respectively, and air was exhausted after disinfection to ensure that there was no air residue in the pressure measuring tube. The pressure of the pressurized bag was 300 mm Hg, and heparin saltwater was put into the pressurized bag –6. AccorHeparin cap connector was used to connect the three-way cock on the pressure sensor in the control group, whereas positive-pressure connector was used in the experimental group . PatientThe times of thrombosis and bubbles in the two groups of patients were observed and recorded, and the skin condition of the puncture site was regularly checked. If the patients had red and swollen skin and blood exudation, timely adjustment was made, and if severe tenderness occurred, extubation and reinsertion were conducted.Observation records were made every 5 h to record the effective rate and safety of invasive blood pressure monitoring, and the effective rate refers to the effective rate of puncture and nursing. If blood clots or residual air was discovered at the connector, it was ineffective, and if there was resistance of the syringe pump, it was also ineffective. During the nursing process, if extubation was necessary because of catheter bending thrombosis or that the nursing did not appear in time, the case was considered invalid. The safety index refers to whether the skin at the puncture site is infected; that is, the skin is red, swollen, and prickly, and the blood extravasates, and the wound is seriously purulent. The arterial blood pressure monitoring results of the two groups with different indwelling time were recorded, and the results of the two groups were compared to see whether there was a significant difference.t-test. Enumeration data were expressed as n (%) and examined by X2 test. P < 0.05 was considered statistically significant.The relevant data and data in this article were processed and analyzed by statistical software SPSS version 21.0. Logistic regression was used to score propensity matching. The basic information of the two groups of patients included gender, age, clinical varicose veins, etiology, anatomy, and pathophysiological [Clinical Etiology Anatomic Pathophysiologic Classification System (CEAP)] classification. The CHIVA group and the control group were used as 1/0 binary processing indicators; gender, age, and CEAP classification were used as covariables, and the propensity score matching standard  was set to 0.02, and the logistic regression formula was used to perform the propensity matching score with the ratio of 1:1, the propensity score was calculated, and the cases with similar scores were matched. Measurement data were expressed as (mean ± SD) and examined by P < 0.05). The indwelling time of patients in the experimental group was not statistically different from the control group 5.33 ± 1.02 vs. 5.01 ± 1.74 days, P = 0.24). The influencing factors of puncture efficiency in the two groups are shown in The puncture effective rate of the control group was lower than that of the experimental group, and the difference was significant (P > 0.05). The specific comparison results are shown in The total effective rate of the experimental group was not statistically different from that of the control group . The comparison of factors affecting safety, such as puncture wound infection, is shown in Because invasive blood pressure monitoring requires arterial puncture, and heparin water injection needs to flow through the connector into the body, the use of heparin cap connector during this process will inevitably lead to infection. During the monitoring time of blood pressure in the two groups, only two patients in the experimental group had skin redness and swelling, the puncture safety rate being 93%. A total of 12 patients in the control group showed signs of infection such as skin redness, swelling, tingling, and oozing blood, the puncture safety rate being 67%. Comparison of puncture safety between the two groups were statistically significant . However, whether the nursing work has an effect on the efficiency of invasive blood pressure detection needs further study.In the nursing process, catheter may be bent, resulting in thrombosis and, in severe cases, even extubation and reinsertion –18. In tP = 0.001).Puncture infection is an important factor affecting puncture safety. As invasive blood pressure monitoring requires puncture of the artery, and the injection of heparin water needs to flow through the connector into the body, the use of heparin cap connector during this process will inevitably lead to infection. In this study, two patients in the experimental group had redness and swelling of the puncture site, and the puncture safety was 93%. A total of 12 patients in the control group showed signs of infection such as skin redness, swelling, tingling, etc., and puncture safety was 67%. The comparison of puncture safety between the groups were significantly different (P > 0.05). The results indicated that the difference between positive-pressure connector and heparin cap connector in invasive blood pressure monitoring lies in the possibility of causing complications, which is not closely related to the accuracy of blood pressure monitoring results. This result is similar to the one proposed by Nunes et al. (In addition, the blood pressure waveform and numerical changes in the two groups were recorded, respectively, in the same time period, and no significant difference was found in the blood pressure changes in the two groups in the same time period (s et al.  that theThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Cangzhou Central Hospital. The patients/participants provided their written informed consent to participate in this study.AW and JL contributed to the study design and reviewed the manuscript. WP and AW analyzed the data and wrote the manuscript. YJ, LG, and ZX contributed to the data collection, data interpretation, and manuscript writing. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The treatment of many chronic illnesses involves long-term pharmaceutical therapy, but it is an ongoing challenge to find effective ways to improve medication adherence to promote good health outcomes. Cardioprotective medications can prevent the enlargement of harmful clots, cardiovascular symptoms, and poor therapeutic outcomes, such as uncontrolled high blood pressure and hyperlipidemia, for patients with coronary heart disease. Poor adherence to cardioprotective medications, however, has been reported as a global health concern among patients with coronary heart disease, and it is particularly a concern in China.This study aimed to evaluate the efficacy of a mobile health  intervention using 2 mobile apps to improve medication adherence and health outcomes.A randomized, placebo-controlled, 2-arm parallel study was conducted in a major university-affiliated medical center located in Chengdu, China. Participants were recruited by flyers and health care provider referrals. Each participant was observed for 90 days, including a 60-day period of mHealth intervention and a 30-day period of nonintervention follow-up. The study coordinator used WeChat and Message Express to send educational materials and reminders to take medication, respectively. Participants used WeChat to receive both the educational materials and reminders. Participants in the control group only received educational materials. This study received ethics approval from the Duke Health Institutional Review Board (Pro00073395) on May 5, 2018, and was approved by West China Hospital (20170331180037). Recruitment began on May 20, 2018. The pilot phase of this study was registered on June 8, 2016, and the current, larger-scale study was retrospectively registered on January 11, 2021 .179=2.04, P=.04) and 90 days . Systolic blood pressure and diastolic blood pressure decreased in the experimental group but increased in the control group. The mean decrease in diastolic blood pressure was statistically significant at both 60 days  and 90 days . The mean decrease in systolic blood pressure was significantly different in the groups at 90 days .We recruited 230 patients with coronary heart disease. Of these patients, 196 completed the baseline survey and received the intervention. The majority of participants were married , male , and lived in urban China . Participants’ average age was 61 years, and half were retired . More than half the participants  were prescribed at least 5 medications. The mean decrease in medication nonadherence score was statistically significant at both 60 days (tThe proposed mHealth intervention can improve medication adherence and health outcomes, including systolic blood pressure and diastolic blood pressure.ClinicalTrials.gov NCT02793830; https://clinicaltrials.gov/ct2/show/NCT02793830 and ClinicalTrials.gov NCT04703439; https://clinicaltrials.gov/ct2/show/NCT04703439 Coronary heart disease (CHD) is a heart and blood vessel disease related to atherosclerosis in which plaque builds up in the walls of the coronary arteries, narrowing the arteries and restricting the flow of blood . CHD is In China, however, poor adherence to cardioprotective medications has been reported as a public health concern , contribAfter these pilot studies, mobile phone–based mHealth interventions have been conducted in the field of cardiovascular medicine in China -34, but This study used 2 mobile apps: WeChat (Tencent Inc) and Message Express (Bluemobile.zt). WeChat is the most widely used messaging app in China . MessageThis unblinded, 2-arm, parallel randomized controlled trial was conducted between May and December 2018 at the Cardiology Department of West China Hospital, located in Chengdu. West China Hospital is a major university-affiliated hospital that serves more than 10,000 outpatients a day . A totalThis study received ethical approval from the Duke Health Institutional Review Board (Pro00073395) and West China Hospital (20170331180037).The interventions were refined based on the pilot study . Once a Participants’ demographic characteristics were recorded, including age, gender, ethnicity, weight, height, marital status, job status, education, medical insurance status, living area, number of prescribed medications, and family income. A REDCap survey hyperlink was sent to each participant to collect their demographic characteristics and track their health outcome variables at 7 time points: enrollment ; 15, 30, 45, and 60 days after enrollment ; and 75 and 90 days after enrollment . Health outcome variables included medication nonadherence score, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). The primary outcome  was measured using a validated 3-item, 5-point Likert scale, the Voils Extent Scale . To calct tests were used to determine between-group differences at baseline. The Fisher exact test and Wilcoxon 2-sample test were used as alternatives when a chi-square test was not applicable due to small expected values in some cells or when a 2-sample t test assumption was not met. All statistical tests were nondirectional (2-tailed) and the significance level was set at P=.05. If a difference in a baseline characteristic was significant, the baseline variable was included as a covariate in the modeling stage.All analyses were performed using SAS 9.4. Categorical variables such as gender, ethnicity, marital status, job status, medical insurance, and living area were reported as frequency (n) and percentage (%). Numerical variables including age, weight, height, and number of prescribed medications were reported as mean (SD). The chi-square test and independent t test. Both the control and experimental groups contained individuals with extremely low or high blood pressure and HR, and calculating the mean of these abnormal values was likely to produce values that were misleadingly normal. Therefore, we dichotomized SBP, DBP, and HR values into binary variables: normal and abnormal. We defined normal blood pressure according to the 2010 Chinese Hypertension Guidelines [The mean (SD) for all outcome variables  in each group was computed and graphed to show trends at the 7 time points described above. Differences in outcomes between the experimental and control groups at the critical time points  were determined using the idelines , which dP>.05) in any baseline characteristic between the 2 groups  and 90 days  (The medication nonadherence score  consiste P<.001) .148=–0.28, P=.78) or 90 days . SBP  and 90 days . The difference in the change in SBP between the 2 groups was statistically significant at 90 days , but not significant at 60 days .HR decreased  at 60 da75). SBP  and DBP 75). SBP  decreaseP=.37) or 90 days (P=.41).The proportional rate of participants with normal SBP  and DBP β=−.02, P<.001)  .β=–.08, P<.001) and DBP  between the 2 groups was also statistically significant. However, the difference in the rate of change in HR between the 2 groups was not statistically significant . In the generalized mixed effect model with a logit link for dichotomized binary outcomes, we found that the difference in the change of the proportional rate of participants with a normal SBP between the 2 groups was statistically significant , but that the difference between the 2 groups was not statistically significant for either the proportional rate of participants with normal DBP  or normal HR   .The aim of this study was to assess if a mobile phone–based mHealth intervention could improve medication adherence and relevant health outcomes  among patients with CHD in comparison to a control group that received general educational materials over a period of 2 months. We found that our mHealth intervention increased medication adherence and had a lasting effect in improving medication adherence among patients with CHD, even though no intervention was given after 60 days. We also found that our mHealth intervention improved health outcomes by lowering SBP and DBP, and that this effect continued for 30 days after the intervention. Unlike SBP and DBP, our mHealth intervention did not significantly lower HR, although mean HR consistently remained within the normal range. After dichotomizing SBP, DBP, and HR into binary variables, we found that there was no significant difference between the proportional rate of participants with normal SBP, DBP, and HR at baseline, 60 days, or 90 days between the intervention and control groups.A mixed-effects model for continuous outcomes showed that differences in the rate of change of medication nonadherence, SBP, and DBP were statistically significant between the 2 groups after controlling for the effects of group, time, the group-by-time interaction, and some baseline variables that can influence HR and blood pressure, such as body weight, gender, age, and educational level. Similarly, the generalized mixed-effects model with a logit link used for dichotomized binary outcomes showed that after controlling for the effects of baseline body weight, gender, age, educational level, group, time, and the group-by-time interaction, our mHealth intervention could significantly increase the proportional rate of participants with normal SBP. In summary, these key findings demonstrate that our mHealth intervention could significantly increase medication adherence and the proportional rate of participants with normal SBP, as well as lower SBP and DBP, in patients with CHD.In this study, participants were defined as dropping out if (1) they filled out the baseline survey but deleted the study coordinator’s WeChat account at any time point before their completion of the study; or (2) they told the study coordinator that they wanted to withdraw from the study. Participants were defined as lost to follow-up if they filled out the baseline survey and kept the study coordinator’s WeChat account, but did not fill out later surveys and did not respond to reminders and WeChat calls made by the study coordinator. This could happen at any time point during the study. In this study, 9 participants were lost to follow-up and 6 participants dropped out, which together accounts for 7% of the data. Due to the small amount of missing data, we did not perform missing data imputation. We compared the baseline variables between participants who dropped out or were lost to follow-up with those who completed the study, and found that none of the baseline variables were significantly different between these groups .Heart Disease and Stroke Statistics [In this study, the ratio of male to female patients with CHD was 4:1, which is the same ratio as in our pilot study conducted in 2017. The higher proportion of male participants reflects the higher prevalence of CHD in men in China; Chinese men are more likely to engage in risky behaviors, such as smoking and drinking . This reatistics ,51.This study contributes important knowledge about mHealth as a tool to improve medication adherence, but it has several limitations. First, all participants were recruited at a major university-affiliated hospital; many of them were middle-aged male urban residents and were thus not representative of the general Chinese population. Second, health outcomes such as SBP, DBP, and HR were self-reported by participants. There may therefore have been discrepancies regarding these measurements. Third, during this study, some participants did not provide their health outcome data in a timely manner. To collect these data, some participants had to be reminded by WeChat messages and phone calls. These messages and phone calls might have been covariates that could influence the participants’ medication-taking behaviors, but we did not consider their influence. Finally, the mHealth intervention was not automated and lasted for only 60 days, a comparatively short period of time. To adopt this intervention in real clinical settings, which have thousands of patients, and to create long-term effects, it will be necessary to use automated methods. Finally, this study was unblinded. All participants, data collectors, and data analysts were aware of which treatment arms participants had been assigned to. To increase rigor and reduce bias, future large multisite studies should consider a double-blind design.The treatment of many chronic illnesses involves long-term pharmaceutical therapy. Nevertheless, it is an ongoing challenge to find effective ways to improve medication adherence and other health behaviors to improve health outcomes. For patients with CHD, cardioprotective medications can prevent the enlargement of harmful clots , cardiovAlthough some studies have been conducted in China on using mobile apps  to improve blood pressure and self-management behavior -34, noneThe treatment of many chronic illnesses involves long-term pharmaceutical therapy, but it is an ongoing challenge to find effective ways to improve medication adherence and promote good health outcomes. In this study, we examined an mHealth intervention to remind patients with CHD to take their cardioprotective medications. Our results demonstrate that it is feasible to conduct an mHealth intervention to improve medication adherence and health outcomes, represented by measures including SBP and DBP. In summary, mHealth interventions that are constructed using evidence-based content show promise to help increase medication adherence and improve health outcomes.